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Multiple sclerosis is associated with Epstein–Barr virus (EBV) infection, B‐cell dysfunction, gut dysbiosis, and environmental and genetic risk factors, including female sex. A disease model incorporating all these factors remains elusive. Here, we hypothesise that EBV‐infected memory B cells (MBCs) migrate to gut‐associated lymphoid tissue (GALT) through EBV‐induced expression of LPAM‐1, where they are subsequently activated by gut microbes and/or their products resulting in EBV reactivation and compartmentalised anti‐EBV immune responses. These responses involve marginal zone (MZ) B cells that activate CD4+ T‐cell responses, via HLA‐DRB1, which promote downstream B‐cell differentiation towards CD11c+/T‐bet+ MBCs, as well as conventional MBCs. Intrinsic expression of low‐affinity B‐cell receptors (BCRs) by MZ B cells and CD11c+/T‐bet+ MBCs promotes polyreactive BCR/antibody responses against EBV proteins (e.g. EBNA‐1) that cross‐react with central nervous system (CNS) autoantigens (e.g. GlialCAM). EBV protein/autoantigen‐specific CD11c+/T‐bet+ MBCs migrate to the meningeal immune system and CNS, facilitated by their expression of CXCR3, and induce cytotoxic CD8+ T‐cell responses against CNS autoantigens amplified by BAFF, released from EBV‐infected MBCs. An increased abundance of circulating IgA+ MBCs, observed in MS patients, might also reflect GALT‐derived immune responses, including disease‐enhancing IgA antibody responses against EBV and gut microbiota‐specific regulatory IgA+ plasma cells. Female sex increases MZ B‐cell and CD11c+/T‐bet+ MBC activity while environmental risk factors affect gut dysbiosis. Thus, EBV infection, B‐cell dysfunction and other risk factors converge in GALT to generate aberrant B‐cell responses that drive pathogenic T‐cell responses in the CNS. A novel and comprehensive hypothesis for the pathogenesis of multiple sclerosis that incorporates immunological mechanisms and genetic and environmental risk factors is proposed. Activation of Epstein–Barr virus (EBV)‐infected memory B cells (MBCs) residing in gut‐associated lymphoid tissue results in lytic EBV infection that induces compartmentalised immune responses by marginal zone B cells and CD4+ T cells and production of CD11c+/T‐bet+ memory B cells, influenced by genetic and environmental risk factors. EBV‐specific B‐cell receptors and antibodies produced by these B‐cell subpopulations are cross‐reactive with CNS autoantigens and the CD11c+/T‐bet+ MBCs drive CD8+ T‐cell responses against CNS autoantigens.

Human IgM + B cells vary in their surface levels of IgD, with the major circulating population of IgM + IgD + cells and a minor population (< 5%) of IgM + IgD − cells. In contrast, in gut-associated lymphoid tissue (GALT) derived from individuals undergoing tonsillectomy or appendectomy, IgM + IgD − B cells constitute ~ 30% of B cells. IgM + IgD − cells isolated from both tonsil and appendix lack plasma cell and B1 cell markers, and approximately 50% express the memory marker CD27. Functionally, GALT IgM + IgD − cells spontaneously secrete IgM, and class-switch to IgA in response to both T-dependent and T-independent stimulation ex-vivo. Immune repertoire profiling reveals that GALT IgM + IgD − cells exhibit lower levels of VH4-34 rearrangements, higher levels of somatic hypermutation, shorter CDR3 sequences and greater clonal overlap with switch memory cells than IgM + IgD + cells. Furthermore, clonal lineage analysis reveals that IgM + IgD − clones can include class-switched sequence variants. These findings suggest a maturational scheme starting from CD27 − IgM + IgD + B cells to CD27 + IgM + IgD + , and then to CD27 − IgM + IgD − , and finally to CD27 + IgM + IgD − B cells. In sum, IgM + IgD − B cells in the mucosa have memory features, give rise to class-switched memory B cells and antibody-secreting cells, and likely contribute significantly to the IgA repertoire in human GALT.

Paratuberculosis (PTB) is a chronic granulomatous enteritis caused by Mycobacterium avium subsp. paratuberculosis (Map). Vaccination is one of the most cost-effective tools for PTB control, although alternative treatments like the probiotic Dietzia have been explored with promising results. Using a rabbit model, we investigated the association of immunological and microbiota profiles in Gut Associated Lymphoid Tissue (GALT) with the effects in protection induced by the administration of Dietzia spp., the commercial vaccine (Silirum ® ) and the combination of both. The treatment with the probiotic diminished inflammation, but failed to control Map burden, suggesting a detrimental effect. Rabbits treated with the probiotic presented the highest rates of tissue lesion extension, although the immunological profile was not suggestive of an inflammatory state. Map load in both vaccinated groups was similar indicating that both treatments are equally effective in eliminating the infection, suggesting the role of vaccination in eliminating the infection prevails over the immunomodulatory effects of the probiotic. There were slight variations in the presence of some taxonomic groups depending on the treatment, highlighting the complexity of microbial interactions and the need to optimise treatment combinations in the context of each disease and animal species.

