Fibroblastic reticular cell lineage convergence in Peyer's patches governs intestinal immunity.

Fibroblastic reticular cells (FRCs) determine the organization of lymphoid organs and control immune cell interactions. While the cellular and molecular mechanisms underlying FRC differentiation in lymph nodes and the splenic white pulp have been elaborated to some extent, in Peyer's patches (PPs) they remain elusive. Using a combination of single-cell transcriptomics and cell fate mapping in advanced mouse models, we found that PP formation in the mouse embryo is initiated by an expansion of perivascular FRC precursors, followed by FRC differentiation from subepithelial progenitors. Single-cell transcriptomics and cell fate mapping confirmed the convergence of perivascular and subepithelial FRC lineages. Furthermore, lineage-specific loss- and gain-of-function approaches revealed that the two FRC lineages synergistically direct PP organization, maintain intestinal microbiome homeostasis and control anticoronavirus immune responses in the gut. Collectively, this study reveals a distinct mosaic patterning program that generates key stromal cell infrastructures for the control of intestinal immunity.

CD32 expressing doublets in HIV-infected gut-associated lymphoid tissue are associated with a T follicular helper cell phenotype.

Gut-associated lymphoid tissue (GALT) is a key location for the HIV reservoir. The observation that B-cell-T-cell doublets are enriched for CD32a (a low-affinity IgG receptor) in peripheral blood raises interesting questions, especially as these cells have been associated with HIV DNA in some studies. We sought to determine if similar doublets were present in GALT, the significance of these doublets, and their implications for the HIV reservoir. Given the importance of GALT as a reservoir for HIV, we looked for expression of CD32 on gut CD4 T cells and for evidence of doublets, and any relationship with HIV DNA in HIV + individuals initiated on antiretroviral therapy (ART) during primary HIV infection (PHI). Tonsil tissue was also available for one individual. As previously shown for blood, CD32high CD4 cells were mainly doublets of CD4 T cells and B cells, with T-cell expression of ICOS in tonsil and gut tissue. CD4 T cells associated with CD32 (compared with 'CD32-' CD4 cells) had higher expression of follicular markers CXCR5, PD-1, ICOS, and Bcl-6 consistent with a T follicular helper (TFH) phenotype. There was a significant correlation between rectal HIV DNA levels and CD32 expression on TFH cells. Together, these data suggest that CD32high doublets are primarily composed of TFH cells, a subset known to be preferentially infected by HIV.

Porcine deltacoronavirus induces TLR3, IL-12, IFN-α, IFN-ß and PKR mRNA expression in infected Peyer's patches in vivo.

Porcine deltacoronavirus (PDCoV) is a newly identified swine enteropathogenic coronavirus that causes watery diarrhea in piglets and results in significant economic losses to the pig industry. Currently there are no effective treatments or vaccines for PDCoV. In particular, the pathogenesis of PDCoV infection is still largely unknown. In this study, we reported that inoculating conventional weaned piglets with 1 × 109 TCID50 of the PDCoV CHN-GD-2016 strain by oral feeding could cause severe diarrhea. Virus RNA was detected in rectal swabs from 1 to 7 days post inoculation. In addition, microscopic lesions in small intestine were observed, and viral antigen also detected in the small intestines with PDCoV immunohistochemical staining. Importantly, PDCoV significantly induced mRNA expression of TLR3, IL-12, IFN-α, IFN-ß, and PKR, the genes involved in modulation of the host immune responses, in infected Peyer's patches at 3 d.p.i., indicating that Peyer's patches play an important role in PDCoV immune responses in vivo. Collectively, our findings suggest that the observed gene expression profile might help explain immunological and pathological changes associated with PDCoV infection.

Experimental infection of mice with noncytopathic bovine viral diarrhea virus 2 increases the number of megakaryocytes in bone marrow.

