Immune status of piglets during the first week of life: Current knowledge, significance and assessment – a review

Agata Augustyniak; Ewelina Czyżewska-Dors; Małgorzata Pomorska-Mól

doi:10.2478/aoas-2022-0079

Immune status of piglets during the first week of life: Current knowledge, significance and assessment – a review

Augustyniak, Agata; Czyżewska-Dors, Ewelina; Pomorska-Mól, Małgorzata 2023-04-01 00:00:00 Ann. Anim. Sci., Vol. 23, No. 2 (2023) 391–403 DOI: 10.2478/aoas-2022-0079 Immune status of pIglets durIng the fIrst week of lIfe: Current knowledge, sIgnIfICanCe and assessment – a revIew* 1 2 1♦ Agata Augustyniak , Ewelina Czyżewska-Dors , Małgorzata Pomorska-Mól Department of Preclinical Sciences and Infectious Diseases, Poznan University of Life Sciences, Wołyńska 35, 60-637 Poznań, Poland Department of Internal Diseases and Diagnostics, Poznan University of Life Sciences, Wołyńska 35, 60-637 Poznań, Poland Corresponding author: mpomorska@up.poznan.pl abstract the immune system of neonate piglets differs from adult pigs in structure and competence. although piglets are born immunocompe - tent, they are genuinely immunologically defenseless. t o survive in the environment, piglets need passive protection provided by sow’s colostrum and milk when constantly exposed to numerous pathogens. early assessment of piglets’ immune status may enable rapid intervention in case of detection of any deficiencies or disorders. Moreover, awareness of the piglets’ immunocompetence and the level of maternally-derived antibodies (mda) may allow the creation of a proper vaccine schedule. hence, extending knowledge of prenatal ontogeny of the porcine immune system, the immune status of neonate piglets’ and the immunological components of porcine colostrum is crucial. since animal welfare has become a more critical element of animal production, new, non-invasive sampling methodologies are highly desirable for the evaluation of piglets’ immune status. key words: neonate, piglets, immune status The piglet’s immune system begins to develop in the 2002). It has been confirmed that fetuses can produce early stages of prenatal ontogeny, during the embryonic their own antibodies against antigens in the final third period of embryogenesis (Šinkora and Butler, 2009). of gestation (Martinez-Boixaderas et al., 2022); how- However, neonate piglets’ immune systems differ from ever, their ability to respond to antigen stimuli is feeble those of adult pigs in both morphology and function. For (Martínez-Boixaderas et al., 2022). Therefore, although example, the mesenteric lymph nodes and Peyer’s patch- piglets are born immunocompetent, they are immunolog- es are smaller in piglets and have fewer Ig-secreting cells ically vulnerable and rely on passive immunity early in than do those of adult pigs (Levast et al., 2014). Moreo- life (Pomorska-Mól and Markowska-Daniel, 2009). With ver, the jejunal lymph nodes of newborn piglets consist the beginning of extrauterine life, piglets are exposed to of a chain of single lymph nodes parallel to the small various environmental antigens, unlike during prenatal intestine on both sides of the mesentery; in contrast, in life. The development of primary immunity is too slow two-week-old piglets the jejunal lymph nodes merge into to protect piglets from pathogens, and piglets’ adaptive an almost confluent band of lymphatic tissue (Schnap- immunity is primitive compared to adults’ (Pomorska- per et al., 2003). The cellular components of the piglet’s Mól and Markowska-Daniel, 2010 a). The acquisition immune system are not fully operational by the end of of appropriate amounts of high-quality colostrum is thus gestation (Stepanova et al., 2007; Pomorska-Mól and significant. Colostrum, defined as the first secretion of Markowska-Daniel, 2011). They have limited external a mammary gland, usually released within 24 hours af- antigen stimulation during the fetal period, which results ter farrowing, provides newborn piglets with energy and in a minimal number of peripheral double-positive αβ T passive immunity (Inoue and Tsukahara, 2021). Its early cells (effector or memory T cells). Moreover, the lym- ingestion by newborn piglets is crucial for their further phocyte B population consists of immature cells (Šinkora healthy development and growth (Inoue and Tsukahara, and Butler, 2009). In addition, an epitheliochorial struc- 2021). The immune components of the colostrum in- ture of the porcine placenta effectively precludes the clude highly concentrated immunoglobulins and many transfer of immunoglobulins or immune cells (Rooke other elements, such as cytokines, cellular components and Bland, 2002). Colostrum and milk thus constitute the (e.g., lymphocytes, and phagocytes), and various growth only sources of maternal immunity (Rooke and Bland, factors (Inoue and Tsukahara, 2021). Piglets’ immune __________ *This work was supported by the National Science Centre (DEC- 2020/37/B/NZ7/00021). 392 A. Augustyniak et al. systems are of great interest to researchers, and gain- first leucocytes with CD45 phenotype were observed in ing knowledge of this subject would allow for improve- their research on day 35 of gestation in the fetal spleen ments in the immune status of piglets, as well their future and cord blood, and at day 40 of gestation in the mes- healthy growth and performance; this all brings measur- enterium. However, there was an absence of cells with able effects to the pig production sector (Šinkora et al., typical lymphocyte markers (CD3 ). Among the lympho- 1998 a; Pomorska-Mól and Markowska-Daniel, 2010 b). cyte population, B lymphocytes appeared at the earliest In addition, a piglet’s immunological status shortly after in the periphery. Their presence was detected at day 40 birth is an important question for effective vaccination of gestation and they remained the predominant lym- management. Knowledge of the immune status of piglets phocyte population in lymph nodes, spleen, and blood may also enable rapid intervention when a deficiency or up to day 55 of gestation. The authors considered that disorder is detected. The ideal situation is when all litters, these findings, in combination with those of the study of as well as all piglets in each litter within a herd, have Cukrowska et al. (1996), indicate that sIgM B cells may a similar immune status. Such similarities are desirable be one of the first functional lymphocyte subpopulations both in immunocompetence as well as in the level of co- in porcine fetuses (Šinkora et al., 1998 a). Cukrowska lostrum (maternal) antibodies against pathogens that are et al. (1996) observed the presence of immunoglobulin present in the herd. G (IgG), immunoglobulin A (IgA), and immunoglobulin In this paper, we review the early prenatal ontogeny M (IgM) in fetus plasma and noted the ability of surface + + - of the swine immune system, the immunological compo- immunoglobulin M (sIgM ) CD5 B cells isolated from nents of porcine colostrum, and piglets’ immunological the fetal liver to secrete IgM. Every fetal sIgM B lym- status during the first week of life. phocyte was similar to an adult sIgM B cell on account of CD45RC and SLA-DR positivity. Furthermore, over + + prenatal ontogeny of swine immune system 90% of sIgM cells were CD2 , and this marker was ex- Morphogenesis, hematopoiesis, and lymphopoiesis pressed as the B cells developing before sIgM, which is Porcine gestation lasts about 114–116 days (Belt et normally considered a B-cell precursor (Šinkora et al., al., 1971). By the end of porcine organogenesis, on day 1998 a). The development of thymic tissues was observed 35 of gestation, the lymphatic system has already been as early as the day 21 of porcine gestation (Šinkora and physiologically formed; nevertheless, when the bone Butler, 2009). The thymus is a specialized lymphatic or- marrow starts its hematopoietic activity, lymphoid com- gan in which T lymphocytes mature. Around day 40 of ponents and lymphocytes are rare in the various organs gestation, the first T cells can be detected in this organ (Šinkora and Butler, 2009). Due to the expansion of pe- (Šinkora and Butler, 2009). Subsequently, T cells have ripheral lymphatic organs between days 60 and 90 of been observed on day 45 of gestation in the spleen and gestation, the lymph nodes, including mesenteric lymph umbilical blood and, on day 50 in the mesenterium. In all nodes, are negligible up to day 70 of gestation. Porcine cases, their appearance was delayed relative to that of the lymphopoiesis is known as lymphoid hematopoiesis, as first sIgM lymphocytes (Šinkora et al., 1998 a). Among the B cells develop in the primary hematopoietic organs the T lymphocytes, γδ T cells appeared first, developing and the pro-T cell progenitors that settle the thymus are primarily in the thymus; five days later they were also derived from the same hematopoietic centers; the lym- detectable in the periphery. The occurrence of γδ T cells phopoiesis of lymphocytes B and T is thus closely as- remains relatively constant up to day 90 of gestation; sociated (Šinkora and Butler, 2009). The yolk sac is the however, around farrowing, a sharp growth of γδ T cells first lymphopoietic organ. Hematopoiesis can be detected in the blood and spleen was noted (Šinkora et al., 1998 a). here as soon as the day 16 of gestation (Trebichavský et After that time, the blood and spleen selectively ac- + - al., 1996; Šinkora et al., 2002). Nevertheless, its contri- cumulated a great percentage of CD2 CD8 γδ T cells - - bution to overall lymphocyte production is rather small, and CD2 CD8 γδ T cells, respectively (Šinkora et al., + + since the yolk sac involutes early, around day 24 or 27 of 1998 a). The count of T-cell receptor αβ (TCRαβ ) gestation. Subsequently, first the liver, and later (around lymphocytes began to increase around day 55 of gesta- day 45 of gestation) the bone marrow, are responsible for tion, and soon after they outnumbered the T cells sub- lymphopoietic activity and for the development of the set in the thymus and periphery (Šinkora et al., 1998 a). preimmune B cell receptor repertoire (Šinkora and But- At about day 90 of gestation, the concentration of αβ T ler, 2009). cells plateaued (Šinkora et al., 1998 a). A growth in the number of B cells was also observed; hence sIgM and Development of individual adaptive immunity com- TCRαβ T lymphocytes are prominent cells in the fetal ponents periphery at this time (Šinkora et al., 1998 a). During Šinkora et al. (1998 a) investigated the surface phe- late gestation, the relative proportion of αβ T cells and B notype of fetal lymphoid cells in the thymus, cord blood, cells varies between individual organs. However, they are spleen and mesenteric lymph nodes at different stages similar to those observed in neonate piglets (Šinkora et al., + - of gestation. This study indicates that the second trimes- 1998 a). CD4 CD8 αβ T helper cells were the first ter of gestation is the period when the major subpopu- prominent subset of αβ T lymphocytes. Moreover, lations of lymphocytes begin to appear (Table 1). The they also made up the greatest αβ T cell subpopulation Immune status of neonatal piglet 393 - hi within gestation (Šinkora et al., 1998 a). CD4 CD8 αβ (Šinkora and Butler, 2009). Subsequently, NK cells cytotoxic T cells were absent up to day 55 of gestation; were also detected in mesenteric lymph nodes (MLN) subsequently, their number increased until birth (Šinkora at about day 50 of gestation. However, their concen- et al., 1998 a). In the study of Cukrowska et al. (1996), tration was low (Šinkora et al., 1998 a). Later in the serum immunoglobulins of all isotypes were detected in ontogeny, at approximately day 70 of gestation, the NK fetuses at day 44 of gestation. The predominant immuno- cell concentrations stabilize and then remain relatively globulin was IgM, and the overall immunoglobulin con- constant until birth (Šinkora and Butler, 2009). Previ- centration was increased during ontogeny, independently ous studies have shown that fetal NK cells lack the abil- of external stimuli. Moreover, antibody activity against ity to kill before birth, and killing was delayed in germ- autoantigens, phylogenetically conserved proteins, hap- free piglets. This may suggest that colonization with tens, and bacterial components was found in the sera of microflora may be crucial to the complete functional fetuses at the end of embryonic life. Preimmune immu- development of these cells (Šinkora and Butler, 2009). noglobulins can display a large spectrum of physiologi- Interferon-α secreting cells (IFN-α SC) were found in cal functions, and many remain unknown. With other the fetal liver at a very early stage of fetal development, natural factors, they constitute the first line of defense at day 26 of gestation, when differentiated lymphocytes during gestation and the early extrauterine stage of life were still not detectable (Splichal et al., 1994). After (Cukrowska et al., 1996). that, they were also detected in other tissues such as cord blood, spleen, and bone marrow. The authors sug- Development of individual innate immunity compo- gested that IFN-α SC may represent an early antiviral nents defense mechanism (Splichal et al., 1994). An in vitro Data on the development and maturation of porcine study performed on pig fetus macrophages and lym- innate immunity components is limited. Along with phocytes showed high cytoplasmic expression of tumor the beginning of hematopoietic activity of the primary necrosis factor (TNF-α) when stimulated with bacterial lymphoid organs, cellular elements of the innate im- mitogens (Trebichavský et al., 1995). The main pro- munological system such as morphonuclear leukocytes, ducers of TNF-α at a later stage of development were macrophages, and dendritic cells begin to appear (Ta- macrophages. According to those authors, their findings ble 1) (Šinkora and Butler, 2009). For example, mac- may suggest that lymphocytes and macrophages play a rophages were detected as soon as day 25 of gestation pivotal role in the induction of inflammatory responses (Trebichavský et al., 1996). Cells with the natural killer in fetuses (Trebichavský et al., 1995). Elevated inter- (NK) phenotype also appeared early in the ontogeny, feron γ (IFN-γ) and TNF-α mRNA levels were observed IO + and CD3ε CD8 CD2 lymphocytes were observed in in the tissues from porcine fetuses infected with porcine the umbilical blood and spleen around day 45 of ges- reproductive and respiratory syndrome virus (PRRSV), tation (Šinkora et al., 1998 a). Their abundance varies and corresponded to elevated cytokine proteins in se- from 1% to 10%, with an upward tendency over time rum (Rowland, 2010). Table 1. The first appearance of the particular immune components in porcine fetuses during prenatal ontogeny First appearance Immune component Location References (day of gestation) Macrophages 25 No data Trebichavský et al., 1996 CD45+leukocytes 35 Spleen, cord blood Šinkora et al., 1998 a 40 Mesenterium Šinkora et al., 1998 a sIgM+ cells 30 Liver Šinkora et Butler, 2009 40 Periphery Šinkora et al., 1998 a γδ T cells 40 Thymus Šinkora and Butler, 2009 45 Liver, cord blood, spleen Šinkora and Butler, 2009 60 Bone marrow Šinkora and Butler, 2009 αβ T cells 55 Thymus Šinkora nad Butler, 2009 58 Liver, cord blood, spleen Šinkora and Butler, 2009 60 Mesenteric lymph nodes, bone Šinkora and Butler, 2009 marrow NK cells 45 Spleen, umbilical cord Šinkora et al., 1998 a ~50 Mesenteric lymph nodes Šinkora et al., 1998 a Immunoglobulins 44 Blood Cukrowska et al., 1996 Interferon α secreting cells 26 Liver Splichal et al., 1994 394 A. Augustyniak