The use of functional feeds for farmed fish is now regarded as a key factor in improving fish health and performance against infectious disease. However, the mechanisms by which these nutritional components modulate the immune response are not fully understood. The present study was undertaken to identify the suitability of both primary gut-associated lymphoid tissue (GALT) leucocyte cells and established rainbow trout cell lines as potential alternative methods to test functional feed ingredients prior to full fish feeding trials that can take months to complete. In addition to the primary GALT culture cells, the two rainbow cell lines RTS11 and RTgutGC which are from macrophage and gut epithelial cells, respectively. The cells were stimulated with a variety of pathogen associated molecular patterns (PAMPs) (PHA and Poly I:C) and recombinant rainbow trout IL-1β (rIL-1β), a proinflammatory cytokine, additionally two forms of β-glucan, a prebiotic commonly used aquafeeds were used as stimulants. From this, the suitability of cell models as a health screen for functional feeds was assessed. GALT leucocytes were deemed most effective to act as a health screen over the 4hr time point demonstrating responses to Poly I:C, PHA, and rIL-1β. RTS11 and RTgutGC also responded to the stimulants but did not give a strong T-cell response, most likely reflecting the nature of the cell type as opposed to the mixed cell populations from the primary GALT cell cultures. When stimulated with both forms of β-glucan, GALT leucocytes demonstrated a strong proinflammatory and T-cell response.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae , Bifidobacterium animalis , and Adlercreutzia equolifaciens , while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies.

BackgroundDespite successful ART in people living with HIV infection (PLHIV) they experience increased morbidity and mortality compared with HIV-negative controls. A dominant paradigm is that gut-associated lymphatic tissue (GALT) destruction at the time of primary HIV infection leads to loss of gut integrity, pathological microbial translocation across the compromised gastrointestinal barrier and, consequently, systemic inflammation. We aimed to identify and measure specific changes in the gastrointestinal barrier that might allow bacterial translocation, and their persistence despite initiation of antiretroviral therapy (ART).MethodWe conducted a cross-sectional study of the gastrointestinal (GIT) barrier in PLHIV and HIV-uninfected controls (HUC). The GIT barrier was assessed as follows: in vivo mucosal imaging using confocal endomicroscopy (CEM); the immunophenotype of GIT and circulating lymphocytes; the gut microbiome; and plasma inflammation markers Tumour Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6); and the microbial translocation marker sCD14.ResultsA cohort of PLHIV who initiated ART early, during primary HIV infection (PHI), n=5), and late (chronic HIV infection (CHI), n=7) infection were evaluated for the differential effects of the stage of ART initiation on the GIT barrier compared with HUC (n=6). We observed a significant decrease in the CD4 T-cell count of CHI patients in the left colon (p=0.03) and a trend to a decrease in the terminal ileum (p=0.13). We did not find evidence of increased epithelial permeability by CEM. No significant differences were found in microbial translocation or inflammatory markers in plasma. In gut biopsies, CD8 T-cells, including resident intraepithelial CD103+ cells, did not show any significant elevation of activation in PLHIV, compared to HUC. The majority of residual circulating activated CD38+HLA-DR+ CD8 T-cells did not exhibit gut-homing integrins α4ß7, suggesting that they did not originate in GALT. A significant reduction in the evenness of species distribution in the microbiome of CHI subjects (p=0.016) was observed, with significantly higher relative abundance of the genus Spirochaeta in PHI subjects (p=0.042).ConclusionThese data suggest that substantial, non-specific increases in epithelial permeability may not be the most important mechanism of HIV-associated immune activation in well-controlled HIV-positive patients on antiretroviral therapy. Changes in gut microbiota warrant further study.