BACKGROUND: Bovine viral diarrhea virus (BVDV) causes significant economic losses worldwide in the cattle industry through decrease in productive performance and immunosuppression of animals in herds. Recent studies conducted by our group showed that mice can be infected with BVDV-1 by the oral route. The purpose of this study was to assess the clinical signs, hematological changes, histopathological lesions in lymphoid tissues, and the distribution of the viral antigen after oral inoculation with a Korean noncytopathic (ncp) BVDV-2 field isolate in mice. METHODS: Mice were orally administered a low or high dose of BVDV-2; blood and tissue samples were collected on days 2, 5, and 9 postinfection (pi). We monitored clinical signs, hematological changes, histopathological lesions, and tissue distribution of a viral antigen by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) and then compared these parameters with those in ncp BVDV-1 infections. RESULTS: None of the infected mice developed any clinical signs of the illness. Significant thrombocytopenia was found in both low- and high-dose-inoculated mice on day 2 pi. Leukopenia was apparent only in low-dose-inoculated mice on day 2 pi, whereas lymphopenia was not observed in any ncp BVDV-2-infected animal. Viral RNA was found in the spleen in of low- and high-dose-inoculated mice by RT-PCR. According to the results of IHC, the viral antigen was consistently detected in lymphocytes of bone marrow and spleen and less frequently in bronchus-associated lymphoid tissue (BALT), mesenteric lymph nodes, and Peyer's patches. Despite the antigen detection in BALT and mesenteric lymph nodes, histopathological lesions were not observed in these tissues. Lympholysis, infiltration by inflammatory cells, and increased numbers of megakaryocytes were seen in Peyer's patches, spleens, and bone marrow, respectively. In contrast to ncp BVDV-1 infection, lympholysis was found in the spleen of ncp BVDV-2-infected mice. These histopathological lesions were more severe in high-dose-inoculated mice than in low-dose-inoculated mice. CONCLUSIONS: Our results provide insight into the pathogenesis of ncp BVDV-2 infection in mice. Collectively, these results highlight significant differences in pathogenesis between ncp BVDV-1 and ncp BVDV-2 infections in a murine model.

Experimental bovine rotavirus-A (RV-A)infection causes intestinal and extra-intestinal pathology in suckling mice.

We describe here the intestinal and extra-intestinal spread of the species A rotavirus (RV-A) and associated lesions thereof in Swiss albino suckling mice pups, inoculated with a bovine-origin RV-A strain. In total, 35 suckling pups were used, wherein 20 pups received cell culture isolated RV-A @ 160 µL (TCID50/ml, 5 × 106.5) per pup [oral 80 µL and intra peritoneal (IP) 80 µL] and served as an infected group, while 15 pups were kept in the control group and inoculated the same volume of phosphate buffered saline (PBS) of neutral pH orally and IP. Four pups from the infected group and 3 from control group were sacrificed at 3, 5, 7, 9 and 12 day post infection (DPI). Of note, infected pups exhibited signs of dullness and restlessness till 5DPI, but none showed diarrhea at any point of time. No appreciable gross lesions were evident in any of the organs, except for mild congestion of the small intestine and yellowish catarrhal smearing over the luminal surface. However, light microscopic lesions in hematoxylin and eosin (H&E) stained sections of jejunum and ileum revealed vacuolation and pyknosis of nuclei of the mature enterocytes, their lysis and detachment, constriction and detachment of villi, mild mononuclear cells (MNCs) infiltration in the lamina propria and mildcell depletion of Peyer's patches and mesenteric lymph nodes (MLN). The extra-intestinal lesions of the cellular degeneration and mild MNCs infiltration were identified in the liver and kidneys from 3 to 7 DPI, but no lesion was seen in the brain. Interstitial thickening with MNCs of lung parenchyma was visible from 3 to 7 DPI. The lesions in the intestine, lymphoid tissues and lungs resolved after 7 DPI. The presence of viral nucleic acid was seen in the intestinal contents from 3 to 5 DPI by using a RV-A specific reverse-transcription polymerase chain reaction (RT-PCR), while in the MLNs and the lungs it could be detected till 5 DPI by both the RT-PCR and direct fluorescent antigen test (dFAT). However, liver, spleen and brain were tested negative for the presence of RV-A by any of these tests. Nonetheless, the persistence of the RV-A was seen in the MLNs even after the absence of virus from the small intestines. Findings here conclusively indicates that heterologous host origin RV-A has an affinity not only to the intestine but also to extra-intestinal tissues like MLNs and lung tissues.

Simian Varicella Virus Infects Enteric Neurons and α4ß7 Integrin-Expressing Gut-Tropic T-Cells in Nonhuman Primates.

