Histological studies on the ontogeny of bovine gut-associated lymphoid tissue: appearance of T cells and development of IgG+ and IgA+ cells in lymphoid follicles

The development and distribution of lymphocyte subsets in bovine gut-associated lymphoid tissues (ileal and jejunal Peyer's patches (PP)) were examined. Before birth, the composition of lymphocyte subsets in both PP follicles did not differ except for the dimensions of the interfollicular area and the dome region. Many IgM+ cells were observed in these follicles, but very few CD3+, IgG+, and IgA+ cells could be found. At neonatal period, the IgG+ cells, which did not produce IgG mRNA, were dominant within both PP follicles. From 1 month after birth, many CD3+ cells, IgG mRNA expression, and IgA mRNA expression were detected within the jejunal PP follicles, but very few were in the ileal PP follicles. These data suggest that the characteristics of the jejunal PP follicles metamorphose into secondary lymphoid tissue such as germinal centers at around 1 month after birth, whereas the characteristics of ileal PP follicles were distinct from those of germinal centers.     

A comparative study of gut-associated lymphoid tissue in calf and chicken

The calf contains two types of Peyer's patches (PPs): jejunal and ileal. The ileal PP has been thought to be equivalent to the bursa of Fabricius (BF) as a central lymphoid organ. The morphologies of ileal and jejunal PPs in the calf were compared with those of the BF and the caecal tonsil (CT) in the chicken. Immunoglobulin G-positive (IgG(+)) cells appear in the follicles of them all and exhibited a dendritic appearance after birth. We investigated whether the IgG in these follicles was produced in situ. IgG-producing cells were detected in the follicular medullas of the jejunal PP and the CT, but not in those of the ileal PP and the BF. CD4(+) cells were distributed in the follicular medullas of the jejunal PP and the CT, but not in those of the ileal PP and the BF. The data suggest that Ig class switching occurs in both jejunal PP follicles and CT follicles, but does not occur in either the ileal PP follicles or the bursal follicles. Because CD4(+) T cells would be prerequisite for Ig class switching in these follicles, IgG(+) cells of the follicular medullas in the ileal PP and the BF would trap immune complexes from the gut lumen. The primary B-cell repertoire might be selected by gut-derived antigens in the ileal PP and the BF before seeding the periphery.     

A comparative study of gut‐associated lymphoid tissue in calf and chicken

The calf contains two types of Peyer's patches (PPs): jejunal and ileal. The ileal PP has been thought to be equivalent to the bursa of Fabricius (BF) as a central lymphoid organ. The morphologies of ileal and jejunal PPs in the calf were compared with those of the BF and the caecal tonsil (CT) in the chicken. Immunoglobulin G–positive (IgG⁺) cells appear in the follicles of them all and exhibited a dendritic appearance after birth. We investigated whether the IgG in these follicles was produced in situ. IgG‐producing cells were detected in the follicular medullas of the jejunal PP and the CT, but not in those of the ileal PP and the BF. CD4⁺ cells were distributed in the follicular medullas of the jejunal PP and the CT, but not in those of the ileal PP and the BF. The data suggest that Ig class switching occurs in both jejunal PP follicles and CT follicles, but does not occur in either the ileal PP follicles or the bursal follicles. Because CD4⁺ T cells would be prerequisite for Ig class switching in these follicles, IgG⁺ cells of the follicular medullas in the ileal PP and the BF would trap immune complexes from the gut lumen. The primary B‐cell repertoire might be selected by gut‐derived antigens in the ileal PP and the BF before seeding the periphery. Anat Rec 266:207–217, 2002. © 2002 Wiley‐Liss, Inc.     

CD40 signaling induces B cell responsiveness to multiple members of the gamma chain-common cytokine family.