et al. Table 2. Characteristic of different classes immunoglobulins in sow’s colostrum Features IgG IgA IgM References Origin Almost 100% derives from 60% produced locally in the 85% derives from sow’s Maciag et al., 2022; sow’s serum mammary gland serum Pomorska-Mól and Markowska-Daniel, 2009 40% derive from sow’s serum 15% produced locally in the mammary gland Predominant immuno- Colostrum Milk – Klobasa et al., 1987; globulin Markowska-Daniel et al., 2010; Markowska-Daniel and Pomorska-Mól, 2010 Influence of sow’s parity Concentration significantly No significant impact on the No significant effect on Klobasa et al., 1986; on colostral concentration higher in multiparous sows colostral concentration the colostral concentra- Cabrera et al., 2012; than in gilts tion Forner et al., 2021; Decreased concentration Maciag et al., 2022 in the lacteal secretions of primiparous sows compared to multiparous sows Highest concentration in At farrowing At farrowing At farrowing Klobasa et al., 1987; sow’s colostrum Markowska-Daniel et al., The concentration of Higher amounts in anterior Higher amounts in anterior No data Ogawa et al., (2014 a) immunoglobulins in teats teats particular teats Table 3. Changes in the concentration of immunoglobulins in the sow colostrum (mg/ml) within time according to different studies Markowska-Daniel Immunoglobulins concentration Klobasa et al., 1987 Bland et al., 1999 et al., 2010 At farrowing IgG 98.17 IgG 95.6 IgG 58.0 IgA 23.20 IgA 21.2 IgM 9.07 IgM 9.1 24 hours post parturition IgG 19.74 IgG 14.2 IgG 8.7 IgA 9.17 IgA 6.3 IgM 4.42 IgM 2.7 The significance of colostrum fringens toxoid substantially reduced piglet losses caused In Suidae species, as mentioned previously, the epi- by C. perfringens type C (Springer and Selbitz, 1999). theliochorial nature of the placenta prevents the sows’ immunoglobulins from being transferred. Colostrum Immunoglobulins is thus the sole source of passive immunity for piglets. The most important element of the sows’ colostrum Besides immunoglobulins, colostrum contains lympho- from an immunological point of view are immunoglobu- cytes, cytokines, nucleotides, and essential growth fac- lins. These constitute the most abundant component of tors that stimulate the postnatal development of the im- whey protein (approximately 80%) (Inoue and Tsuka- mune system and the visceral organs, as well as protein hara, 2021). Because piglets are born with almost no se- synthesis in skeletal muscles (Burrin et al., 1992). rum antibodies, MDAs play a crucial role in protecting Prior to the maturation of the piglets’ own immunity, them against infectious agents before they develop their the maternally derived antibodies (MDA) confer protec- own adaptive immunity (Markowska-Daniel et al., 2010; tion against any infectious agents that the sows had been Forner et al., 2021). However, MDAs can only protect naturally infected with or vaccinated against (Klobasa piglets from infections caused by pathogens that the et al., 1981; Inoue and Tsukahara, 2021). For example, sow’s immune system has faced. a previous study indicated that maternally derived ro- To provide a sufficient level of passive immunity and tavirus-specific IgG significantly alleviates the clinical to significantly reduce the risk of early death, the pig- symptoms following experimental rotaviral infection of let needs to ingest a minimum of 200 mg of colostrum neonatal piglets (Ward et al., 1996). Another study con- within the first 24 hours after birth; consumption of 250 ducted under field conditions documented that antibod- mg per piglet should provide good future health (Quesnel ies passively acquired by neonates through the colostrum et al., 2012). Antibodies can pass to the colostrum from and milk of sows vaccinated against the Clostridium per- sow serum or can be produced directly in the mammary Immune status of neonatal piglet 395 gland (Table 2) (Pomorska-Mól and Markowska-Daniel, amounts of IgA and IgG than the posterior teats (Ogawa 2009). Almost 100% of colostral IgG derives from sow’s et al., 2014 a). Other factors that can affect the final con- serum; meanwhile, more than 50% of IgA is produced centration of IgG in colostrum are the mother’s genotype, locally in the mammary gland (Maciag et al., 2022). age, and vaccination, as well as endocrine status, feeding, A substantial majority (around 85%) of colostral IgM de- and herd management (Kielland et al., 2015; Maciag et rives from sow’s serum (Pomorska-Mól and Markowska- al., 2022). The immunoglobulins ingested by piglets are Daniel, 2009). The predominant colostral immunoglobu- taken up by nonspecific pinocytosis into the enterocytes lin is IgG (Klobasa et al., 1987; Markowska-Daniel et (Rooke and Bland, 2002; Kielland et al., 2015). An im- al., 2010; Markowska-Daniel and Pomorska-Mól, 2010). portant role in the absorption of immunoglobulin from This is followed by IgA (the predominant immunoglobu- the guts is played by trypsin inhibitor, which inhibits the lin of milk) and IgM (Klobasa et al., 1987; Markowska- enzymatic activity of trypsin and prevents denaturation Daniel et al., 2010; Markowska-Daniel and Pomorska- of the immunoglobulins; however, its level in colostrum Mól, 2010). Immunoglobulin concentration in colostrum decreases within time (Jensen and Pedersen, 1979). The is not constant, declining during the first 24 hours after concentration of IgG in the piglet’s serum depends on farrowing; however, the decrease in the level of IgG is several factors, such as the amount of available and in- more drastic than in IgA or IgM (Table 3) (Klobasa et gested colostrum, IgG absorption in the piglet’s intestine, al., 1987; Markowska-Daniel et al., 2010). For example, and gut closure, which occurs 24 to 36 hours after birth in the research of Markowska-Daniel et al. (2010), the (Pomorska-Mól and Markowska-Daniel, 2009; Kielland highest level of immunoglobulin was noted in the first et al., 2015). The study of Kielland et al. (2015) indicates colostrum, which is acquired at farrowing. The mean a strong association between the concentration of colos- initial concentration was 118.5 mg/ml, 23.8 mg/ml, and trum IgG and piglet serum IgG (Kielland et al., 2015). 12.1 mg/ml for IgG, IgA, and IgM, respectively. After Interestingly, this is not consistent with some other stud- 24 hours, the concentration of IgA and IgM had reduced ies, where a lack of correlation is demonstrated between to 4.59 mg/ml and 4.29 mg/ml, respectively, and the level levels of colostral Ig and piglet’s serum Ig (Markows- of IgG decreased to 34% of its initial level (Markowska- ka-Daniel et al., 2010). The concentration of piglet IgG Daniel et al., 2010). This is partially consistent with the decreased with each piglet born. However, this was not findings of Klobasa et al. (1987), where the mean IgG significantly associated with litter size, but was more de- concentration was also highest at farrowing, at 95.6 mg/ pendent on the time of birth relative to farrowing onset ml; IgA was at 21.2 mg/ml and IgM was at 9.1 mg/ml. (Kielland et al., 2015). Litter size affected colostrum in- These were subsequently reduced to 14.2 mg/ml, take but not the concentration of piglet IgG. This may be .3 mg/ml, and 2.7 mg/ml, respectively, 24 hours after due to the flattening of piglets’ plasma IgG concentration birth (Klobasa et al., 1987). Bland et al. (1999) assessed above a certain level of colostrum IgG (Kielland et al., the mean IgG concentration at farrowing as 58.0 mg/ml; 2015). Bland et al. (1999) have shown that, despite dif- 24 hours later, the level had decreased to 8.7 mg/ml ferences in colostrum intake (and hence IgG) between (Bland et al., 1999). These studies also indicated that the piglets, the total concentration of IgG in the piglet’s concentration of colostral immunoglobulins varies be- plasma did not vary between litters. This may indicate tween sows. Kielland et al. (2015) noted that the concen- that piglets can regulate the quantity of plasma IgG inde- tration of colostral IgG varies not only between particu- pendently of the quantity of IgG obtained (Bland et al., lar sows, but also between herds (Kielland et al., 2015). 1999). In Kielland et al. (2015), a significant association Several studies have indicated that the concentration of was observed between body mass index (BMI) and pig- IgG in the colostrum was significantly higher in multipa - lets’ IgG level on day 1. The authors further concluded rous sows than in gilts (Cabrera et al., 2012; Forner et al., that piglets with BMIs of 17 kg/m or lower may not be 2021; Maciag et al., 2022). However, there was no such strong enough to obtain sufficient amounts of IgG. (Kiel- relationship for IgA content (Forner et al., 2021). This land et al., 2015). Bandrick et al. (2014) demonstrated is consistent with Maciag et al. (2022), where the parity that levels of IgG and IgA in the serum of piglets that order did not significantly affect the colostral concentra - ingested colostrum mimicked the distribution of these tion of IgA and IgM (Maciag et al., 2022). On the con- immunoglobulins in the sow’s colostrum. Furthermore, trary, Klobasa et al. (1986) showed that the levels of IgA IgG and IgA were absent from piglet serum before colos- in the lacteal secretions of primiparous sows were lower trum intake. This may indicate nonselective absorption than in multiparous sows (Klobasa et al., 1986). The of colostral immunoglobulins (Bandrick et al., 2014). level of immunoglobulins in colostrum can also vary be- A positive correlation between IgG levels in the serum of tween individual teats (Table 2). According to Ogawa et piglets at 7 days and 56 days of age may point to a posi- al. (2014 a), a higher amount of colostrum was obtained tive relationship between initial antibody concentration from anterior teats. Furthermore, a positive correlation in the piglet’s serum and the development of their active between colostrum secretion volume (CSV) and IgG was immunity (Markowska-Daniel et al., 2010). According observed from 6 hours after farrowing and from 12 hours to Rooke et al. (2003), naturally suckling piglets start after farrowing between CSV and both IgG and IgA. to produce IgG at 7 days of age. Its quantity was posi- This may suggest that the anterior teats contain greater tively correlated with the amount of absorbed colostral 396 A. Augustyniak et al. IgG (Rooke et al., 2003). Curtis and Bourne (1973) indi- in the secretion of the mammary gland on the first and cate that active IgM production by piglets emerges from second days after parturition; this correlated with the 10–12 days of age. Porter and Hill (1970) reported that time of their peak concentrations in the piglet’s serum. IgM in suckling piglets begins to increase from 7 days The predominant cytokine in the sow’s colostrum was of age. Active synthesis of IgA by suckling piglets up to IL-4, followed by TGF-β1. Other cytokines occurred 12 days of age does not contribute significantly to serum at lower levels, and the least concentrated were IL-12, IgA concentrations (Curtis and Bourne, 1973). This sug- IL-10, and TNF-α (Nguyen et al., 2007). One in vitro gests that piglets begin to effectively produce their own study evaluated the impact of various concentrations of IgA at a later age, but to date, there is no conclusive data TGF-β1 and IL-4 on porcine neonatal B cell responses on this issue. Other investigation, with piglets weaned at (Nguyen et al., 2007). High TGF-β1 levels caused sup- different times (7, 14, 21 or 28 days) showed that endog- pressed immunoglobulin-secreting cell responses to enous colostrum/milk factors may be critical to promote LPS and rotavirus, and low TGF-β1 levels led to iso- IgA synthesis (Levast et al., 2010). Ultra-early weaned type switching to IgA antibodies. IL-4 provoked inverse piglets (at 7 and 14 days) showed lower serum IgA con- dose-dependent isotype switching to IgA. Moreover, it centrations at 21 days proving a deficiency in the IgA gut also improved IgM-secreting cell responses to LPS and immune response development. rotavirus. Furthermore, an elevated concentration of Th2 cytokines or TGF-β in newborn piglets may be crucial Cytokines for their acquisition of normal commensal microflora in The presence has been noted in porcine colostrum the intestine, given the reduction of immune and inflam- of granulocyte-macrophage colony-stimulating factor matory response in the gut (Nguyen et al., 2007). Ma- (GM-CSF), interferon γ (IFN-γ), interleukin 1 α (IL-1α), ciag et al. (2022) found that concentrations of GM-CSF, interleukin 1 receptor antagonist (IL-1RA), interleukin IFN-γ, IL-1α, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, 2 (IL-2), interleukin 4 (IL-4), interleukin 6 (IL-6), inter- IL-18, and TNF-α were significantly higher in serum and leukin 10 (IL-10), interleukin 12 (IL-12), interleukin 18 colostrum of multiparous sows than in gilts (Maciag et (IL-18), tumor necrosis factor-alpha (TNF-α), and trans- al., 2022). Moreover, these above cytokines occurred at forming growth factor β (TGF-β) (Table 4) (Nguyen et higher levels in the serum of piglets that received co- al., 2007; Ogawa et al., 2014 b; Maciag et al., 2022). lostrum from multiparous sows than in the serum of Maternal cytokines contained in the colostrum may piglets fed with gilt’s colostrum. The lowest concentra- play an instructive role in the maturation of the neona- tion of these cytokines was observed in the piglets fed tal immune system (Nguyen et al., 2007). It is assumed with milk replacer. A greater tendency to innate inflam- that colostrum is the only source of various cytokines matory and anti-inflammatory responses, and a greater for newborn piglets (Nguyen et al., 2007). The study of propensity to specific Th1 and Th2 responses, during the Nguyen et al. (2007) indicated that the moderate corre- perinatal period was significantly correlated with pig- lation between sow blood and colostrum for IL-4, IL-6, lets that suckled sow colostrum (Maciag et al., 2022). IL-10, IL-12, and IFN-γ indicates that these cytokines Ogawa et al. (2014 b) confirmed the presence of IL-18 pass to the mammary gland from the sow’s bloodstream. in the colostrum, but not in the sow’s milk. This cytokine Given the lack of such a correlation between TNF-α and is believed to regulate the immune system of newborn TGF-β1 (the concentration of both in the colostrum being piglets (Ogawa et al., 2014 b). Elahi et al. (2017), using higher than in the sow’s blood), they must be produced a pertussis model showed that immunization of pregnant directly in the mammary gland (Nguyen et al., 2007). sows with heat-inactivated bacteria may lead to the in- These cytokines were only present in the blood of piglets duction of various cytokines, such as TNF-α, IFN-γ, IL- that ingested colostrum (Nguyen et al., 2007). The pres- 6, IL-8, and IL-12/IL-23p40. Moreover, these cytokines ence of IL-6, TNF-α, INF-γ, IL-4, and IL-10 was not de- were detectable next to pertussis-specific antibodies, not tected in the group of age-matched colostrum-deprived only in vaccinated sow serum and colostrum, but also gnotobiotic piglets. The authors thus assumed that these in their progeny’s serum and bronchoalveolar lavage cytokines do not pass through the placenta. However, fluid. Interestingly, active vaccination of newborn pig- IL-12 and TGF-β1 were detected in the plasma of co- lets with heat-inactivated bacteria led to high levels of lostrum-deprived gnotobiotic piglets. This may indicate IgG and IgA specifically, but no cytokines. Even though that piglets can produce the cytokines by themselves. In the concentration of