The pathogenesis of enteric zoster, a rare debilitating complication of reactivation of latent varicella-zoster virus (VZV) in the enteric nervous system (ENS), is largely unknown. Infection of monkeys with the closely related Varicellovirus simian varicella virus (SVV) mimics VZV disease in humans. In this study, we determined the applicability of the SVV nonhuman primate model to study Varicellovirus infection of the ENS. We confirmed VZV infection of the gut in latently infected adults and demonstrated that SVV DNA was similarly present in gut of monkeys latently infected with SVV using quantitative real-time PCR. In situ analyses showed that enteric neurons expressed SVV open reading frame (ORF) 63 RNA, but not viral nucleocapsid proteins, suggestive of latent ENS infection. During primary infection, SVV-infected T-cells were detected in gut-draining mesenteric lymph nodes and located in close vicinity to enteric nerves in the gut. Furthermore, flow cytometric analysis of blood from acutely SVV-infected monkeys demonstrated that virus-infected T-cells expressed the gut-homing receptor α4ß7 integrin. Collectively, the data demonstrate that SVV infects ENS neurons during primary infection and supports the role of T-cells in virus dissemination to the gut. Because SVV reactivation can be experimentally induced, the SVV nonhuman primate model holds great potential to study the pathogenesis of enteric zoster.

Jaagsiekte Sheep Retrovirus Can Reach Peyer's Patches and Mesenteric Lymph Nodes of Lambs Nursed by Infected Mothers.

Ovine pulmonary adenocarcinoma (OPA) is a contagious lung cancer of sheep caused by jaagsiekte sheep retrovirus (JSRV). It is generally accepted that transmission by the respiratory route occurs under natural conditions. However recent studies strongly indicate that JSRV can also be transmitted to lambs perinatally via colostrum and milk (C/M). The aim of this work was to confirm that C/M can transmit JSRV infection to lambs under natural conditions and investigate the initial events associated with this transmission route. We have analyzed the presence of JSRV in C/M samples from 22 naturally infected, asymptomatic ewes throughout a lactation period, and in various tissues collected from a group of 36 of their lambs that were fed naturally. The lambs were euthanized at 12, 24, 48, and 72 hours and at 5 and 10 days after birth. We detected JSRV-provirus by PCR in the somatic C/M cells from 10/22 ewes (45.45%). The virus was also detected in 9/36 lambs (25%). JSRV-infected cells, with lymphoreticular-like morphology, were observed by immunohistochemistry (IHC) and in situ hybridization (ISH) in Peyer's patches (PP) from the small intestine of the youngest lambs and in mesenteric lymph nodes (MLN) from lambs older than 72 hours. The virus was also detected by PCR in white blood cells (WBC) in 2/36 lambs (5.5%). These results confirm colostral transmission of JSRV to lambs under natural conditions. Infected lymphoreticular cells contained in C/M appear to be involved. These cells can cross the intestinal barrier of newborn lambs, reach the MLN and enter into circulation.

Oral Norovirus Infection Is Blocked in Mice Lacking Peyer's Patches and Mature M Cells.

UNLABELLED: A critical early step in murine norovirus (MNV) pathogenesis is crossing the intestinal epithelial barrier to reach the target cells for replication, i.e., macrophages, dendritic cells, and B cells. Our previous work showed that MNV replication decreases in the intestines of mice conditionally depleted of microfold (M) cells. To define the importance of Peyer's patch (PP) M cells during MNV pathogenesis, we used a model of BALB/c mice deficient in recombination-activating gene 2 (Rag2) and the common gamma chain (γc) (Rag-γc(-/-)), which lack gut-associated lymphoid tissues (GALT), such as Peyer's patches, and mature GP2(+) M cells. Rag-γc(-/-) mice were infected intraperitoneally or perorally with MNV-1 or CR3 for 24 or 72 h. Although the intestinal laminae propriae of Rag-γc(-/-) mice have a higher frequency of certain MNV target cells (dendritic cells and macrophages) than those of wild-type mice and lack others (B cells), Rag-γc(-/-) and wild-type BALB/c mice showed relatively similar viral loads in the intestine following infection by the intraperitoneal route, which provides direct access to target cells. However, Rag-γc(-/-) mice were not productively infected with MNV by the oral route, in which virions must cross the intestinal epithelial barrier. These data are consistent with a model whereby PP M cells are the primary route by which MNV crosses the intestinal epithelia of BALB/c mice. IMPORTANCE: Noroviruses (NoVs) are prevalent pathogens that infect their hosts via the intestine. Identifying key factors during the initial stages of virus infection in the host may provide novel points of intervention. Microfold (M) cells, antigen-sampling cells in the intestine, were previously shown to provide a gateway for murine NoV (MNV) into the host, but the relative importance of this uptake pathway remained unknown. Here we show that the absence of gut-associated lymphoid tissues (GALT), such as Peyer's patches, which contain high numbers of mature M cells, renders BALB/c mice refractory to oral infection with MNV. These findings are consistent with the model that M cells represent the primary route by which MNV crosses the intestinal epithelial barrier and infects underlying immune cells during a productive infection.