CD40 signaling induces B cell proliferative and differentiation responses that can be modulated by many different cytokines. Cytokines in the IL-2 receptor gamma chain (gammac)-common family are known to play an integral role in B cell development. Therefore, we investigated the possibility that CD40 signaling induced B cell responsiveness to multiple gammac-common cytokines and that individual gammac-common cytokines induced distinct B cell responses. B cells were isolated from lymphoid follicles of sheep Peyer's patches (PP) and co-cultured with murine CD40 ligand (mCD40L). CD40 signaling induced PP B cell responsiveness to recombinant human IL-2, IL-4, IL-7 and IL-15. mCD40L-induced B cell growth was enhanced by combining IL-4 with a second gammac-common cytokine and sustained B cell growth required co-stimulation with IL-4 plus IL-2, IL-7 and IL-15. gammac-common cytokine responsiveness remained dependent upon CD40 signaling, and removal of mCD40L resulted in B cell differentiation and cell death. Similar proliferative responses to mCD40L and gammac-common cytokines were observed for both immature (ileal) and mature (jejunal) PP B cells. Finally, the capacity of CD40-activated B cells to respond to multiple gammac-common cytokines was analyzed with individual PP B cell clones. All B cell clones displayed similar proliferative responses to IL-2 but quantitatively different responses to IL-4, IL-7 and IL-15. The biological significance of B cell responsiveness to multiple gammac-common cytokines is discussed.     

A Novel Molecular Complex Expressed on Immature B Cells: A Possible Role in T Cell-Independent B Cell Development

To identify surface molecules that may play a role in regulating ileal Peyer''s patch (PP) B cell growth, we generated monoclonal antibodies (mAbs) and then selected them for a unique reactivity with ileal PP B cells. Flow cytometric analysis identified a mAb (SIC4.8R) that labeled 97% of ileal and 50–60% of jejunal PP sIgM⁺B cells. SIC4.8R also labeled a subpopulation of cortical thymocytes but few B or T cells in other lymphoid tissues, including bone marrow. Immunohistochemistry revealed intense SIC4.8R staining of B cells in the cortex of ileal PP follicles. SIC4.8R also labeled bovine PP B cells, a murine pro-B cell line, and pre-B cells in human bone marrow. Protein chemistry revealed that a structurally similar molecular complex was expressed on sheep ileal PP B cells and thymocytes and murine pro-B cells. Addition of soluble SIC4.8R to cultured ileal PP B cells reduced apoptotic cell death, elevated proliferative responses, partially inhibited anti-Ig-induced cell death, and induced IL-4 responsiveness. In contrast, soluble SIC4.8R had an antiproliferative effect on a mouse pro-B cell line. Finally, SIC4.8R labeling declined following the stimulation of ileal PP B cells with CD40 ligand. In conclusion, the present investigation determined that SIC4.8R identified a novel molecular complex that is expressed at several stages of T cell-independent B cell development in a variety of mammalian species. This observation confirmed that PP B cells are developmentally distinct from other B cell populations in sheep and suggested that the bone marrow may not be a site of B lymphopoiesis in young lambs.     

Surface expression of differentiation antigens on lymphocytes in the ileal and jejunal Peyer's patches of lambs