antibodies in vaccinated piglets and the mentioned study, the authors did not detect TNF-α of passively obtained antibodies were similar, the au- in the plasma of piglets in either group. The lack of this thors did not observe any protection against Bordetella cytokine in the serum of sows and piglets is probably pertussis infection in the vaccinated individuals. Elahi due to some control mechanism that prevents prolonged et al. (2017) hence conclude that the presence of pas- inflammatory responses, which could further damage sively transferred cytokines or antibodies affects new- tissue (Nguyen et al., 2007). However, data concerning born piglets’ ability to secrete cytokines, and that this this cytokine is inconsistent: its presence in piglet plas- may suggest that the vaccinating the sow can affect the ma was observed in Maciag et al. (2022). Nguyen et al. newborn’s cytokine milieu and impact immune cell dif- (2007) found the highest concentration of the cytokines ferentiation (Elahi et al., 2017). Immune status of neonatal piglet 397 Table 4. Characteristic of cytokines present in sow’s colostrum and piglets’ serum Features Cytokines References Presence in sow’s colostrum GM-CSF, IFN-γ, IL-1α, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, Nguyen et al., 2007; IL-18, TNF-α, TGF-β Ogawa et al., 2014 b; Maciag et al., 2022 Originating from sow’s serum IL-4, IL-6, IL-10, IL-12, IFN-γ Nguyen et al., 2007 Production directly in the mammary gland TNF-α, TGF-β1 Nguyen et al., 2007 Predominant cytokine of sow’s colostrum IL-4 Nguyen et al., 2007 Least concentrated in sow’s colostrum IL-12, IL-10, TNF-α Nguyen et al., 2007 Concentration higher in multiparous sow than GM-CSF, IFN-γ, IL-1α, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, Maciag et al., 2022 gilts IL-18, TNF-α Likely production by neonate piglets IL-12, TGF-β1 Nguyen et al., 2007 the differences in the distribution of colostrum’s humoral Cellular components and cellular composition over 40 gilts and 40 sows (par- Porcine colostrum, apart from multiple proteins, also ity orders 3–4). Their results show that parity does not contains several types of cells (Wagstrom et al., 2000). It influence the total count of macrophages, granulocytes, has been estimated that piglets ingest some 500–700 mil- or T and B cells. Nevertheless, multiparous sow colos- lion colostral cells daily (Nguyen et al., 2007), including trum contained significantly larger T lymphocyte subsets epithelial cells, lymphocytes (T and B cells), and phago- than gilts (i.e., central and effector memory CD4 T cells cytes (neutrophils and macrophages) (Wagstrom et al., or central memory CD8 T cells). The authors concluded 2000). In contrast to many mammal species, epithelial that parity order may influence the cell population and cells constitute a great fraction of sow mammary gland piglet immune adaptive response, which induces neutral- secretions, representing approximately 20%–40% of all izing antibodies and cellular immune responses (Forner the colostral cells (Le Jan, 1996). Epithelial cells in the et al., 2021). Williams (1993) demonstrated that the lym- colostrum are small in size and have little or no IgA (Le phocytes contained in colostrum could cross the intesti- Jan, 1996). They furthermore exhibit low expression lev- nal wall and migrate via the piglet’s bloodstream to vari- els of secretory components (Le Jan, 1996). Small epi- ous organs (including the liver, lungs, lymph nodes, and thelial cells can be propagated in vitro for at least three spleen). Moreover, Nechvatalova et al. (2011) demon- passages. When cultured in the presence of the serum of strated that these cells possess functional abilities (they lactating sows, these cells differentiate and begin to pro- can become activated) and display an antigen-specific ac- duce α-lactoglobulin (Le Jan, 1996). Depending on their tivity in organs (Nechvatalova et al., 2011). Goubier et al. differentiation level, they display the ability to express (2009) detected antigen-specific lymphocytes that were major histocompatibility complex II (MHC II antigen) able to produce IFNγ and TNFα after in vitro stimulation (Wagstrom et al., 2000). Moreover, it is considered that with circoviral antigens vaccinated against PCV2 sow porcine colostral epithelial cells can produce cytokines colostrum (Goubier et al., 2009). Bandrick et al. (2008) and can function as antigen-presenting cells (Wagastrom demonstrated that lymphocytes obtained by piglets from et al., 2000). Macrophages constitute about 7%–11% of vaccinated sow colostrum can proliferate and participate cells (Maciag et al., 2022). 10%–25% of all porcine co- in functional response to Mycoplasma hyopneumoniae lostrum cells are lymphocytes, of which 70%–80% are T (Bandrick et al., 2008). Hlavova et al. (2014) assessed cells (Hlavova et al., 2014). According to Hlavova et al., the activation status of T and NK cells in colostrum using (2014) the predominant cell types in colostrum are CD8 + + the expression of CCR7, CD11b, CD25, CD45RA, and single-positive T cells (53.6%), followed by CD4 CD8 + + MHC class II receptors. They managed to observe the double-positive T cells (21.1%), CD2 CD8 γδ T cells expression of markers consistent with an effector mem- (15.0%), and NK cells (13.5%). The CD4 single-positive ory phenotype on T cells; this might suggest that these T cells (4.4%) and other γδ T cell subpopulations were were antigen-experienced cells. Based on the phenotype less common. The proportion of individual lymphocytes of colostrum-derived T lymphocytes and NK cells, those varies between colostrum and sow peripheral blood: the authors concluded that these components may play a role proportion of cytotoxic and double-positive T cells was in mucosal immunity, and potentially in the transfer of significantly higher in colostrum than in peripheral blood passive immunity (Hlavova et al., 2014). A study by Ban- (Hlavova et al., 2014). On the contrary, the proportion of drick et al. (2014) demonstrated that colostral lympho- helper T cells was higher in peripheral blood (Hlavova et cytes are selectively transferred into the suckling blood- al., 2014). The greatest number of T cells are found in the stream. These can then influence neonatal piglets’ innate colostrum obtained around parturition, with their num- and adaptive immune responses (Bandrick et al., 2014). ber significantly decreasing after the first eight hours of B lymphocytes constitute about 20% of all lymphocytes lactation. Afterwards, the number of T cells remains con- in mammary secretions (Pomorska-Mól et al., 2010), and stant (Hlavova et al., 2014). Forner et al. (2021) assessed 398 A. Augustyniak et al. the concentration of SWC7+ CD5+ cells turned out to be Solano-Aguilar et al. (2001) have described changes in significantly higher in multiparous sow colostrum than lymphocyte subsets in mucosal tissues with increasing in gilts (Forner et al., 2021). Maciag et al. (2022) indi- age. According to this study, the GALT of piglets varies cated that levels of activated B and T cells were higher in from the GALT of adult pigs in the presence or count piglets fed multiparous sow colostrum. Lymphocytes can of the respective lymphocyte subsets. The authors also cross the intestinal wall of newborn piglets only when pointed out that the majority of the phenotypes charac- they are viable and have derived from the dam of a par- terized by increasing trends during the pre-weaning time ticular piglet (Bandrick et al., 2011). This is not the case were located on lymphocytes isolated from mesenteric with immunoglobulins, which can be absorbed across the lymph nodes and ileal Peyer’s patches, which can fur- intestinal mucosa of neonatal piglets, regardless of the ther imply that these lymphocytes are key populations maternal source or donor species (Bandrick et al., 2011). in the early postnatal period during the development of As a result, fostered piglets that suckled colostrum from lymphoid cells (Solano-Agilar et al., 2001). Rothkötter another sow than their natural dam will have deficiencies et al. (1991) studied lamina propria (LP) of normal and in maternal cell-mediated immunity (CMI) (Bandrick et germ-free piglets in early postnatal period. According to al., 2011). Bandrick et al. (2011) had demonstrated that this study, the number of LP lymphocytes has increased transfer of Mycoplasma hyopneumoniae-specific CMI to two-fold between the first and 29th day after farrowing. piglets occurs only when piglets were maintained with Moreover, the authors observed that the distribution of their biological dams for at least twelve hours after par- lymphocyte subsets exhibited an unusual pattern. Ap- turition (Bandrick et al., 2011). To conclude, maternal proximately 80% of T cells of piglets aged 1 to 5 days + - - antigen-specific leukocytes, delivered to piglets via co- belonged to CD2 CD4 CD8 subset. However, around 12 lostrum, may constitute an extra line of active defense days post-parturition, this subset started to disappear. In- against infection for neonatal piglets (Goubier et al., terestingly, 49 days old germ-free piglets displayed simi- 2009). lar T cell subset patterns as above mentioned convention- ally raised piglets between 1 and 5 days. Ig-positive cells Immunity of neonatal piglet were observed later than T cells. On the first-day post- Mucosal immunity parturition, a minimal number of IgM was noted. Forty + + After birth, neonatal piglets are exposed to plenty days later, the number of IgA was higher than IgM . The of various antigens. Most of them enter a host via mu- authors conclude that the results obtained in the germ- cosal membranes (Solano-Aguilar et al., 2001). Thus, free piglets may prove that the major changes in the LP these structures are equipped with specialised protec- are caused by the appearance of microbial antigens in tive elements called mucosa-associated lymphoid tis- the intestine (Rothkötter et al., 1991). Schnapper et al. sue (MALT), distinct from remaining lymphatic tissue (2003) have observed rapid changes occurring in piglet’s (Solano-Aguilar et al., 2001). Based on its distribution lymphoid tissue – the weight of Peyer’s patches, tonsil of in the organism, several types of MALT were distin- the soft palate, lymph nodes (cranial mesenteric lymph guished, i.e. gut-associated lymphoid tissue (GALT), center and bronchial lymph center), spleen and thymus nasopharynx-associated lymphoid tissue (NALT) or have grown faster than the body weight of piglets and had bronchus-associated lymphoid tissue (BALT) (Mazzoni been significantly enlarged during the first two weeks of et al., 2011). Due to the risk related to numerous poten- life (Schnapper et al., 2003). The mammalian intestine is tial pathogens or food-borne antigens and the presence colonized with normal gut flora during the first few days of commensal microbiota, GALT is well developed and of life (Butler et al., 2000). This component is believed to consists of the following structures: the Peyer’s patches, have an important role in providing health to its host, by mesenteric lymph nodes and intraepithelial lymphocytes among others inhibiting intestine colonization with path- and lamina propria lymphocytes (Solano-Aguilar et al., ogenic bacteria (Butler et al., 2000). Colostrum and milk 2001; Mazzoni et al., 2011). GALT of neonatal piglets constitute one of the sources that deliver gut microbes is a relatively developed structure with pre-existing Pe- to newborn piglets (Mardiaga et al., 2018). Maradiaga yer’s patches (Levast et al., 2014). However, shortly after et al. (2018) investigated gastrointestinal microflora and birth, the piglet’s gut is characterized by a small number mucosal immune gene expression in newborn piglets that of lymphocytes T and antigen-presenting cells (Levast et were reared in a cross-fostering model. Results of the al., 2014). Given exposure to numerous external antigens above study show that although cross-fostering does not and commensal microorganisms, GALT enlarges in size affect bacterial communities present in the neonate’s in- and lymphocyte subset content and reaches maturity in testine, the mRNA expression of TLR and inflammatory conventionally-raised piglets within two months (Levast cytokines change within the location in the gastrointesti- et al., 2014). At that time, the GALT of conventionally- nal tract. The authors suggested that the results presented raised piglets can respond to intestinal antigens with in their study may indicate the influence of colostrum good T and B lymphocyte activation and IgA production and maternal microbial communities on microflora de- (Levast et al., 2014). However, mesenteric lymph nodes velopment as well as mucosal immune gene expression and Peyer’s patches are still smaller and have fewer in newborn piglets (Maradiaga et al., 2018). The second- Ig-secreting cells than adult ones (Levast et al., 2014). ary function of the mucosal system is to discriminate be- Immune status of neonatal piglet 399 tween pathogen-associated and non-pathogenic antigens. cells. However, no evident changes in phenotype or quan- This phenomenon is called mucosal tolerance (Bailey et tity caused by environmental changes or piglet ageing al., 2005). According to Bailey et al. (2005), data con- were observed for NK cells (Talker et al., 2013). Llamas cerning response to intestine microflora are still incon- Moya et al. (2007) investigated age-related changes in sistent. One of the mechanisms involved in maintaining proinflammatory cytokines, acute phase proteins (APP), tolerance may be anergy or deletion of specific T-cells and cortisol concentrations during the first week of a pig- clones. It is grounded on the recognition of antigen on let’s life (Llamas Moya et al., 2007). According to this wrong presenting cells by antigen-naive T cells. It is study, the concentration of TNF-α and haptoglobin (Hp) worth emphasizing here the role of dendritic cells, which increased with age, while the serum amyloid A (SAA) are responsible for the presentation of antigens to naive level decreased. The lowest level of plasma TNF-α was T cells. These cells exhibit the ability to switch naive T observed on the first day after birth. On day 5, the con- cells to active response or tolerance. Thus, the interaction centration of TNF-α achieved its peak, and remained el- between these two types of cells is believed to determine evated on day 7. Similarly, the level of Hp was lowest the reaction. However, there are reports showing that the on day 1, and after that increased with age. On the other outcome of antigen recognition is determined by antigen- hand, the concentration of plasma SAA was elevated on non-specific signals arrived directly at mucosal regula- days 1, 3, and 5, but had significantly reduced by day 7. tory T cells (Bailey et al., 2005). As mentioned earlier, There were no age-dependent changes in the plasma con- the mucosal system of neonates is immature after birth in centration of IL-1β or C-reactive protein (CRP). Inter- comparison to adult ones. This agent may be responsible estingly, husbandry practices such as ear notching, teeth for the lack of active immune responses as well as the clipping, and tail docking did not affect other measured development of tolerance (Bailey et al., 2005). parameters, other than Hp. The authors thus suggested that such management practices did not result in systemic Innate immunity inflammation in the early postnatal life of piglets (Llamas The components of porcine innate immunity are simi- Moya et al., 2007). Similarly, Martin et al. (2005) found lar to those in many other mammals (Šinkora and Butler, that the Hp concentration in neonatal piglets’ plasma was 2009). Innate immunity is based on two main mecha- also low on day 1 after birth and subsequently increased nisms: activation of cellular components, such as mac- (Martin et al., 2005). Moreover, an age-dependent in- rophages, neutrophils, NK cells, or dendritic cells; and crease in the level of plasma major acute-phase protein the release of various extracellular mediators – such as (Pig-MAP) from birth up to 4 days of age was observed. cytokines, chemokines, and complement or antimicrobial After that, the concentration of Pig-MAP remained rela- peptides (Šinkora and Butler, 2009). The total number of tively high. The authors suggested that the rapid increase leukocytes increases during the first week of neonate life in the levels of proteins that were low at birth suggests (Talker et al., 2013). Pomorska-Mól et al. (2011) indi- some variety of acute-phase response, and that this re- cate that, on the first day of a piglet’s life, the number sponse may be an evolutionary adaptation of the piglets of granulocytes is similar to the number of lymphocytes to managing during the first critical period of extrauterine (Pomorska-Mól and Markowska-Daniel, 2011). Howev- life (Martin et al., 2005). er, the absolute granulocyte size and lymphocyte number predominance decreases during the next three weeks. In Adaptive immunity addition, a positive correlation between the mean number The development of the cellular components of the and mean percentage of granulocytes and the piglet’s age pig immune system is not fully complete by the end of was observed (Pomorska-Mól and Markowska-Daniel, gestation (Stepanova et al., 2007; Pomorska-Mól and 2011). They also showed that piglet granulocytes have Markowska-Daniel, 2011). The T cells, B cells, and pe- decreased phagocytosis and weaker adhesive molecule ripheral blood mononuclear cells (PMBC) of neonatal expression than adults (Pomorska-Mól and Markowska- piglets have a less developed ability to respond to mi- Daniel, 2010 a). The median value of NK-cell numbers in togens and a lower number of antigen-presenting cells piglets’ blood is lowest at birth and increases from there (Maciag et al., 2022). The total number of lymphocytes (Talker et al., 2013). Talker et al. (2013) indicate that the increases during the first week of a piglet’s life (Talker et presence of perforin was noted in all NK cells as early al., 2013). Some studies have indicated that CD4 lym- as the day of birth. This finding may imply that piglets’ phocytes form the predominant subpopulation of T cells NK cells exhibit immediate cytotoxic activity (Talker et in neonate piglets at farrowing, while CD8 lymphocytes al., 2013). Nevertheless, it contrasts with previous re- are less common (Stepanova et al., 2007). On the other search, where NK cells were isolated from pigs for up to hand, in Pomorska-Mól and Markowska-Daniel (2011), two weeks after birth, and showed weak cytolytic activ- the number of CD8 cells was greater than the number + + + ity against K562 target cells (Yang and Schultz, 1986). of CD4 cells. The ratio of CD4 to CD8 cells decreased Moreover, Talker et al. (2013) observed that pigs possess with age as the CD8 increased, which was accompanied - + - + CD3 CD8α NKp46 cells with entirely functional char- by a proportional decrease in CD4 lymphocyte numbers acteristics of NK cells; this is interesting because NKp46 (Stepanova et al., 2007; Pomorska-Mól and Markowska- + + was believed to be a species-spanning marker for NK Daniel, 2011). Double-positive CD4 CD8 are less fre- 400 A. Augustyniak et al. quent in neonate piglets than in adults, and their popu- lins are obtained with the colostrum and whether there lation increases with age, probably as a result of the is any interaction with environmental microorganisms. antigen-dependent maturation of naive CD4 T helper These are essential for the appearance of primed T and lymphocytes into antigen-specific memory T helper lym- B cells that subsequently develop into their effector and phocytes (Saalmüller et al., 2002; Stepanova et al., 2007). memory progeny (Šinkora and Butler, 2009). Primed T However, there is some variance, depending on the lev- lymphocytes with elevated expression levels of CD25 + + els of double-positive CD4 CD8 lymphocytes in piglets. meanwhile become effector/memory cells with elevated + + According to Stepanova et al. (2007), these cells were expression of MHC II and display a CD4 CD8α and + + rare during the first month of piglets’ life, at 0.5%, while CD2 CD8α γδT phenotype (Šinkora and Butler, 2009). Pomorska-Mól and Markowska-Daniel (2011) indicated that the proportion of this subset on the first day of pig- assessment of piglets’ immune status: current lets’ life was 6.63%. This discrepancy might result from possibilities and perspectives the animals’ conditions (experimental conditions versus Although piglets are born immunocompetent – i.e. commercial breeding farm) (Stepanova et al., 2007; Po- able to respond – they are at the same time immunologi- morska-Mól and Markowska-Daniel, 2011). Stepanova cally defenseless. To survive in an environment where et al. (2007) have noted changes in the subpopulations they are exposed to pathogens, they need their mother’s of T lymphocytes in the peripheral blood and secondary protection, which is provided as passive immunity that lymphoid tissue during the first month of the piglet’s life. comes with the colostrum and milk, in the form of anti- A significant age-dependent increase in the total concen- bodies and other regulatory elements involved in the im- tration of γδ T cells was noted in the blood and spleen, mune response. Early assessment of a piglet’s immune but not in the lymph nodes. However, there was signifi- status may enable rapid intervention in case of deficien- cant growth in the percentage of the γδ TCR+CD8+ sub- cies or disorders. In addition, knowledge of a piglet’s im- population (Stepanova et al., 2007). Strong growth in the munocompetence and MDA levels is crucial to design- total number of γδ T cells since birth was also confirmed ing a proper vaccination schedule (Martínez-Boixaderas in Talker et al. (2013), who observed significant pheno- et al., 2022). Piglet protection can be achieved either typic changes only within the CD2 subset. Neverthe- passively, through the transfer of maternally derived less, the increase in overall amounts was proportional immunity, or actively through vaccination. However, to the increase of the CD2-T-cell subset (Talker et al., vaccinating piglets in the presence of remaining MDA 2013). Due to the involvement of γδ lymphocytes in in- might interfere with vaccine efficacy. Most works in the nate immune efficiency, they are also considered to con- literature have dealt with the acquisition of passive hu- stitute part of the innate immunity (Šinkora and Butler, moral immunity by newborns, although the transmission 2009). The pool of B lymphocytes in neonatal piglets is of specific cellular immunity has also been reported (Le immature (Šinkora and Butler, 2009). The more signifi- Jan, 1996; Nguyen et al., 2007; Pravieux et al., 2007). cant percentage of peripheral sIgM B cells consists of For example, it has been shown that colostrum-derived + + + - sIgM CD2 B cells, and sIgM CD2 are relatively rare T cells could cross the intestinal barrier and enter the (Šinkora et al., 1998 b). This is interesting, as porcine B systemic circulation and lymphoid organs (Tuboly et al., cells were considered not to express CD2 (Šinkora et al., 1995). These lymphocytes are also a potential source of 1998 a). According to Šinkora et al. (1998 b), after the cytokines and chemokines that may exert a regulatory piglet’s gut has been colonized with a complex intestinal effect on antigen-presenting cells and specific antigen microflora, this proportion changes, and the number of responses. Mammary gland secretions thus also have CD2 B cells increases with age, reaching 15%–35% of immunoregulatory properties. Besides, colostrum con- sIgM peripheral blood lymphocytes in week-old piglets. tains numerous other components involved in the sys- They suggested that the expression of CD2 may be re- temic immune processes, such as cytokines, interferons, lated to the functional status of porcine B cells, but can lysozyme, lactoferrin, peroxidase, complement compo- then be lost as a consequence of the maturation process nents, hormones, and other compounds involved in the (Šinkora et al., 1998 b). Thus, the microflora-dependent mechanisms of innate immunity (Salmon, 1999; Schultz, + – sIgM CD2 lymphocytes in pigs can be activated/mem- 2006). These substances participate in the maturation ory B cells (Šinkora et al., 1998 b). Antigen stimulation of both local and systemic defense processes, as well due to colonization of the intestinal duct, as well as con- as in the induction and orientation of the piglets’ active tact with the extrauterine environment, results in the acti- response to the antigen (Salmon, 1999; Schultz, 2006). vation of T and B cells (Pomorska-Mól and Markowska- After being absorbed in the first 24 to 36 hours of life, an- Daniel, 2010 a). Šinkora and Butler (2009) indicate that, tibodies and other colostrum components are transferred in germ-free piglets, the development of the immune into the blood, where they provide systemic resistance to system is slower than in an age-matched control group, infectious agents in piglets (Inoue and Tsukahara, 2021). and these piglets were also unable to perform a humoral It is known that Ig plasma concentrations in piglets response (Šinkora and Butler, 2009). The maturation shortly after birth positively correlate with their chance of the elements of adaptive immunity thus arises from of surviving the critical perinatal period (Devillers et al., several factors, such as whether maternal immunoglobu- 2011). Cytokines passed to piglets by their mother with Immune status of neonatal piglet 401 colostrum can play the role of “teacher” in the matura- Several advantages of the use of such noninvasive sam- tion of suckling piglets’ immune system (Nguyen et al., pling have been reported: it allows efficient and low-cost 2007). However, cytokine transmission with colostrum collection of large numbers of diagnostic samples, and it or milk is not well documented. permits repeated sampling without the risk of discomfort Studies on the immunological status of piglets are or stress (Turlewicz-Podbielska et al., 2020). Recently, presently performed using blood samples. Blood collec- processing fluid (PF) has become more widely used in tion from individual animals has been the method most diagnostic practice (Trevisan et al., 2019; López et al., commonly used in veterinary practice to obtain samples 2022). PF consists of blood and tissue fluids obtained for monitoring and surveying herd health status, includ- during castration and tail-docking, which are usually per- ing for pigs. However, the technique is time-consuming, formed during the first week of a piglet’s life (3–5 days) laborious, and stressful for both animals and collecting (Turlewicz-Podbielska et al., 2020). As castration is still staff. In addition, sampling piglet blood is relatively performed on many farms, gaining PF does not require difficult and carries a high mortality risk. For this rea- additional procedures or animal restraint, and thus does son, farmers and veterinarians often refrain from car- not generate additional stressful situations. PF is consid- rying out such tests, or postpone monitoring until later ered a promising, practical, and inexpensive specimen in production. This can significantly delay the detection that may improve the monitoring of some porcine dis- of important health problems in the herd, including the eases, such as PRRS (Turlewicz-Podbielska et al., 2020). identification of lactation problems in sows, irregulari - The idea of using this type of specimen to monitor other ties in the vaccination of dams, or transmission of ma- swine diseases, as well as immune parameters such as cy- ternal immunity to piglets. A specimen that could be tokines, immunoglobulins, and APP shows some prom- collected noninvasively and without inducing stress in ise. An additional advantage of PF is that the specimen the animal, while still offering accurate diagnostic in- comes from piglets less than one week old. Studies in- formation, would greatly benefit herd health status and dicate that collecting PF from such young piglets is very disease monitoring. In the EU, noninvasive sampling difficult, if not impossible (Jabłoński et al., 2011). Re- methodologies for monitoring the health status of farm placing traditional samples, such as blood or serum, with animals must comply with the EU’s general objectives PF has numerous benefits, saving time, work, and costs on food safety policy (Regulation 652/2014), in which while minimizing the stress associated with sampling, animal welfare and wellbeing are major issues. In the which positively impacts animal welfare and immunity. assessment of the immunological status of piglets, only However, there is a lack of experimental data on its use one component of the immune response is usually con- for assessing the immunological status of piglets, includ- sidered – namely, humoral immunity, including its level ing the correlation between the concentration of various and duration. It seems that a more detailed analysis of immunological parameters in PF and the corresponding immunological parameters in this period (taking into ac- sera, which until now have been the material used in this count specific antibodies, and also the types of particular type of determination (the gold standard). groups of immunoglobulins, cytokines, APP, and so on) would shed more light on the significance of maternal declaration of Competing Interest immunity and its level in piglets in the first days of life The authors declare that there is no conflict of interest for their further development. The duration of maternal regarding the publication of this article. MDA refers to the age of the piglet at which their MDA levels fall below the limit of detection of the test used for evaluation (Opriessnig et al., 2004), or the rate of decay references (“half-life”) of MDA (the time required for a 50% de- crease in MDA levels) (Fort et al., 2009). The amount Bailey M., Haverson K., Inman C., Harris C., Jones P., Corfield G., of antibodies and other immune factors transferred from Miller B., Stokes C. (2005). The development of the mucosal im- sows to offspring is determined by the sow’s immunity mune system pre- and post-weaning: balancing regulatory and ef- fector function. Proc. Nutr. Soc., 64: 451–457. level near parturition, the timing of colostrum intake, Bandrick M., Pieters M., Pijoan C., Molitor T.W. (2008). Passive and the volume of colostrum ingested (Klobasa et al., transfer of maternal Mycoplasma hyopneumoniae-specific cel - 1981). Strengthening sow herd immunity through vac- lular immunity to piglets. Clin. Vaccine Immunol., 15: 540–543. cination is an important management tool for preventing Bandrick M., Pieters M., Pijoan C., Baidoo S.K., Molitor T.W. (2011). Effect of cross-fostering on transfer of maternal immunity to My- clinical signs in piglets and for delaying infection until coplasma hyopneumoniae to piglets. Vet. Record, 168: 100–100. the piglet immune system is fully developed (Poonsuk Bandrick M., Ariza-Niet C., Baidoo S.K., Molitor T.W. (2014). Colos- and Zimmerman, 2018). Noninvasive sample collection tral antibody-mediated and cell-mediated immunity contributes to methods are thus desirable and of great research interest. innate and antigen-specific immunity in piglets. Dev. Comp. Im - munol., 43: 114–120. The usefulness of oral fluid (OF) specimens for detecting Belt W.D., Anderson L.L., Cavazos L.F., Melampy R.M. (1971). 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Received: 15 VII 2022 Šinkora M., Sinkora J., Reháková Z., Splíchal I., Yang H., Parkhouse Accepted: 21 X 2022 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Animal Science de Gruyter http://www.deepdyve.com/lp/de-gruyter/immune-status-of-piglets-during-the-first-week-of-life-current-dhLRVmHLaW