Identification of a novel cellular target and a co-factor for norovirus infection - B cells & commensal bacteria.

Human noroviruses are a leading cause of gastroenteritis worldwide but research on these important enteric pathogens has long been restricted by their uncultivability. Extensive efforts to infect intestinal epithelial cells with murine and human noroviruses in vitro have been thus far unsuccessful while murine noroviruses efficiently and lytically infect innate immune cells including macrophages and dendritic cells. We have recently discovered that murine and human noroviruses infect B cells in vitro. The nature of B cell infection was distinct from innate immune cell infection in that mature B cells were infected noncytopathically in contrast to the lytic infection of macrophages and dendritic cells. Human norovirus infection of B cells was facilitated by commensal bacteria expressing an appropriate histo-blood group antigen. Importantly, we used the mouse model of norovirus infection to confirm that Peyer's patch B cells are infected, and that commensal bacteria stimulate infection, in vivo.

Enteric bacteria promote human and mouse norovirus infection of B cells.

The cell tropism of human noroviruses and the development of an in vitro infection model remain elusive. Although susceptibility to individual human norovirus strains correlates with an individual's histo-blood group antigen (HBGA) profile, the biological basis of this restriction is unknown. We demonstrate that human and mouse noroviruses infected B cells in vitro and likely in vivo. Human norovirus infection of B cells required the presence of HBGA-expressing enteric bacteria. Furthermore, mouse norovirus replication was reduced in vivo when the intestinal microbiota was depleted by means of oral antibiotic administration. Thus, we have identified B cells as a cellular target of noroviruses and enteric bacteria as a stimulatory factor for norovirus infection, leading to the development of an in vitro infection model for human noroviruses.

Diminished viral control during simian immunodeficiency virus infection is associated with aberrant PD-1hi CD4 T cell enrichment in the lymphoid follicles of the rectal mucosa.

The inhibitory receptor programmed death-1 (PD-1) has been shown to regulate CD8 T cell function during chronic SIV infection; however, its role on CD4 T cells, specifically in the gut-associated lymphoid tissue, is less well understood. In this study, we show that a subset of CD4 T cells expresses high levels of PD-1 (PD-1(hi)) in the rectal mucosa, a preferential site of virus replication. The majority of these PD-1(hi) CD4 T cells expressed Bcl-6 and CXCR5, markers characteristic of T follicular helper cells in the lymph nodes. Following a pathogenic SIV infection, the frequency of PD-1(hi) cells (as a percentage of CD4 T cells) dramatically increased in the rectal mucosa; however, a significant fraction of them did not express CXCR5. Furthermore, only a small fraction of PD-1(hi) cells expressed CCR5, and despite this low level of viral coreceptor expression, a significant fraction of these cells were productively infected. Interestingly, vaccinated SIV controllers did not present with this aberrant PD-1(hi) CD4 T cell enrichment, and this lack of enrichment was associated with the presence of higher frequencies of SIV-specific granzyme B(+) CD8 T cells within the lymphoid tissue, suggesting a role for antiviral CD8 T cells in limiting aberrant expansion of PD-1(hi) CD4 T cells. These results highlight the importance of developing vaccines that enhance antiviral CD8 T cells at sites of preferential viral replication and support the need for developing therapeutic interventions that limit expansion of SIV(+)PD-1(hi) CD4 T cells at mucosal sites as a means to enhance viral control.

Latency locus complements MicroRNA 155 deficiency in vivo.

MicroRNA-155 (miR-155) is expressed in many cancers. It also executes evolutionary conserved functions in normal B cell development. We show that the Kaposi's sarcoma-associated herpesvirus (KSHV) latency locus, which contains an ortholog of miR-155, miR-K12-11, complements B cell deficiencies in miR-155 knockout mice. Germinal center (GC) formation was rescued in spleen, lymph node, and Peyer's patches. Immunoglobulin levels were restored. This demonstrates that KSHV can complement the normal, physiological function of miR-155.

Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice.