The surface phenotype of lymphocytes in the ileal (IPP) and jejunal (JPP) Peyer's patches (PP) of lambs was compared using flow cytometry and immunohistology with a panel of monoclonal antibodies (mAb). The B-cell markers p220, BAS9A and surface Ig molecules were detected on 70-95% of cells from the IPP. T-cell markers were detected on less than 1% of IPP lymphocytes, confirming that the IPP in lambs contains virtually only B lymphocytes. The JPP contained a lower proportion of B cells and 16% T cells, nearly all of which expressed the CD4 molecule. Interestingly, the reactivity of a fourth B-cell markers, BAQ44a, differed from this pattern; only 12% of IPP lymphocytes were positive whereas 70% of JPP lymphocytes expressed this marker. A majority of both IPP and JPP lymphocytes (80-95%) expressed the cell adhesion molecules CD11a (LFA-1) and LFA-3. Other adhesion molecules, such as CD2 and CD44, were expressed by fewer cells from the IPP than from the JPP. MHC class I antigens were detected on more than 95% of lymphocytes from both the IPP and JPP. In the case of MHC class II antigens, more positive cells occurred in the IPP (greater than 95%) than in the JPP (80%). The in situ localization of cell-surface antigens was assessed by immunohistology. CD4+ T cells occurred in the interfollicular T-cell regions and in JPP follicles, whereas CD8+ T cells localized only in the interfollicular regions and were absent from follicles. The pattern of expression of B-cell markers, adhesion molecules and MHC antigens indicated that a gradient of increasing maturity of B cells existed within follicles from the base towards the dome region. The data presented here lend support to the notion that the IPP in lambs represents a novel B-cell lymphoid tissue with a function different from that of the conventional Peyer's patches found in the jejunum.     

Ileal and jejunal Peyer’s patches play distinct roles in mucosal immunity of sheep

The majority of pathogens enter the body through mucosal surfaces and it is now evident that mucosal immunity can provide effective disease protection. However, the induction of mucosal immunity will require efficient targeting of mucosal vaccines to appropriate mucosa-associated lymphoid tissue. An animal model, based upon the surgical preparation of sterile intestinal 'loops' (blind-ended segments of intestine), was developed to evaluate mucosal and systemic immune responses to enteric vaccines in ruminants. The effectiveness of end-to-end intestinal anastomoses was evaluated and fetal surgery did not disrupt normal intestinal function in lambs up to 6-7 months after birth. The immunological competence of Peyer's patches (PP) within the intestinal 'loops' was evaluated with a human adenovirus 5 vector expressing the gD gene of bovine herpesvirus-1. This vaccine vector induced both mucosal and systemic immune responses when injected into intestinal 'loops' of 5-6-week-old lambs. Antibodies to the gD protein were detected in the lumen of intestinal 'loops' and serum and PP lymphocytes proliferated in response to gD protein. The immune competence of ileal and jejunal PP was compared and these analyses confirmed that jejunal PP are an efficient site for the induction of mucosal immune responses. This was confirmed by the presence of gD-specific antibody-secreting cells in jejunal but not ileal PP. Systemic but not mucosal immune responses were detected when the vaccine vector was delivered to the ileal PP. In conclusion, this model provided an effective means to evaluate the immunogenicity of potential oral vaccines and to assess the immunological competence of ileal and jejunal Peyer's patches.     

Immunohistological characterization of proximal colonic lymphoid tissue in the rat.

Proximal colonic lymphoid tissue (PCLT) is a lymphoid structure located in the proximal colon of the mouse and the rat. In the present investigation we studied the immunomorphology and cytology of PCLT in the rat. We also studied sites of lymphocyte proliferation using the BrdU-anti BrdU technique. Results demonstrated no evident phenotypical differences between the lymphocyte populations of PCLT and either jejunal or ileal Peyer's patches (PP). The majority of the lymphocytes within PCLT were B cells localized in follicles, which were separated from each other by interfollicular T cell areas. Germinal centers (GC), containing ED5+ follicular dendritic cells, are found within PCLT follicles. The T cell areas contained both MHC Class II+ interdigitating cells and high endothelial venules. Studies using BrdU-anti BrdU indicated that lymphocyte proliferation within PCLT takes place mainly in germinal centers. Together the data show that the organization, lymphoid constituents, and sites of lymphocyte production are very similar in PCLT and PP. We therefore conclude that PCLT in the rat is not a Bursa equivalent, but more likely a PP with some special characteristics.     

Characterization of B-cell phenotypic changes during ileal and jejunal Peyer's patch development in sheep.