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Publisher: de Gruyter
Copyright: © 2023 Agata Augustyniak et al., published by Sciendo
ISSN: 1642-3402
eISSN: 2300-8733
DOI: 10.2478/aoas-2022-0079
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Abstract

Ann. Anim. Sci., Vol. 23, No. 2 (2023) 391–403 DOI: 10.2478/aoas-2022-0079 Immune status of pIglets durIng the fIrst week of lIfe: Current knowledge, sIgnIfICanCe and assessment – a revIew* 1 2 1♦ Agata Augustyniak , Ewelina Czyżewska-Dors , Małgorzata Pomorska-Mól Department of Preclinical Sciences and Infectious Diseases, Poznan University of Life Sciences, Wołyńska 35, 60-637 Poznań, Poland Department of Internal Diseases and Diagnostics, Poznan University of Life Sciences, Wołyńska 35, 60-637 Poznań, Poland Corresponding author: mpomorska@up.poznan.pl abstract the immune system of neonate piglets differs from adult pigs in structure and competence. although piglets are born immunocompe - tent, they are genuinely immunologically defenseless. t o survive in the environment, piglets need passive protection provided by sow’s colostrum and milk when constantly exposed to numerous pathogens. early assessment of piglets’ immune status may enable rapid intervention in case of detection of any deficiencies or disorders. Moreover, awareness of the piglets’ immunocompetence and the level of maternally-derived antibodies (mda) may allow the creation of a proper vaccine schedule. hence, extending knowledge of prenatal ontogeny of the porcine immune system, the immune status of neonate piglets’ and the immunological components of porcine colostrum is crucial. since animal welfare has become a more critical element of animal production, new, non-invasive sampling methodologies are highly desirable for the evaluation of piglets’ immune status. key words: neonate, piglets, immune status The piglet’s immune system begins to develop in the 2002). It has been confirmed that fetuses can produce early stages of prenatal ontogeny, during the embryonic their own antibodies against antigens in the final third period of embryogenesis (Šinkora and Butler, 2009). of gestation (Martinez-Boixaderas et al., 2022); how- However, neonate piglets’ immune systems differ from ever, their ability to respond to antigen stimuli is feeble those of adult pigs in both morphology and function. For (Martínez-Boixaderas et al., 2022). Therefore, although example, the mesenteric lymph nodes and Peyer’s patch- piglets are born immunocompetent, they are immunolog- es are smaller in piglets and have fewer Ig-secreting cells ically vulnerable and rely on passive immunity early in than do those of adult pigs (Levast et al., 2014). Moreo- life (Pomorska-Mól and Markowska-Daniel, 2009). With ver, the jejunal lymph nodes of newborn piglets consist the beginning of extrauterine life, piglets are exposed to of a chain of single lymph nodes parallel to the small various environmental antigens, unlike during prenatal intestine on both sides of the mesentery; in contrast, in life. The development of primary immunity is too slow two-week-old piglets the jejunal lymph nodes merge into to protect piglets from pathogens, and piglets’ adaptive an almost confluent band of lymphatic tissue (Schnap- immunity is primitive compared to adults’ (Pomorska- per et al., 2003). The cellular components of the piglet’s Mól and Markowska-Daniel, 2010 a). The acquisition immune system are not fully operational by the end of of appropriate amounts of high-quality colostrum is thus gestation (Stepanova et al., 2007; Pomorska-Mól and significant. Colostrum, defined as the first secretion of Markowska-Daniel, 2011). They have limited external a mammary gland, usually released within 24 hours af- antigen stimulation during the fetal period, which results ter farrowing, provides newborn piglets with energy and in a minimal number of peripheral double-positive αβ T passive immunity (Inoue and Tsukahara, 2021). Its early cells (effector or memory T cells). Moreover, the lym- ingestion by newborn piglets is crucial for their further phocyte B population consists of immature cells (Šinkora healthy development and growth (Inoue and Tsukahara, and Butler, 2009). In addition, an epitheliochorial struc- 2021). The immune components of the colostrum in- ture of the porcine placenta effectively precludes the clude highly concentrated immunoglobulins and many transfer of immunoglobulins or immune cells (Rooke other elements, such as cytokines, cellular components and Bland, 2002). Colostrum and milk thus constitute the (e.g., lymphocytes, and phagocytes), and various growth only sources of maternal immunity (Rooke and Bland, factors (Inoue and Tsukahara, 2021). Piglets’ immune __________ *This work was supported by the National Science Centre (DEC- 2020/37/B/NZ7/00021). 392 A. Augustyniak et al. systems are of great interest to researchers, and gain- first leucocytes with CD45 phenotype were observed in ing knowledge of this subject would allow for improve- their research on day 35 of gestation in the fetal spleen ments in the immune status of piglets, as well their future and cord blood, and at day 40 of gestation in the mes- healthy growth and performance; this all brings measur- enterium. However, there was an absence of cells with able effects to the pig production sector (Šinkora et al., typical lymphocyte markers (CD3 ). Among the lympho- 1998 a; Pomorska-Mól and Markowska-Daniel, 2010 b). cyte population, B lymphocytes appeared at the earliest In addition, a piglet’s immunological status shortly after in the periphery. Their presence was detected at day 40 birth is an important question for effective vaccination of gestation and they remained the predominant lym- management. Knowledge of the immune status of piglets phocyte population in lymph nodes, spleen, and blood may also enable rapid intervention when a deficiency or up to day 55 of gestation. The authors considered that disorder is detected. The ideal situation is when all litters, these findings, in combination with those of the study of as well as all piglets in each litter within a herd, have Cukrowska et al. (1996), indicate that sIgM B cells may a similar immune status. Such similarities are desirable be one of the first functional lymphocyte subpopulations both in immunocompetence as well as in the level of co- in porcine fetuses (Šinkora et al., 1998 a). Cukrowska lostrum (maternal) antibodies against pathogens that are et al. (1996) observed the presence of immunoglobulin present in the herd. G (IgG), immunoglobulin A (IgA), and immunoglobulin In this paper, we review the early prenatal ontogeny M (IgM) in fetus plasma and noted the ability of surface + + - of the swine immune system, the immunological compo- immunoglobulin M (sIgM ) CD5 B cells isolated from nents of porcine colostrum, and piglets’ immunological the fetal liver to secrete IgM. Every fetal sIgM B lym- status during the first week of life. phocyte was similar to an adult sIgM B cell on account of CD45RC and SLA-DR positivity. Furthermore, over + + prenatal ontogeny of swine immune system 90% of sIgM cells were CD2 , and this marker was ex- Morphogenesis, hematopoiesis, and lymphopoiesis pressed as the B cells developing before sIgM, which is Porcine gestation lasts about 114–116 days (Belt et normally considered a B-cell precursor (Šinkora et al., al., 1971). By the end of porcine organogenesis, on day 1998 a). The development of thymic tissues was observed 35 of gestation, the lymphatic system has already been as early as the day 21 of porcine gestation (Šinkora and physiologically formed; nevertheless, when the bone Butler, 2009). The thymus is a specialized lymphatic or- marrow starts its hematopoietic activity, lymphoid com- gan in which T lymphocytes mature. Around day 40 of ponents and lymphocytes are rare in the various organs gestation, the first T cells can be detected in this organ (Šinkora and Butler, 2009). Due to the expansion of pe- (Šinkora and Butler, 2009). Subsequently, T cells have ripheral lymphatic organs between days 60 and 90 of been observed on day 45 of gestation in the spleen and gestation, the lymph nodes, including mesenteric lymph umbilical blood and, on day 50 in the mesenterium. In all nodes, are negligible up to day 70 of gestation. Porcine cases, their appearance was delayed relative to that of the lymphopoiesis is known as lymphoid hematopoiesis, as first sIgM lymphocytes (Šinkora et al., 1998 a). Among the B cells develop in the primary hematopoietic organs the T lymphocytes, γδ T cells appeared first, developing and the pro-T cell progenitors that settle the thymus are primarily in the thymus; five days later they were also derived from the same hematopoietic centers; the lym- detectable in the periphery. The occurrence of γδ T cells phopoiesis of lymphocytes B and T is thus closely as- remains relatively constant up to day 90 of gestation; sociated (Šinkora and Butler, 2009). The yolk sac is the however, around farrowing, a sharp growth of γδ T cells first lymphopoietic organ. Hematopoiesis can be detected in the blood and spleen was noted (Šinkora et al., 1998 a). here as soon as the day 16 of gestation (Trebichavský et After that time, the blood and spleen selectively ac- + - al., 1996; Šinkora et al., 2002). Nevertheless, its contri- cumulated a great percentage of CD2 CD8 γδ T cells - - bution to overall lymphocyte production is rather small, and CD2 CD8 γδ T cells, respectively (Šinkora et al., + + since the yolk sac involutes early, around day 24 or 27 of 1998 a). The count of T-cell receptor αβ (TCRαβ ) gestation. Subsequently, first the liver, and later (around lymphocytes began to increase around day 55 of gesta- day 45 of gestation) the bone marrow, are responsible for tion, and soon after they outnumbered the T cells sub- lymphopoietic activity and for the development of the set in the thymus and periphery (Šinkora et al., 1998 a). preimmune B cell receptor repertoire (Šinkora and But- At about day 90 of gestation, the concentration of αβ T ler, 2009). cells plateaued (Šinkora et al., 1998 a). A growth in the number of B cells was also observed; hence sIgM and Development of individual adaptive immunity com- TCRαβ T lymphocytes are prominent cells in the fetal ponents periphery at this time (Šinkora et al., 1998 a). During Šinkora et al. (1998 a) investigated the surface phe- late gestation, the relative proportion of αβ T cells and B notype of fetal lymphoid cells in the thymus, cord blood, cells varies between individual organs. However, they are spleen and mesenteric lymph nodes at different stages similar to those observed in neonate piglets (Šinkora et al., + - of gestation. This study indicates that the second trimes- 1998 a). CD4 CD8 αβ T helper cells were the first ter of gestation is the period when the major subpopu- prominent subset of αβ T lymphocytes. Moreover, lations of lymphocytes begin to appear (Table 1). The they also made up the greatest αβ T cell subpopulation Immune status of neonatal piglet 393 - hi within gestation (Šinkora et al., 1998 a). CD4 CD8 αβ (Šinkora and Butler, 2009). Subsequently, NK cells cytotoxic T cells were absent up to day 55 of gestation; were also detected in mesenteric lymph nodes (MLN) subsequently, their number increased until birth (Šinkora at about day 50 of gestation. However, their concen- et al., 1998 a). In the study of Cukrowska et al. (1996), tration was low (Šinkora et al., 1998 a). Later in the serum immunoglobulins of all isotypes were detected in ontogeny, at approximately day 70 of gestation, the NK fetuses at day 44 of gestation. The predominant immuno- cell concentrations stabilize and then remain relatively globulin was IgM, and the overall immunoglobulin con- constant until birth (Šinkora and Butler, 2009). Previ- centration was increased during ontogeny, independently ous studies have shown that fetal NK cells lack the abil- of external stimuli. Moreover, antibody activity against ity to kill before birth, and killing was delayed in germ- autoantigens, phylogenetically conserved proteins, hap- free piglets. This may suggest that colonization with tens, and bacterial components was found in the sera of microflora may be crucial to the complete functional fetuses at the end of embryonic life. Preimmune immu- development of these cells (Šinkora and Butler, 2009). noglobulins can display a large spectrum of physiologi- Interferon-α secreting cells (IFN-α SC) were found in cal functions, and many remain unknown. With other the fetal liver at a very early stage of fetal development, natural factors, they constitute the first line of defense at day 26 of gestation, when differentiated lymphocytes during gestation and the early extrauterine stage of life were still not detectable (Splichal et al., 1994). After (Cukrowska et al., 1996). that, they were also detected in other tissues such as cord blood, spleen, and bone marrow. The authors sug- Development of individual innate immunity compo- gested that IFN-α SC may represent an early antiviral nents defense mechanism (Splichal et al., 1994). An in vitro Data on the development and maturation of porcine study performed on pig fetus macrophages and lym- innate immunity components is limited. Along with phocytes showed high cytoplasmic expression of tumor the beginning of hematopoietic activity of the primary necrosis factor (TNF-α) when stimulated with bacterial lymphoid organs, cellular elements of the innate im- mitogens (Trebichavský et al., 1995). The main pro- munological system such as morphonuclear leukocytes, ducers of TNF-α at a later stage of development were macrophages, and dendritic cells begin to appear (Ta- macrophages. According to those authors, their findings ble 1) (Šinkora and Butler, 2009). For example, mac- may suggest that lymphocytes and macrophages play a rophages were detected as soon as day 25 of gestation pivotal role in the induction of inflammatory responses (Trebichavský et al., 1996). Cells with the natural killer in fetuses (Trebichavský et al., 1995). Elevated inter- (NK) phenotype also appeared early in the ontogeny, feron γ (IFN-γ) and TNF-α mRNA levels were observed IO + and CD3ε CD8 CD2 lymphocytes were observed in in the tissues from porcine fetuses infected with porcine the umbilical blood and spleen around day 45 of ges- reproductive and respiratory syndrome virus (PRRSV), tation (Šinkora et al., 1998 a). Their abundance varies and corresponded to elevated cytokine proteins in se- from 1% to 10%, with an upward tendency over time rum (Rowland, 2010). Table 1. The first appearance of the particular immune components in porcine fetuses during prenatal ontogeny First appearance Immune component Location References (day of gestation) Macrophages 25 No data Trebichavský et al., 1996 CD45+leukocytes 35 Spleen, cord blood Šinkora et al., 1998 a 40 Mesenterium Šinkora et al., 1998 a sIgM+ cells 30 Liver Šinkora et Butler, 2009 40 Periphery Šinkora et al., 1998 a γδ T cells 40 Thymus Šinkora and Butler, 2009 45 