Oral administration of Lentinula edodes mycelia extract (L.E.M.) has been shown to stimulate systemic T cell–mediated antitumor immunity and inhibit tumor growth in mice, suggesting its potential to modulate host immune responses. However, the route of this systemic antitumor effect remains unclear. This study focused on gut-associated immune mechanisms by analyzing mesenteric lymph nodes (MLNs), a major component of the gut-associated lymphoid tissue (GALT), and examined whether oral L.E.M. enhances the antitumor efficacy of radiation therapy (RT) in a B16F10-OVA melanoma model. L.E.M. administration upregulated MHC class II and CD86 expression on CD11c + dendritic cells (DCs) in MLNs and significantly increased the proportion of CD103 + subsets, indicating DC maturation within the GALT. In a B16F10-OVA melanoma model treated with X-ray irradiation, L.E.M. further enhanced DC maturation and increased CD8α + DCs in the spleen, accompanied by elevated effector and central memory fractions of CD8 + T cells in peripheral blood. Antigen-specific CD8 + T cells (OVA tetramer + ) were significantly enriched within tumors, and L.E.M. combined with RT achieved greater tumor growth inhibition than RT alone. These findings demonstrate that oral L.E.M. activates GALT-mediated DC and CD8 + T-cell responses, thereby augmenting the antitumor immune effects of RT.

Infectious bursal disease virus (IBDV) is one of the most important infectious diseases of poultry around the world. Gut-associated lymphoid tissues (GALT) are the first line of defense of the host against the infection. The purpose of this study was to investigate the role of innate immune antiviral signaling triggered by Toll-like receptor 3 (TLR3), as well as macrophage activation and cytokine response in the intestinal lamina propria (ILP) cells after the oral challenge of IBDV in relation to IBDV virulence and disease pathogenesis. The results showed that the expression levels of TLR3, IRF7, IFN-α/β and the corresponding downstream antiviral factors OAS, PKR and Mx were all upregulated in the SPF chicken ILP cells at 8 h post-infection (hpi) and 12 hpi. Similarly, macrophages were activated, with the initial macrophage M1 activation observed at 8 hpi, but then it rapidly shifted to a non-protective M2-type. Both Th1 (IFN-γ, TNF-α, IL-12) and Th2 (IL-4 and IL-10) types of cytokines were differentially upregulated during the early stage of infection; however, the Th1 cytokines exhibited stronger activation before 8 hpi compared to those of the Th2 cytokines. Interestingly, differential regulations of gene expression induced by different IBDV strains with different virulence were detected. The HLJ0504-like very virulent (vv) IBDV strain NN1172 induced stronger activation of TLR3-IFN-α/β pathway, macrophages and the Th1/2 cytokines’ expression, compared to those induced by the attenuated strain B87 at 8 hpi and 12 hpi in the ILP cells. In conclusion, the innate antiviral response mediated by the TLR3-IRF7 pathway, macrophage activation and cytokine expression in the GALT cells at the early stage of IBDV infection was differentially modulated, and the HLJ0504-like vvIBDV strain triggered stronger activation than the attenuated vaccine strain, and that may play an important role in the progression of disease.

The intrinsic nervous system of the gut interacts with the gut-associated lymphoid tissue (GALT) via bidirectional neuroimmune interactions. The caecum is an understudied region of the gastrointestinal (GI) tract that houses a large supply of microbes and is involved in generating immune responses. The caecal patch is a lymphoid aggregate located within the caecum that regulates microbial content and immune responses. People with Autism Spectrum Disorder (ASD; autism) experience serious GI dysfunction, including inflammatory disorders, more frequently than the general population. Autism is a highly prevalent neurodevelopmental disorder defined by the presence of repetitive behaviour or restricted interests, language impairment, and social deficits. Mutations in genes encoding synaptic adhesion proteins such as the R451C missense mutation in neuroligin-3 (NL3) are associated with autism and impair synaptic transmission. We previously reported that NL3R451C mice, a well-established model of autism, have altered enteric neurons and GI dysfunction; however, whether the autism-associated R451C mutation alters the caecal enteric nervous system and immune function is unknown. We assessed for gross anatomical changes in the caecum and quantified the proportions of caecal submucosal and myenteric neurons in wild-type and NL3R451C mice using immunofluorescence. In the caecal patch, we assessed total cellular density as well as the density and morphology of Iba-1 labelled macrophages to identify whether the R451C mutation affects neuro-immune interactions. NL3R451C mice have significantly reduced caecal weight compared to wild-type mice, irrespective of background strain. Caecal weight is also reduced in mice lacking Neuroligin-3. NL3R451C caecal ganglia contain more neurons overall and increased numbers of Nitric Oxide (NO) producing neurons (labelled by Nitric Oxide Synthase; NOS) per ganglion in both the submucosal and myenteric plexus. Overall caecal patch cell density was unchanged however NL3R451C mice have an increased density of Iba-1 labelled enteric macrophages. Macrophages in NL3R451C were smaller and more spherical in morphology. Here, we identify changes in both the nervous system and immune system caused by an autism-associated mutation in Nlgn3 encoding the postsynaptic cell adhesion protein, Neuroligin-3. These findings provide further insights into the potential modulation of neural and immune pathways.