Changes in B-cell phenotype during development of ileal and jejunal Peyer's patches (PP) of sheep were investigated using flow cytometry and immunoperoxidase-stained cryosections. On Day 104 of gestation (term at 150 days) B-cell clusters were identified in the lamina propria of the ileum. These clusters were composed of cells that expressed surface IgM (sIgM), lambda or kappa light chain, and BAQ44A, a B-cell differentiation molecule. No cells in the clusters stained for terminal deoxynucleotide transferase. On Day 132 gestation, a change was evident in the phenotype of ileal PP B cells. Most B cells expressed a reduced level of sIgM and 20% were BAQ44A-. The B cells in the dome region were BAQ44A+ but few BAQ44A+ cells were present in the follicles. At 6-8 weeks of age BAQ44A+ cells were restricted to the dome region of the ileal PP; flow cytometric analysis confirmed that 25% of B cells isolated from the dome/follicle complex were BAQ44A+. Thus, the primordial PP was populated with B cells that were phenotypically similar to circulating B cells (sIgMhigh, BAQ44A+). After 132 days gestation, the predominant B-cell phenotype in the ileal PP changed to sIgMlow and BAQ44A-. This phenotypic change could be the result of either early immigrant B-cell differentiation or subsequent colonization by sIgMlow BAQ44A- B cells. The phenotypic changes of ileal PP follicular B cells were not complete until after birth and different phenotypic changes were observed in follicles of the jejunal PP of young lambs.     

Immunohistological characterization of proximal colonic lymphoid tissue in the rat

Proximal colonic lymphoid tissue (PCLT) is a lymphoid structure located in the proximal colon of the mouse and the rat. In the present investigation we studied the immunomorphology and cytology of PCLT in the rat. We also studied sites of lymphocyte proliferation using the BrdU-anti BrdU technique. Results demonstrated no evident phenotypical differences between the lymphocyte populations of PCLT and either jejunal or ileal Peyer's patches (PP). The majority of the lymphocytes within PCLT were B cells localized in follicles, which were separated from each other by interfollicular T cell areas. Germinal centers (GC), containing ED5⁺ follicular dendritic cells, are found within PCLT follicles. The T cell areas contained both MHC Class II⁺ interdigitating cells and high endothelial venules. Studies using BrdU-anti BrdU indicated that lymphocyte proliferation within PCLT taken place mainly in germinal centers. Together the data show that the organization, lymphoid constituents, and sites of lymphocyte production are very similar in PCLT and PP. We therefore conclude that PCLT in the rats is not a Bursa equivalent, but more likely a PP with some special characteristics. © 1992 Wiley-Liss, Inc.     

Ileal Peyer's patch emigrants are predominantly B cells and travel to all lymphoid tissues in sheep

The ileal Peyer's patch (PP) was selectively labeled with fluorescein isothiocyanate by extracorporeal perfusion in 7-12 week-old lambs and the lymphocyte lineage and fate of the emigrants was determined by fluorescence microscopy and flow cytometry. PP emigrants were found in all tissues examined, accounting for 10%-15% of ileal mesenteric lymph node (MLN). 1%-2% of jejunal MLN, jejunal PP, prescapular lymph node (PLN) and 3%-4% of spleen cells. All ileal PP emigrants enter the ileal MLN on their way to the circulation. Removal of the MLN prior to perfusion enabled emigrants to go directly to the circulation and extravasate in distant tissues faster than in intact animals. The ileal MLN might provide an additional level of regulation for ileal PP emigrants. The perfused ileal PP contained about 25 times more B cells than T cells. The emigrant cells found in different tissues included both T and B cells but came to reflect, although to a lesser degree, the B cell composition of the tissue from which they were derived. One day after perfusion the composition of PP emigrants was similar to that of the tissue within which they were found; the spleen was the exception with a bias towards B cells. By day 3 the ratio of B to T cells in the PP emigrants was 1 for jejunal MLN and PLN. 1.5 for ileal MLN and jejunal PP, and 4-5 for the spleen and blood. It was concluded that the PP-derived T cells were recirculating T cells that were in the ileal PP at the time of perfusion. These cells emigrated rapidly and equilibrated such that they accounted for about 1.5% of the T cell pool in various tissues. Most PP-derived B cells were probably produced in the PP. The greatest contribution (24.4%) that ileal PP emigrants made to the B cell pool of a tissue was with the ileal MLN through which they are obliged to pass. The contribution was lower but still very significant in blood (8.9%), spleen (6.8%), PLN (3.9%), jejunal MLN (3.5%) and jejunal PP (1.8%). There was no evidence that ileal PP emigrants made a greater relative contribution to either T or B cell populations in MLN or jejunal PP than to non-gut-associated sites. The B cells were distributed throughout the immune system, which is in accordance with the proposal that the ileal PP is a site of primary B cell genesis in sheep.     