Liver, cord blood, spleen Šinkora and Butler, 2009 60 Bone marrow Šinkora and Butler, 2009 αβ T cells 55 Thymus Šinkora nad Butler, 2009 58 Liver, cord blood, spleen Šinkora and Butler, 2009 60 Mesenteric lymph nodes, bone Šinkora and Butler, 2009 marrow NK cells 45 Spleen, umbilical cord Šinkora et al., 1998 a ~50 Mesenteric lymph nodes Šinkora et al., 1998 a Immunoglobulins 44 Blood Cukrowska et al., 1996 Interferon α secreting cells 26 Liver Splichal et al., 1994 394 A. Augustyniak et al. Table 2. Characteristic of different classes immunoglobulins in sow’s colostrum Features IgG IgA IgM References Origin Almost 100% derives from 60% produced locally in the 85% derives from sow’s Maciag et al., 2022; sow’s serum mammary gland serum Pomorska-Mól and Markowska-Daniel, 2009 40% derive from sow’s serum 15% produced locally in the mammary gland Predominant immuno- Colostrum Milk – Klobasa et al., 1987; globulin Markowska-Daniel et al., 2010; Markowska-Daniel and Pomorska-Mól, 2010 Influence of sow’s parity Concentration significantly No significant impact on the No significant effect on Klobasa et al., 1986; on colostral concentration higher in multiparous sows colostral concentration the colostral concentra- Cabrera et al., 2012; than in gilts tion Forner et al., 2021; Decreased concentration Maciag et al., 2022 in the lacteal secretions of primiparous sows compared to multiparous sows Highest concentration in At farrowing At farrowing At farrowing Klobasa et al., 1987; sow’s colostrum Markowska-Daniel et al., The concentration of Higher amounts in anterior Higher amounts in anterior No data Ogawa et al., (2014 a) immunoglobulins in teats teats particular teats Table 3. Changes in the concentration of immunoglobulins in the sow colostrum (mg/ml) within time according to different studies Markowska-Daniel Immunoglobulins concentration Klobasa et al., 1987 Bland et al., 1999 et al., 2010 At farrowing IgG 98.17 IgG 95.6 IgG 58.0 IgA 23.20 IgA 21.2 IgM 9.07 IgM 9.1 24 hours post parturition IgG 19.74 IgG 14.2 IgG 8.7 IgA 9.17 IgA 6.3 IgM 4.42 IgM 2.7 The significance of colostrum fringens toxoid substantially reduced piglet losses caused In Suidae species, as mentioned previously, the epi- by C. perfringens type C (Springer and Selbitz, 1999). theliochorial nature of the placenta prevents the sows’ immunoglobulins from being transferred. Colostrum Immunoglobulins is thus the sole source of passive immunity for piglets. The most important element of the sows’ colostrum Besides immunoglobulins, colostrum contains lympho- from an immunological point of view are immunoglobu- cytes, cytokines, nucleotides, and essential growth fac- lins. These constitute the most abundant component of tors that stimulate the postnatal development of the im- whey protein (approximately 80%) (Inoue and Tsuka- mune system and the visceral organs, as well as protein hara, 2021). Because piglets are born with almost no se- synthesis in skeletal muscles (Burrin et al., 1992). rum antibodies, MDAs play a crucial role in protecting Prior to the maturation of the piglets’ own immunity, them against infectious agents before they develop their the maternally derived antibodies (MDA) confer protec- own adaptive immunity (Markowska-Daniel et al., 2010; tion against any infectious agents that the sows had been Forner et al., 2021). However, MDAs can only protect naturally infected with or vaccinated against (Klobasa piglets from infections caused by pathogens that the et al., 1981; Inoue and Tsukahara, 2021). For example, sow’s immune system has faced. a previous study indicated that maternally derived ro- To provide a sufficient level of passive immunity and tavirus-specific IgG significantly alleviates the clinical to significantly reduce the risk of early death, the pig- symptoms following experimental rotaviral infection of let needs to ingest a minimum of 200 mg of colostrum neonatal piglets (Ward et al., 1996). Another study con- within the first 24 hours after birth; consumption of 250 ducted under field conditions documented that antibod- mg per piglet should provide good future health (Quesnel ies passively acquired by neonates through the colostrum et al., 2012). Antibodies can pass to the colostrum from and milk of sows vaccinated against the Clostridium per- sow serum or can be produced directly in the mammary Immune status of neonatal piglet 395 gland (Table 2) (Pomorska-Mól and Markowska-Daniel, amounts of IgA and IgG than the posterior teats (Ogawa 2009). Almost 100% of colostral IgG derives from sow’s et al., 2014 a). Other factors that can affect the final con- serum; meanwhile, more than 50% of IgA is produced centration of IgG in colostrum are the mother’s genotype, locally in the mammary gland (Maciag et al., 2022). age, and vaccination, as well as endocrine status, feeding, A substantial majority (around 85%) of colostral IgM de- and herd management (Kielland et al., 2015; Maciag et rives from sow’s serum (Pomorska-Mól and Markowska- al., 2022). The immunoglobulins ingested by piglets are Daniel, 2009). The predominant colostral immunoglobu- taken up by nonspecific pinocytosis into the enterocytes lin is IgG (Klobasa et al., 1987; Markowska-Daniel et (Rooke and Bland, 2002; Kielland et al., 2015). An im- al., 2010; Markowska-Daniel and Pomorska-Mól, 2010). portant role in the absorption of immunoglobulin from This is followed by IgA (the predominant immunoglobu- the guts is played by trypsin inhibitor, which inhibits the lin of milk) and IgM (Klobasa et al., 1987; Markowska- enzymatic activity of trypsin and prevents denaturation Daniel et al., 2010; Markowska-Daniel and Pomorska- of the immunoglobulins; however, its level in colostrum Mól, 2010). Immunoglobulin concentration in colostrum decreases within time (Jensen and Pedersen, 1979). The is not constant, declining during the first 24 hours after concentration of IgG in the piglet’s serum depends on farrowing; however, the decrease in the level of IgG is several factors, such as the amount of available and in- more drastic than in IgA or IgM (Table 3) (Klobasa et gested colostrum, IgG absorption in the piglet’s intestine, al., 1987; Markowska-Daniel et al., 2010). For example, and gut closure, which occurs 24 to 36 hours after birth in the research of Markowska-Daniel et al. (2010), the (Pomorska-Mól and Markowska-Daniel, 2009; Kielland highest level of immunoglobulin was noted in the first et al., 2015). The study of Kielland et al. (2015) indicates colostrum, which is acquired at farrowing. The mean a strong association between the concentration of colos- initial concentration was 118.5 mg/ml, 23.8 mg/ml, and trum IgG and piglet serum IgG (Kielland et al., 2015). 12.1 mg/ml for IgG, IgA, and IgM, respectively. After Interestingly, this is not consistent with some other stud- 24 hours, the concentration of IgA and IgM had reduced ies, where a lack of correlation is demonstrated between to 4.59 mg/ml and 4.29 mg/ml, respectively, and the level levels of colostral Ig and piglet’s serum Ig (Markows- of IgG decreased to 34% of its initial level (Markowska- ka-Daniel et al., 2010). The concentration of piglet IgG Daniel et al., 2010). This is partially consistent with the decreased with each piglet born. However, this was not findings of Klobasa et al. (1987), where the mean IgG significantly associated with litter size, but was more de- concentration was also highest at farrowing, at 95.6 mg/ pendent on the time of birth relative to farrowing onset ml; IgA was at 21.2 mg/ml and IgM was at 9.1 mg/ml. (Kielland et al., 2015). Litter size affected colostrum in- These were subsequently reduced to 14.2 mg/ml, take but not the concentration of piglet IgG. This may be .3 mg/ml, and 2.7 mg/ml, respectively, 24 hours after due to the flattening of piglets’ plasma IgG concentration birth (Klobasa et al., 1987). Bland et al. (1999) assessed above a certain level of colostrum IgG (Kielland et al., the mean IgG concentration at farrowing as 58.0 mg/ml; 2015). Bland et al. (1999) have shown that, despite dif- 24 hours later, the level had decreased to 8.7 mg/ml ferences in colostrum intake (and hence IgG) between (Bland et al., 1999). These studies also indicated that the piglets, the total concentration of IgG in the piglet’s concentration of colostral immunoglobulins varies be- plasma did not vary between litters. This may indicate tween sows. Kielland et al. (2015) noted that the concen- that piglets can regulate the quantity of plasma IgG inde- tration of colostral IgG varies not only between particu- pendently of the quantity of IgG obtained (Bland et al., lar sows, but also between herds (Kielland et al., 2015). 1999). In Kielland et al. (2015), a significant association Several studies have indicated that the concentration of was observed between body mass index (BMI) and pig- IgG in the colostrum was significantly higher in multipa - lets’ IgG level on day 1. The authors further concluded rous sows than in gilts (Cabrera et al., 2012; Forner et al., that piglets with BMIs of 17 kg/m or lower may not be 2021; Maciag et al., 2022). However, there was no such strong enough to obtain sufficient amounts of IgG. (Kiel- relationship for IgA content (Forner et al., 2021). This land et al., 2015). Bandrick et al. (2014) demonstrated is consistent with Maciag et al. (2022), where the parity that levels of IgG and IgA in the serum of piglets that order did not significantly affect the colostral concentra - ingested colostrum mimicked the distribution of these tion of IgA and IgM (Maciag et al., 2022). On the con- immunoglobulins in the sow’s colostrum. Furthermore, trary, Klobasa et al. (1986) showed that the levels of IgA IgG and IgA were absent from piglet serum before colos- in the lacteal secretions of primiparous sows were lower trum intake. This may indicate nonselective absorption than in multiparous sows (Klobasa et al., 1986). The of colostral immunoglobulins (Bandrick et al., 2014). level of immunoglobulins in colostrum can also vary be- A positive correlation between IgG levels in the serum of tween individual teats (Table 2). According to Ogawa et piglets at 7 days and 56 days of age may point to a posi- al. (2014 a), a higher amount of colostrum was obtained tive relationship between initial antibody concentration from anterior teats. Furthermore, a positive correlation in the piglet’s serum and the development of their active between colostrum secretion volume (CSV) and IgG was immunity (Markowska-Daniel et al., 2010). According observed from 6 hours after farrowing and from 12 hours to Rooke et al. (2003), naturally suckling piglets start after farrowing between CSV and both IgG and IgA. to produce IgG at 7 days of age. Its quantity was posi- This may suggest that the anterior teats contain greater tively correlated with the amount of absorbed colostral 396 A. Augustyniak et al. IgG (Rooke et al., 2003). Curtis and Bourne (1973) indi- in the secretion of the mammary gland on the first and cate that active IgM production by piglets emerges from second days after parturition; this correlated with the 10–12 days of age. Porter and Hill (1970) reported that time of their peak concentrations in the piglet’s serum. IgM in suckling piglets begins to increase from 7 days The predominant cytokine in the sow’s colostrum was of age. Active synthesis of IgA by suckling piglets up to IL-4, followed by TGF-β1. Other cytokines occurred 12 days of age does not contribute significantly to serum at lower levels, and the least concentrated were IL-12, IgA concentrations (Curtis and Bourne, 1973). This sug- IL-10, and TNF-α (Nguyen et al., 2007). One in vitro gests that piglets begin to effectively produce their own study evaluated the impact of various concentrations of IgA at a later age, but to date, there is no conclusive data TGF-β1 and IL-4 on porcine neonatal B cell responses on this issue. Other investigation, with piglets weaned at (Nguyen et al., 2007). High TGF-β1 levels caused sup- different times (7, 14, 21 or 28 days) showed that endog- pressed immunoglobulin-secreting cell responses to enous colostrum/milk factors may be critical to promote LPS and rotavirus, and low TGF-β1 levels led to iso- IgA synthesis (Levast et al., 2010). Ultra-early weaned type switching to IgA antibodies. IL-4 provoked inverse piglets (at 7 and 14 days) showed lower serum IgA con- dose-dependent isotype switching to IgA. Moreover, it centrations at 21 days proving a deficiency in the IgA gut also improved IgM-secreting cell responses to LPS and immune response development. rotavirus. Furthermore, an elevated concentration of Th2 cytokines or TGF-β in newborn piglets may be crucial Cytokines for their acquisition of normal commensal microflora in The presence has been noted in porcine colostrum the intestine, given the reduction of immune and inflam- of granulocyte-macrophage colony-stimulating factor matory response in the gut (Nguyen et al., 2007). Ma- (GM-CSF), interferon γ (IFN-γ), interleukin 1 α (IL-1α), ciag et al. (2022) found that concentrations of GM-CSF, interleukin 1 receptor antagonist (IL-1RA), interleukin IFN-γ, IL-1α, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, 2 (IL-2), interleukin 4 (IL-4), interleukin 6 (IL-6), inter- IL-18, and TNF-α were significantly higher in serum and leukin 10 (IL-10), interleukin 12 (IL-12), interleukin 18 colostrum of multiparous sows than in gilts (Maciag et (IL-18), tumor necrosis factor-alpha (TNF-α), and trans- al., 2022). Moreover, these above cytokines occurred at forming growth factor β (TGF-β) (Table 4) (Nguyen et higher levels in the serum of piglets that received co- al., 2007; Ogawa et al., 2014 b; Maciag et al., 2022). lostrum from multiparous sows than in the serum of Maternal cytokines contained in the colostrum may piglets fed with gilt’s colostrum. The lowest concentra- play an instructive role in the maturation of the neona- tion of these cytokines was observed in the piglets fed tal immune system (Nguyen et al., 2007). It is assumed with milk replacer. A greater tendency to innate inflam- that colostrum is the only source of various cytokines matory and anti-inflammatory responses, and a greater for newborn piglets (Nguyen et al., 2007). The study of propensity to specific Th1 and Th2 responses, during the Nguyen et al. (2007) indicated that the moderate corre- perinatal period was significantly correlated with pig- lation between sow blood and colostrum for IL-4, IL-6, lets that suckled sow colostrum (Maciag et al., 2022). IL-10, IL-12, and IFN-γ indicates that these cytokines Ogawa et al. (2014 b) confirmed the presence of IL-18 pass to the mammary gland from the sow’s bloodstream. in the colostrum, but not in the sow’s milk. This cytokine Given the lack of such a correlation between TNF-α and is believed to regulate the immune system of newborn TGF-β1 (the concentration of both in the colostrum being piglets (Ogawa et al., 2014 b). Elahi et al. (2017), using higher than in the sow’s blood), they must be produced a pertussis model showed that immunization of pregnant directly in the mammary gland (Nguyen et al., 2007). sows with heat-inactivated bacteria may lead to the in- These cytokines were only present in the blood of piglets duction of various cytokines, such as TNF-α, IFN-γ, IL- that ingested colostrum (Nguyen et al., 2007). The pres- 6, IL-8, and IL-12/IL-23p40. Moreover, these cytokines ence of IL-6, TNF-α, INF-γ, IL-4, and IL-10 was not de- were detectable next to pertussis-specific antibodies, not tected in the group of age-matched colostrum-deprived only in vaccinated sow serum and colostrum, but also gnotobiotic piglets. The authors thus assumed