Early in the course of infection, detection of pathogen-associated molecular patterns by innate immune receptors can shape the subsequent adaptive immune response. Here we investigate the influence of virus-associated innate immune activation on lymphocyte distribution in secondary lymphoid organs. We show for the first time that virus infection of mice induces rapid disruption of the Peyer's patches but not of other secondary lymphoid organs. The observed effect was not dependent on an active infectious process, but due to innate immune activation and could be mimicked by virus-associated molecular patterns such as the synthetic double-stranded RNA poly(I:C). Profound histomorphologic changes in Peyer's patches were associated with depletion of organ cellularity, most prominent among the B-cell subset. We demonstrate that the disruption is entirely dependent on type I interferon (IFN). At the cellular level, we show that virus-associated immune activation by IFN-α blocks B-cell trafficking to the Peyer's patches by downregulating expression of the homing molecule α4ß7-integrin. In summary, our data identify a mechanism that results in type I IFN-dependent rapid but reversible disruption of intestinal lymphoid organs during systemic viral immune activation. We propose that such rerouted lymphocyte trafficking may impact the development of B-cell immunity to systemic viral pathogens.

Innate and adaptive immune mechanisms are effectively induced in ileal Peyer's patches of Salmonella typhimurium infected pigs.

In this report we employed laser-capture microdissection (LCM) coupled to qPCR technology and bioinformatic analysis to characterize, for the first time, the response of Peyer's patches (PP) from orally infected animals to Salmonella typhimurium, in a model of non-typhoidal salmonellosis. Pathogen was highly found in the cytoplasm of phagocytes in PP and differential gene expression analysis indicated an up-regulation of proinflammatory molecules, establishment of a Th1 driven response and triggering of DC and T-cell activity. Furthermore, predictions by bioinformatic analysis pointed to an activation of processes regarding stimulation and maturation of DC, influx of leukocytes in tissue and T lymphocytes priming and differentiation. In short, the approach used in this study proved to be a promising strategy to explore infectious processes. Indeed, it revealed an effective induction of innate and adaptive immune mechanisms in swine PP which appear to be distinct from those observed in mesenteric lymph nodes and closely related to response of gut mucosa.

Preliminary findings of a previously unrecognized porcine primary immunodeficiency disorder.

Weaned pigs from a line bred for increased feed efficiency were enrolled in a study of the role of host genes in the response to infection with Porcine Reproductive and Respiratory Syndrome Virus (PRRSV). Four of the pigs were euthanatized early in the study due to weight loss with illness and poor body condition; 2 pigs before PRRSV infection and the other 2 pigs approximately 2 weeks after virus inoculation. The 2 inoculated pigs failed to produce PRRSV-specific antibodies. Gross findings included pneumonia, absence of a detectable thymus, and small secondary lymphoid tissues. Histologically, lymph nodes, spleen, tonsils, and Peyer's patches were sparsely cellular with decreased to absent T and B lymphocytes.

18ß-glycyrrhetinic acid delivered orally induces isolated lymphoid follicle maturation at the intestinal mucosa and attenuates rotavirus shedding.

Glycyrrhizin, an abundant bioactive component of the medicinal licorice root is rapidly metabolized by gut commensal bacteria into 18ß-glycyrrhetinic acid (GRA). Either or both of these compounds have been shown to have antiviral, anti-hepatotoxic, anti-ulcerative, anti-tumor, anti-allergenic and anti-inflammatory activity in vitro or in vivo. In this study, the ability of GRA to modulate immune responses at the small intestinal mucosa when delivered orally was investigated. Analysis of cytokine transcription in duodenal and ileal tissue in response to GRA treatment revealed a pattern of chemokine and chemokine receptor gene expression predictive of B cell recruitment to the gut. Consistent with this finding, GRA induced increases in CD19(+) B cells in the lamina propria and B220(+) B cell aggregates framed by CD11c(+) dendritic cells in structures resembling isolated lymphoid follicles (ILF). Using a mouse model of rotavirus infection, GRA reduced the duration of viral antigen shedding, and endpoint serum antibody titers were higher in GRA-treated animals. Together the data suggest GRA delivered orally augments lymphocyte recruitment to the intestinal mucosa and induces maturation of B cell-rich ILF independently of ectopic antigenic stimulus. These results provide further support a role for dietary ligands in modulation of dynamic intestinal lymphoid tissue.

Prevention of virus-induced type 1 diabetes with antibiotic therapy.