Peyer's patches in experimental Salmonella dublin infection in calves. Microvascular and epithelial changes contributing to atrophy of lymphoid follicles.

Six calves were infected per os with Salmonella dublin and killed nine hours to seven days later. Early changes included occlusion of capillaries with a hyaline material, particularly in the ileal Peyer's patch (PP). Central areas of the follicles contained hemorrhages and edema. In later stages the follicle-associated epithelium (FAE) of both the jejunal and ileal PP was fused with the adjacent epithelium and the follicles were collapsed. As judged from 5'nucleotidase histochemistry, follicles were depleted of lymphocytes whereas reticular cells were retained. Carbonic anhydrase (CA) histochemistry showed a decreased reaction in the ileal FAE and a reduced amount of CA reactive material in the follicles of the ileal PP, indicating loss of FAE differentiation and function. Hyaline material and fibrinous thrombi were seen occluding the blood capillaries and the lymphatics, respectively. The villi were atrophied and covered with thick fibrin deposits. Using antifibrinogen antibodies, immunoperoxidase stained fibrin in the lymphatics and the lumenal deposits but not the hyaline material in the capillaries. Reaction for CA indicated that this hyaline material originated from erythrocytes. Factors contributing to the follicle atrophy may include anoxia due to stasis in the microcirculation with the formation of erythrocyte thrombi, and reduced lymphopoiesis due to a decrease in the stimulating factors provided by the FAE.     

Jejunal and ileal Peyer’s patches in pigs differ in their postnatal development

The postnatal development of the jejunal and ileal Peyer’s patches was studied before and after weaning in 1-, 1.5- and 2-month-old pigs. The follicles of the jejunal Peyer’s patches grew with age and were two times longer and wider in specified pathogen-free and conventional pigs than in germ-free animals, thus indicating an influence of the living microbial antigens from the gut lumen. In germ-free pigs the size of the ileal Peyer’s patch follicles increased between the 1st and 2nd month, whereas in the specified pathogen-free and conventional animals these follicles were comparable in size in all three age groups. In 1- to 1.5-month-old pigs the interfollicular area of jejunal Peyer’s patches was wider (0.1 ± 0.04 mm) than that of the ileal Peyer’s patch (0.04 ± 0.03 mm). Immunohistological studies showed that in germ-free pigs preferentially surface IgM⁺ but few IgA⁺ B cells were present in the follicles, domes and dome epithelia. In specified pathogen-free and conventional pigs the B cells expressed different levels of surface or cytoplasmic IgM or IgA. In all groups studied, more T cells were observed in the jejunal than in the ileal Peyer’s patch. Here, few T lymphocytes were found because of the small interfollicular areas. Small numbers of Null cells were distributed in the interfollicular regions of all animals. The results show that living microbial antigens have a major influence on the jejunal and ileal Peyer’s patches in pigs. The morphological differences between the two types of Peyer’s patches are an indication that they develop differently during postnatal life. So far it remains unclear whether these morphological differences reflect a specific function of the pig’s ileal Peyer’s patch, such as the expansion of the genetically determined B cell repertoire as has been reported for sheep.     