that these in their progeny’s serum and bronchoalveolar lavage cytokines do not pass through the placenta. However, fluid. Interestingly, active vaccination of newborn pig- IL-12 and TGF-β1 were detected in the plasma of co- lets with heat-inactivated bacteria led to high levels of lostrum-deprived gnotobiotic piglets. This may indicate IgG and IgA specifically, but no cytokines. Even though that piglets can produce the cytokines by themselves. In the concentration of antibodies in vaccinated piglets and the mentioned study, the authors did not detect TNF-α of passively obtained antibodies were similar, the au- in the plasma of piglets in either group. The lack of this thors did not observe any protection against Bordetella cytokine in the serum of sows and piglets is probably pertussis infection in the vaccinated individuals. Elahi due to some control mechanism that prevents prolonged et al. (2017) hence conclude that the presence of pas- inflammatory responses, which could further damage sively transferred cytokines or antibodies affects new- tissue (Nguyen et al., 2007). However, data concerning born piglets’ ability to secrete cytokines, and that this this cytokine is inconsistent: its presence in piglet plas- may suggest that the vaccinating the sow can affect the ma was observed in Maciag et al. (2022). Nguyen et al. newborn’s cytokine milieu and impact immune cell dif- (2007) found the highest concentration of the cytokines ferentiation (Elahi et al., 2017). Immune status of neonatal piglet 397 Table 4. Characteristic of cytokines present in sow’s colostrum and piglets’ serum Features Cytokines References Presence in sow’s colostrum GM-CSF, IFN-γ, IL-1α, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, Nguyen et al., 2007; IL-18, TNF-α, TGF-β Ogawa et al., 2014 b; Maciag et al., 2022 Originating from sow’s serum IL-4, IL-6, IL-10, IL-12, IFN-γ Nguyen et al., 2007 Production directly in the mammary gland TNF-α, TGF-β1 Nguyen et al., 2007 Predominant cytokine of sow’s colostrum IL-4 Nguyen et al., 2007 Least concentrated in sow’s colostrum IL-12, IL-10, TNF-α Nguyen et al., 2007 Concentration higher in multiparous sow than GM-CSF, IFN-γ, IL-1α, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, Maciag et al., 2022 gilts IL-18, TNF-α Likely production by neonate piglets IL-12, TGF-β1 Nguyen et al., 2007 the differences in the distribution of colostrum’s humoral Cellular components and cellular composition over 40 gilts and 40 sows (par- Porcine colostrum, apart from multiple proteins, also ity orders 3–4). Their results show that parity does not contains several types of cells (Wagstrom et al., 2000). It influence the total count of macrophages, granulocytes, has been estimated that piglets ingest some 500–700 mil- or T and B cells. Nevertheless, multiparous sow colos- lion colostral cells daily (Nguyen et al., 2007), including trum contained significantly larger T lymphocyte subsets epithelial cells, lymphocytes (T and B cells), and phago- than gilts (i.e., central and effector memory CD4 T cells cytes (neutrophils and macrophages) (Wagstrom et al., or central memory CD8 T cells). The authors concluded 2000). In contrast to many mammal species, epithelial that parity order may influence the cell population and cells constitute a great fraction of sow mammary gland piglet immune adaptive response, which induces neutral- secretions, representing approximately 20%–40% of all izing antibodies and cellular immune responses (Forner the colostral cells (Le Jan, 1996). Epithelial cells in the et al., 2021). Williams (1993) demonstrated that the lym- colostrum are small in size and have little or no IgA (Le phocytes contained in colostrum could cross the intesti- Jan, 1996). They furthermore exhibit low expression lev- nal wall and migrate via the piglet’s bloodstream to vari- els of secretory components (Le Jan, 1996). Small epi- ous organs (including the liver, lungs, lymph nodes, and thelial cells can be propagated in vitro for at least three spleen). Moreover, Nechvatalova et al. (2011) demon- passages. When cultured in the presence of the serum of strated that these cells possess functional abilities (they lactating sows, these cells differentiate and begin to pro- can become activated) and display an antigen-specific ac- duce α-lactoglobulin (Le Jan, 1996). Depending on their tivity in organs (Nechvatalova et al., 2011). Goubier et al. differentiation level, they display the ability to express (2009) detected antigen-specific lymphocytes that were major histocompatibility complex II (MHC II antigen) able to produce IFNγ and TNFα after in vitro stimulation (Wagstrom et al., 2000). Moreover, it is considered that with circoviral antigens vaccinated against PCV2 sow porcine colostral epithelial cells can produce cytokines colostrum (Goubier et al., 2009). Bandrick et al. (2008) and can function as antigen-presenting cells (Wagastrom demonstrated that lymphocytes obtained by piglets from et al., 2000). Macrophages constitute about 7%–11% of vaccinated sow colostrum can proliferate and participate cells (Maciag et al., 2022). 10%–25% of all porcine co- in functional response to Mycoplasma hyopneumoniae lostrum cells are lymphocytes, of which 70%–80% are T (Bandrick et al., 2008). Hlavova et al. (2014) assessed cells (Hlavova et al., 2014). According to Hlavova et al., the activation status of T and NK cells in colostrum using (2014) the predominant cell types in colostrum are CD8 + + the expression of CCR7, CD11b, CD25, CD45RA, and single-positive T cells (53.6%), followed by CD4 CD8 + + MHC class II receptors. They managed to observe the double-positive T cells (21.1%), CD2 CD8 γδ T cells expression of markers consistent with an effector mem- (15.0%), and NK cells (13.5%). The CD4 single-positive ory phenotype on T cells; this might suggest that these T cells (4.4%) and other γδ T cell subpopulations were were antigen-experienced cells. Based on the phenotype less common. The proportion of individual lymphocytes of colostrum-derived T lymphocytes and NK cells, those varies between colostrum and sow peripheral blood: the authors concluded that these components may play a role proportion of cytotoxic and double-positive T cells was in mucosal immunity, and potentially in the transfer of significantly higher in colostrum than in peripheral blood passive immunity (Hlavova et al., 2014). A study by Ban- (Hlavova et al., 2014). On the contrary, the proportion of drick et al. (2014) demonstrated that colostral lympho- helper T cells was higher in peripheral blood (Hlavova et cytes are selectively transferred into the suckling blood- al., 2014). The greatest number of T cells are found in the stream. These can then influence neonatal piglets’ innate colostrum obtained around parturition, with their num- and adaptive immune responses (Bandrick et al., 2014). ber significantly decreasing after the first eight hours of B lymphocytes constitute about 20% of all lymphocytes lactation. Afterwards, the number of T cells remains con- in mammary secretions (Pomorska-Mól et al., 2010), and stant (Hlavova et al., 2014). Forner et al. (2021) assessed 398 A. Augustyniak et al. the concentration of SWC7+ CD5+ cells turned out to be Solano-Aguilar et al. (2001) have described changes in significantly higher in multiparous sow colostrum than lymphocyte subsets in mucosal tissues with increasing in gilts (Forner et al., 2021). Maciag et al. (2022) indi- age. According to this study, the GALT of piglets varies cated that levels of activated B and T cells were higher in from the GALT of adult pigs in the presence or count piglets fed multiparous sow colostrum. Lymphocytes can of the respective lymphocyte subsets. The authors also cross the intestinal wall of newborn piglets only when pointed out that the majority of the phenotypes charac- they are viable and have derived from the dam of a par- terized by increasing trends during the pre-weaning time ticular piglet (Bandrick et al., 2011). This is not the case were located on lymphocytes isolated from mesenteric with immunoglobulins, which can be absorbed across the lymph nodes and ileal Peyer’s patches, which can fur- intestinal mucosa of neonatal piglets, regardless of the ther imply that these lymphocytes are key populations maternal source or donor species (Bandrick et al., 2011). in the early postnatal period during the development of As a result, fostered piglets that suckled colostrum from lymphoid cells (Solano-Agilar et al., 2001). Rothkötter another sow than their natural dam will have deficiencies et al. (1991) studied lamina propria (LP) of normal and in maternal cell-mediated immunity (CMI) (Bandrick et germ-free piglets in early postnatal period. According to al., 2011). Bandrick et al. (2011) had demonstrated that this study, the number of LP lymphocytes has increased transfer of Mycoplasma hyopneumoniae-specific CMI to two-fold between the first and 29th day after farrowing. piglets occurs only when piglets were maintained with Moreover, the authors observed that the distribution of their biological dams for at least twelve hours after par- lymphocyte subsets exhibited an unusual pattern. Ap- turition (Bandrick et al., 2011). To conclude, maternal proximately 80% of T cells of piglets aged 1 to 5 days + - - antigen-specific leukocytes, delivered to piglets via co- belonged to CD2 CD4 CD8 subset. However, around 12 lostrum, may constitute an extra line of active defense days post-parturition, this subset started to disappear. In- against infection for neonatal piglets (Goubier et al., terestingly, 49 days old germ-free piglets displayed simi- 2009). lar T cell subset patterns as above mentioned convention- ally raised piglets between 1 and 5 days. Ig-positive cells Immunity of neonatal piglet were observed later than T cells. On the first-day post- Mucosal immunity parturition, a minimal number of IgM was noted. Forty + + After birth, neonatal piglets are exposed to plenty days later, the number of IgA was higher than IgM . The of various antigens. Most of them enter a host via mu- authors conclude that the results obtained in the germ- cosal membranes (Solano-Aguilar et al., 2001). Thus, free piglets may prove that the major changes in the LP these structures are equipped with specialised protec- are caused by the appearance of microbial antigens in tive elements called mucosa-associated lymphoid tis- the intestine (Rothkötter et al., 1991). Schnapper et al. sue (MALT), distinct from remaining lymphatic tissue (2003) have observed rapid changes occurring in piglet’s (Solano-Aguilar et al., 2001). Based on its distribution lymphoid tissue – the weight of Peyer’s patches, tonsil of in the organism, several types of MALT were distin- the soft palate, lymph nodes (cranial mesenteric lymph guished, i.e. gut-associated lymphoid tissue (GALT), center and bronchial lymph center), spleen and thymus nasopharynx-associated lymphoid tissue (NALT) or have grown faster than the body weight of piglets and had bronchus-associated lymphoid tissue (BALT) (Mazzoni been significantly enlarged during the first two weeks of et al., 2011). Due to the risk related to numerous poten- life (Schnapper et al., 2003). The mammalian intestine is tial pathogens or food-borne antigens and the presence colonized with normal gut flora during the first few days of commensal microbiota, GALT is well developed and of life (Butler et al., 2000). This component is believed to consists of the following structures: the Peyer’s patches, have an important role in providing health to its host, by mesenteric lymph nodes and intraepithelial lymphocytes among others inhibiting intestine colonization with path- and lamina propria lymphocytes (Solano-Aguilar et al., ogenic bacteria (Butler et al., 2000). Colostrum and milk 2001; Mazzoni et al., 2011). GALT of neonatal piglets constitute one of the sources that deliver gut microbes is a relatively developed structure with pre-existing Pe- to newborn piglets (Mardiaga et al., 2018). Maradiaga yer’s patches (Levast et al., 2014). However, shortly after et al. (2018) investigated gastrointestinal microflora and birth, the piglet’s gut is characterized by a small number mucosal immune gene expression in newborn piglets that of lymphocytes T and antigen-presenting cells (Levast et were reared in a cross-fostering model. Results of the al., 2014). Given exposure to numerous external antigens above study show that although cross-fostering does not and commensal microorganisms, GALT enlarges in size affect bacterial communities present in the neonate’s in- and lymphocyte subset content and reaches maturity in testine, the mRNA expression of TLR and inflammatory conventionally-raised piglets within two months (Levast cytokines change within the location in the gastrointesti- et al., 2014). At that time, the GALT of conventionally- nal tract. The authors suggested that the results presented raised piglets can respond to intestinal antigens with in their study may indicate the influence of colostrum good T and B lymphocyte activation and IgA production and maternal microbial communities on microflora de- (Levast et al., 2014). However, mesenteric lymph nodes velopment as well as mucosal immune gene expression and Peyer’s patches are still smaller and have fewer in newborn piglets (Maradiaga et al., 2018). The second- Ig-secreting cells than adult ones (Levast et al., 2014). ary function of the mucosal system is to discriminate be- Immune status of neonatal piglet 399 tween pathogen-associated and non-pathogenic antigens. cells. However, no evident changes in phenotype or quan- This phenomenon is called mucosal tolerance (Bailey et tity caused by environmental changes or piglet ageing al., 2005). According to Bailey et al. (2005), data con- were observed for NK cells (Talker et al., 2013). Llamas cerning response to intestine microflora are still incon- Moya et al. (2007) investigated age-related changes in sistent. One of the mechanisms involved in maintaining proinflammatory cytokines, acute phase proteins (APP), tolerance may be anergy or deletion of specific T-cells and cortisol concentrations during the first week of a pig- clones. It is grounded on the recognition of antigen on let’s life (Llamas Moya et al., 2007). According to this wrong presenting cells by antigen-naive T cells. It is study, the concentration of TNF-α and haptoglobin (Hp) worth emphasizing here the role of dendritic cells, which increased with age, while the serum amyloid A (SAA) are responsible for the presentation of antigens to naive level decreased. The lowest level of plasma TNF-α was T cells. These cells exhibit the ability to switch naive T observed on the first day after birth. On day 5, the con- cells to active response or tolerance. Thus, the interaction centration of TNF-α achieved its peak, and remained el- between these two types of cells is believed to determine evated on day 7. Similarly, the level of Hp was lowest the reaction. However, there are reports showing that the on day 1, and after that increased with age. On the other outcome of antigen recognition is determined by antigen- hand, the concentration of plasma SAA was elevated on non-specific signals arrived directly at mucosal regula- days 1, 3, and 5, but had significantly reduced by day 7. tory T cells (Bailey et al., 2005). As mentioned earlier, There were no age-dependent changes in the plasma con- the mucosal system of neonates is immature after birth in centration of IL-1β or C-reactive protein (CRP). Inter- comparison to adult ones. This agent may be responsible estingly, husbandry practices such as ear notching, teeth for the lack