Microbes were hypothesized to play a key role in the progression of type 1 diabetes (T1D). We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to test the hypothesis that the intestinal microbiota is involved in the mechanism leading to islet destruction. Treating LEW1.WR1 rats with KRV and a combination of trimethoprim and sulfamethoxazole (Sulfatrim) beginning on the day of infection protected the rats from insulitis and T1D. Pyrosequencing of bacterial 16S rRNA and quantitative RT-PCR indicated that KRV infection resulted in a transient increase in the abundance of Bifidobacterium spp. and Clostridium spp. in fecal samples from day 5- but not day 12-infected versus uninfected animals. Similar alterations in the gut microbiome were observed in the jejunum of infected animals on day 5. Treatment with Sulfatrim restored the level of intestinal Bifidobacterium spp. and Clostridium spp. We also observed that virus infection induced the expression of KRV transcripts and the rapid upregulation of innate immune responses in Peyer's patches and pancreatic lymph nodes. However, antibiotic therapy reduced the virus-induced inflammation as reflected by the presence of lower amounts of proinflammatory molecules in both the Peyer's patches and pancreatic lymph nodes. Finally, Sulfatrim treatment reduced the number of B cells in Peyer's patches and downmodulated adaptive immune responses to KRV, but did not interfere with antiviral Ab responses or viral clearance from the spleen, pancreatic lymph nodes, and serum. The data suggest that gut microbiota may be involved in promoting virus-induced T1D in the LEW1.WR1 rat model.

Trafficking and replication patterns reveal splenic macrophages as major targets of dengue virus in mice.

Human postmortem studies of natural dengue virus (DENV) infection have reported systemically distributed viral antigen. Although it is widely accepted that DENV infects mononuclear phagocytes, the sequence in which specific tissues and cell types are targeted remains uncharacterized. We previously reported that mice lacking alpha/beta and gamma interferon receptors permit high levels of DENV replication and show signs of systemic disease (T. R. Prestwood et al., J. Virol. 82:8411-8421, 2008). Here we demonstrate that within 6 h, DENV traffics to and replicates in both CD169(+) and SIGN-R1(+) macrophages of the splenic marginal zone or draining lymph node, respectively, following intravenous or intrafootpad inoculation. Subsequently, high levels of replication are detected in F4/80(+) splenic red pulp macrophages and in the bone marrow, lymph nodes, and Peyer's patches. Intravenously inoculated mice begin to succumb to dengue disease 72 h after infection, at which time viral replication occurs systemically, except in lymphoid tissues. In particular, high levels of replication occur in CD68(+) macrophages of the kidneys, heart, thymus, and gastrointestinal tract. Over the course of infection, proportionately large quantities of DENV traffic to the liver and spleen. However, late during infection, viral trafficking to the spleen decreases, while trafficking to the liver, thymus, and kidneys increases. The present study demonstrates that macrophage populations, initially in the spleen and other lymphoid tissues and later in nonlymphoid tissues, are major targets of DENV infection in vivo.

Default in plasma and intestinal IgA responses during acute infection by simian immunodeficiency virus.

BACKGROUND: Conflicting results regarding changes in mucosal IgA production or in the proportions of IgA plasma cells in the small and large intestines during HIV-infection have been previously reported. Except in individuals repeatedly exposed to HIV-1 but yet remaining uninfected, HIV-specific IgAs are frequently absent in mucosal secretions from HIV-infected patients. However, little is known about the organization and functionality of mucosal B-cell follicles in acute HIV/SIV infection during which a T-dependent IgA response should have been initiated. In the present study, we evaluated changes in B-cell and T-cell subsets as well as the extent of apoptosis and class-specific plasma cells in Peyer's Patches, isolated lymphoid follicles, and lamina propria. Plasma levels of IgA, BAFF and APRIL were also determined. RESULTS: Plasma IgA level was reduced by 46% by 28 days post infection (dpi), and no IgA plasma cells were found within germinal centers of Peyer's Patches and isolated lymphoid follicles. This lack of a T-dependent IgA response occurs although germinal centers remained functional with no sign of follicular damage, while a prolonged survival of follicular CD4+ T-cells and normal generation of IgG plasma cells is observed. Whereas the average plasma BAFF level was increased by 4.5-fold and total plasma cells were 1.7 to 1.9-fold more numerous in the lamina propria, the relative proportion of IgA plasma cells in this effector site was reduced by 19% (duodemun) to 35% (ileum) at 28 dpi. CONCLUSION: Our data provide evidence that SIV is unable to initiate a T-dependent IgA response during the acute phase of infection and favors the production of IgG (ileum) or IgM (duodenum) plasma cells at the expense of IgA plasma cells. Therefore, an early and generalized default in IgA production takes place during the acute of phase of HIV/SIV infection, which might impair not only the virus-specific antibody response but also IgA responses to other pathogens and vaccines as well. Understanding the mechanisms that impair IgA production during acute HIV/SIV infection is crucial to improve virus-specific response in mucosa and control microbial translocation.