Protein phosphatase 1 is involved in IL-2-induced IL-5 and IL-13 expression in human T cells

IL-2 plays an important role in immunological and other biological functions. This cytokine directly induces the production of several cytokines, such as IL-5 and IL-13. The mechanisms of IL-2-mediated cytokine synthesis are mostly unclear; however, the involvement of IL-2 receptor (IL-2R)β has been suggested. In this study, the signaling molecule downstream of IL-2Rβ was investigated, employing a proteomic approach. Full-length IL-2Rβ and its mutant in which the intracellular component was truncated were introduced in an IL-2Rα- and IL-2Rγ-stably transfected T cell hybridoma, S1. The differential phosphorylation profiles of protein tyrosine residues in these cells upon IL-2 stimulation were examined by two-dimensional gel electrophoresis. The candidate phosphoproteins of interest were re-covered, in-gel digested and mass spectrometry fingerprinted. Among proteins specifically phosphorylated in full-length IL-2Rβ-expressing cells in response to IL-2 stimulation, protein phosphatase (PP)1β and FK506-binding protein 4 were identified. Particularly, PP1β augmented IL-5 and IL-13 expression stimulated by IL-2 but not by anti-CD3 antibody in human peripheral CD4+ T cells upon ectopic expression. IL-2-induced cytokine expression was suppressed by overexpression of PP1 regulatory subunit 2. A PP1 inhibitor, tautomycin, but not a PP2A inhibitor, okadaic acid, also inhibited the IL-2R-mediated responses. It was conclusively shown that PP1 is crucially involved in IL-2-mediated IL-5 and IL-13 synthesis in human T cells.     

Distribution of lymphocyte subsets in the large intestinal lymphoid follicles of lambs

The phenotypes of lymphocytes in the large intestinal patches (LIP) of lambs were examined by flow cytometry and immunohistology, using a panel of monoclonal antibodies (mAb), and compared to those found in the jejunal (JPP) and ileal Peyer's patches (IPP). T-cell markers were detected on 25% of the LIP and JPP lymphocytes by cytofluorometry, and nearly all T cells expressed the CD4 molecule. In contrast, T cells were scarce in the IPP (less than 1%). The B-cell marker p220 was expressed by 74% of the LIP lymphocytes, whereas surface immunoglobulin-positive cells comprised 50-60% of the lymphocyte population. The adhesion molecule CD2 was expressed by a larger proportion of cells from the LIP and JPP than from the IPP, whereas the adhesion molecule CD44 was detected on more IPP lymphocytes. Major histocompatibility complex (MHC) class I antigens were expressed by nearly all lymphocytes from the LIP, JPP and IPP. The LIP contained 70-80% cells with MHC class II expression, whereas the majority of IPP cells (greater than 95%) were MHC class II positive. Immunohistology showed many CD4+ T lymphocytes in the follicles of the LIP and JPP, but none in the IPP follicles. CD8+ lymphocytes were found in the interfollicular areas and were absent from the follicles. The interfollicular areas of the rectal patch contained about 15% tau delta T cells. In contrast, the JPP, IPP and the colon patch at the beginning of spiral colon contained less than 3% tau delta T cells.     

Fetal lambs are depleted of IgM+ cells following a single injection of an anti-IgM antibody early in gestation.

B-cell depleted fetal sheep were created following a single injection of an anti-IgM monoclonal antibody early in gestation. Six sheep fetuses were given a single intraperitoneal injection of a monoclonal antibody directed against IgM at 63 days of gestation (gestation in sheep = 150 days). The fetuses were killed at 138-142 days of gestation and lymphoid tissues were collected for subsequent light microscopy and immunohistochemical examination. The ileal and jejunal Peyer's patch (PP) follicles in four of the six injected fetuses were markedly reduced in size. Cells in the rudimentary follicles of the ileal PP of these animals showed no reactivity for IgM and most were negative for CD45. The dome regions contained many T cells, which were predominantly CD8+ cells and included gamma delta T cells. The interfollicular areas of the PP of the markedly affected fetuses contained large populations of T cells. The spleen and lymph nodes were also markedly depleted of IgM+ cells and these tissues contained only a small, scattered population of weakly IgM+ cells. Follicular accumulations of IgM+ cells were absent. Large populations of T cells were present in the white pulp of the spleen and cortex of the lymph nodes. The liver did not contain IgM+ cells and the medulla of the thymus was depleted of IgM+ cells. The results of this study suggest that a surface IgM+ B-cell population is present in the sheep fetus at 63 days of gestation, which is essential for the colonization of the ileal PP and subsequent B-cell development.     