of active immune responses as well as the clipping, and tail docking did not affect other measured development of tolerance (Bailey et al., 2005). parameters, other than Hp. The authors thus suggested that such management practices did not result in systemic Innate immunity inflammation in the early postnatal life of piglets (Llamas The components of porcine innate immunity are simi- Moya et al., 2007). Similarly, Martin et al. (2005) found lar to those in many other mammals (Šinkora and Butler, that the Hp concentration in neonatal piglets’ plasma was 2009). Innate immunity is based on two main mecha- also low on day 1 after birth and subsequently increased nisms: activation of cellular components, such as mac- (Martin et al., 2005). Moreover, an age-dependent in- rophages, neutrophils, NK cells, or dendritic cells; and crease in the level of plasma major acute-phase protein the release of various extracellular mediators – such as (Pig-MAP) from birth up to 4 days of age was observed. cytokines, chemokines, and complement or antimicrobial After that, the concentration of Pig-MAP remained rela- peptides (Šinkora and Butler, 2009). The total number of tively high. The authors suggested that the rapid increase leukocytes increases during the first week of neonate life in the levels of proteins that were low at birth suggests (Talker et al., 2013). Pomorska-Mól et al. (2011) indi- some variety of acute-phase response, and that this re- cate that, on the first day of a piglet’s life, the number sponse may be an evolutionary adaptation of the piglets of granulocytes is similar to the number of lymphocytes to managing during the first critical period of extrauterine (Pomorska-Mól and Markowska-Daniel, 2011). Howev- life (Martin et al., 2005). er, the absolute granulocyte size and lymphocyte number predominance decreases during the next three weeks. In Adaptive immunity addition, a positive correlation between the mean number The development of the cellular components of the and mean percentage of granulocytes and the piglet’s age pig immune system is not fully complete by the end of was observed (Pomorska-Mól and Markowska-Daniel, gestation (Stepanova et al., 2007; Pomorska-Mól and 2011). They also showed that piglet granulocytes have Markowska-Daniel, 2011). The T cells, B cells, and pe- decreased phagocytosis and weaker adhesive molecule ripheral blood mononuclear cells (PMBC) of neonatal expression than adults (Pomorska-Mól and Markowska- piglets have a less developed ability to respond to mi- Daniel, 2010 a). The median value of NK-cell numbers in togens and a lower number of antigen-presenting cells piglets’ blood is lowest at birth and increases from there (Maciag et al., 2022). The total number of lymphocytes (Talker et al., 2013). Talker et al. (2013) indicate that the increases during the first week of a piglet’s life (Talker et presence of perforin was noted in all NK cells as early al., 2013). Some studies have indicated that CD4 lym- as the day of birth. This finding may imply that piglets’ phocytes form the predominant subpopulation of T cells NK cells exhibit immediate cytotoxic activity (Talker et in neonate piglets at farrowing, while CD8 lymphocytes al., 2013). Nevertheless, it contrasts with previous re- are less common (Stepanova et al., 2007). On the other search, where NK cells were isolated from pigs for up to hand, in Pomorska-Mól and Markowska-Daniel (2011), two weeks after birth, and showed weak cytolytic activ- the number of CD8 cells was greater than the number + + + ity against K562 target cells (Yang and Schultz, 1986). of CD4 cells. The ratio of CD4 to CD8 cells decreased Moreover, Talker et al. (2013) observed that pigs possess with age as the CD8 increased, which was accompanied - + - + CD3 CD8α NKp46 cells with entirely functional char- by a proportional decrease in CD4 lymphocyte numbers acteristics of NK cells; this is interesting because NKp46 (Stepanova et al., 2007; Pomorska-Mól and Markowska- + + was believed to be a species-spanning marker for NK Daniel, 2011). Double-positive CD4 CD8 are less fre- 400 A. Augustyniak et al. quent in neonate piglets than in adults, and their popu- lins are obtained with the colostrum and whether there lation increases with age, probably as a result of the is any interaction with environmental microorganisms. antigen-dependent maturation of naive CD4 T helper These are essential for the appearance of primed T and lymphocytes into antigen-specific memory T helper lym- B cells that subsequently develop into their effector and phocytes (Saalmüller et al., 2002; Stepanova et al., 2007). memory progeny (Šinkora and Butler, 2009). Primed T However, there is some variance, depending on the lev- lymphocytes with elevated expression levels of CD25 + + els of double-positive CD4 CD8 lymphocytes in piglets. meanwhile become effector/memory cells with elevated + + According to Stepanova et al. (2007), these cells were expression of MHC II and display a CD4 CD8α and + + rare during the first month of piglets’ life, at 0.5%, while CD2 CD8α γδT phenotype (Šinkora and Butler, 2009). Pomorska-Mól and Markowska-Daniel (2011) indicated that the proportion of this subset on the first day of pig- assessment of piglets’ immune status: current lets’ life was 6.63%. This discrepancy might result from possibilities and perspectives the animals’ conditions (experimental conditions versus Although piglets are born immunocompetent – i.e. commercial breeding farm) (Stepanova et al., 2007; Po- able to respond – they are at the same time immunologi- morska-Mól and Markowska-Daniel, 2011). Stepanova cally defenseless. To survive in an environment where et al. (2007) have noted changes in the subpopulations they are exposed to pathogens, they need their mother’s of T lymphocytes in the peripheral blood and secondary protection, which is provided as passive immunity that lymphoid tissue during the first month of the piglet’s life. comes with the colostrum and milk, in the form of anti- A significant age-dependent increase in the total concen- bodies and other regulatory elements involved in the im- tration of γδ T cells was noted in the blood and spleen, mune response. Early assessment of a piglet’s immune but not in the lymph nodes. However, there was signifi- status may enable rapid intervention in case of deficien- cant growth in the percentage of the γδ TCR+CD8+ sub- cies or disorders. In addition, knowledge of a piglet’s im- population (Stepanova et al., 2007). Strong growth in the munocompetence and MDA levels is crucial to design- total number of γδ T cells since birth was also confirmed ing a proper vaccination schedule (Martínez-Boixaderas in Talker et al. (2013), who observed significant pheno- et al., 2022). Piglet protection can be achieved either typic changes only within the CD2 subset. Neverthe- passively, through the transfer of maternally derived less, the increase in overall amounts was proportional immunity, or actively through vaccination. However, to the increase of the CD2-T-cell subset (Talker et al., vaccinating piglets in the presence of remaining MDA 2013). Due to the involvement of γδ lymphocytes in in- might interfere with vaccine efficacy. Most works in the nate immune efficiency, they are also considered to con- literature have dealt with the acquisition of passive hu- stitute part of the innate immunity (Šinkora and Butler, moral immunity by newborns, although the transmission 2009). The pool of B lymphocytes in neonatal piglets is of specific cellular immunity has also been reported (Le immature (Šinkora and Butler, 2009). The more signifi- Jan, 1996; Nguyen et al., 2007; Pravieux et al., 2007). cant percentage of peripheral sIgM B cells consists of For example, it has been shown that colostrum-derived + + + - sIgM CD2 B cells, and sIgM CD2 are relatively rare T cells could cross the intestinal barrier and enter the (Šinkora et al., 1998 b). This is interesting, as porcine B systemic circulation and lymphoid organs (Tuboly et al., cells were considered not to express CD2 (Šinkora et al., 1995). These lymphocytes are also a potential source of 1998 a). According to Šinkora et al. (1998 b), after the cytokines and chemokines that may exert a regulatory piglet’s gut has been colonized with a complex intestinal effect on antigen-presenting cells and specific antigen microflora, this proportion changes, and the number of responses. Mammary gland secretions thus also have CD2 B cells increases with age, reaching 15%–35% of immunoregulatory properties. Besides, colostrum con- sIgM peripheral blood lymphocytes in week-old piglets. tains numerous other components involved in the sys- They suggested that the expression of CD2 may be re- temic immune processes, such as cytokines, interferons, lated to the functional status of porcine B cells, but can lysozyme, lactoferrin, peroxidase, complement compo- then be lost as a consequence of the maturation process nents, hormones, and other compounds involved in the (Šinkora et al., 1998 b). Thus, the microflora-dependent mechanisms of innate immunity (Salmon, 1999; Schultz, + – sIgM CD2 lymphocytes in pigs can be activated/mem- 2006). These substances participate in the maturation ory B cells (Šinkora et al., 1998 b). Antigen stimulation of both local and systemic defense processes, as well due to colonization of the intestinal duct, as well as con- as in the induction and orientation of the piglets’ active tact with the extrauterine environment, results in the acti- response to the antigen (Salmon, 1999; Schultz, 2006). vation of T and B cells (Pomorska-Mól and Markowska- After being absorbed in the first 24 to 36 hours of life, an- Daniel, 2010 a). Šinkora and Butler (2009) indicate that, tibodies and other colostrum components are transferred in germ-free piglets, the development of the immune into the blood, where they provide systemic resistance to system is slower than in an age-matched control group, infectious agents in piglets (Inoue and Tsukahara, 2021). and these piglets were also unable to perform a humoral It is known that Ig plasma concentrations in piglets response (Šinkora and Butler, 2009). The maturation shortly after birth positively correlate with their chance of the elements of adaptive immunity thus arises from of surviving the critical perinatal period (Devillers et al., several factors, such as whether maternal immunoglobu- 2011). Cytokines passed to piglets by their mother with Immune status of neonatal piglet 401 colostrum can play the role of “teacher” in the matura- Several advantages of the use of such noninvasive sam- tion of suckling piglets’ immune system (Nguyen et al., pling have been reported: it allows efficient and low-cost 2007). However, cytokine transmission with colostrum collection of large numbers of diagnostic samples, and it or milk is not well documented. permits repeated sampling without the risk of discomfort Studies on the immunological status of piglets are or stress (Turlewicz-Podbielska et al., 2020). Recently, presently performed using blood samples. Blood collec- processing fluid (PF) has become more widely used in tion from individual animals has been the method most diagnostic practice (Trevisan et al., 2019; López et al., commonly used in veterinary practice to obtain samples 2022). PF consists of blood and tissue fluids obtained for monitoring and surveying herd health status, includ- during castration and tail-docking, which are usually per- ing for pigs. However, the technique is time-consuming, formed during the first week of a piglet’s life (3–5 days) laborious, and stressful for both animals and collecting (Turlewicz-Podbielska et al., 2020). As castration is still staff. In addition, sampling piglet blood is relatively performed on many farms, gaining PF does not require difficult and carries a high mortality risk. For this rea- additional procedures or animal restraint, and thus does son, farmers and veterinarians often refrain from car- not generate additional stressful situations. PF is consid- rying out such tests, or postpone monitoring until later ered a promising, practical, and inexpensive specimen in production. This can significantly delay the detection that may improve the monitoring of some porcine dis- of important health problems in the herd, including the eases, such as PRRS (Turlewicz-Podbielska et al., 2020). identification of lactation problems in sows, irregulari - The idea of using this type of specimen to monitor other ties in the vaccination of dams, or transmission of ma- swine diseases, as well as immune parameters such as cy- ternal immunity to piglets. A specimen that could be tokines, immunoglobulins, and APP shows some prom- collected noninvasively and without inducing stress in ise. An additional advantage of PF is that the specimen the animal, while still offering accurate diagnostic in- comes from piglets less than one week old. Studies in- formation, would greatly benefit herd health status and dicate that collecting PF from such young piglets is very disease monitoring. In the EU, noninvasive sampling difficult, if not impossible (Jabłoński et al., 2011). Re- methodologies for monitoring the health status of farm placing traditional samples, such as blood or serum, with animals must comply with the EU’s general objectives PF has numerous benefits, saving time, work, and costs on food safety policy (Regulation 652/2014), in which while minimizing the stress associated with sampling, animal welfare and wellbeing are major issues. In the which positively impacts animal welfare and immunity. assessment of the immunological status of piglets, only However, there is a lack of experimental data on its use one component of the immune response is usually con- for assessing the immunological status of piglets, includ- sidered – namely, humoral immunity, including its level ing the correlation between the concentration of various and duration. It seems that a more detailed analysis of immunological parameters in PF and the corresponding immunological parameters in this period (taking into ac- sera, which until now have been the material used in this count specific antibodies, and also the types of particular type of determination (the gold standard). groups of immunoglobulins, cytokines, APP, and so on) would shed more light on the significance of maternal declaration of Competing Interest immunity and its level in piglets in the first days of life The authors declare that there is no conflict of interest for their further development. The duration of maternal regarding the publication of this article. MDA refers to the age of the piglet at which their MDA levels fall below the limit of detection of the test used for evaluation (Opriessnig et al., 2004), or the rate of decay references (“half-life”) of MDA (the time required for a 50% de- crease in MDA levels) (Fort et al., 2009). 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Annals of Animal Science – de Gruyter

Published: Apr 1, 2023

Keywords: neonate; piglets; immune status

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Immune status of piglets during the first week of life: Current knowledge, significance and assessment – a review

Immune status of piglets during the first week of life: Current knowledge, significance and assessment – a review

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Immune status of piglets during the first week of life: Current knowledge, significance and assessment – a review

Immune status of piglets during the first week of life: Current knowledge, significance and assessment – a review

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