Increased Expression of Activation-Induced Cytidine Deaminase is Associated with Anti-CCP and Rheumatoid Factor in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is associated with higher levels of autoantibodies and IL-17. Here, we investigated if ectopic lymphoid follicles and peripheral blood mononuclear cells (PBMCs) from RA patients exhibit increased activation-induced cytidine deaminase (AID), and if increased AID is correlated with serum levels of autoantibodies and IL-17. The results of immunohistochemical staining showed that organized AID⁺ germinal centres were observed in six of the 12 RA synovial samples, and AID⁺ cells were found almost exclusively in the B-cell areas of these follicles. Aggregated but not organized lymphoid follicles were found in only one OA synovial sample without AID⁺ cells. Significantly higher levels of AID mRNA ( Aicda ) detected by RT-PCR were found in the PBMCs from RA patients than PBMCs from normal controls ( P  < 0.01). In the PBMCs from RA patients, AID was expressed predominately by the CD10⁺IgM⁺CD20⁺ B-cell population and the percentage of these cells that expressed AID was significantly higher than in normal controls ( P  < 0.01). AID expression in the PBMCs correlated significantly and positively with the serum levels of rheumatoid factor (RF) ( P  ≤ 0.0001) and anti-cyclic citrullinated peptide (CCP) ( P  = 0.0005). Serum levels of IFN-γ ( P  = 0.0005) and IL-17 ( P  = 0.007), but not IL-4, also exhibited positive correlation with the expression of AID. These results suggest that the higher levels of AID expression in B cells of RA patients correlate with, and may be associated with the higher levels of T helper cell cytokines IFN-γ and IL-17, leading to the development of anti-CCP and RF.     

Lesions in subclinical paratuberculosis of goats are associated with persistent gut-associated lymphoid tissue

The organized gut-associated lymphoid tissue (the Peyer's patches [PPs] of domestic ruminants) is an important site of lesions caused by Mycobacterium avium subsp. paratuberculosis. To investigate the association between PP morphology and the lesions of paratuberculosis in goats, two experiments were performed. Five healthy kids aged 4-5 weeks were examined and the morphology of organized lymphoid tissue in the small intestine was described. Morphological similarities were observed between the ileocaecal-valve PP (ICVPP) and the jejunal PPs (JPPs), with pear-shaped follicles, large submucosal interfollicular T-cell areas, and many intraepithelial leucocytes in the follicle-associated epithelium. The ileal PP (IPP) consisted of elongated follicles, small T-cell areas and few intraepithelial leucocytes. The association between these three locations of PPs and lesions of paratuberculosis was then studied in seven goats inoculated with M. a. paratuberculosis at 5-8 weeks of age and killed 2 years later, while in the subclinical phase of infection. Gross lesions were recorded in five animals and microscopic lesions were observed in the intestine and mesenteric lymph nodes of six animals. The lesions in the small intestine were mainly located in the PPs of the mid-jejunum (JPPs) and ICVPP. Lesions were not present in the intestinal segments that had contained IPP, which had undergone involution during the first 12-18 months of life. These observations indicate that the persistent organized lymphoid tissue in the JPPs and ICVPP, but not the involuted IPP, sustains the development of granulomatous inflammation due to paratuberculosis during the subclinical phase of infection.