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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.

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.

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.

Gut-associated lymphoid tissue (GALT) is crucial for the maintenance of the intestinal homeostasis, but it is also the potential site of the activation of autoreactive cells and initiation/propagation of autoimmune diseases in the gut and in the distant organs. Type 3 innate lymphoid cells (ILC3) residing in the GALT integrate signals from food ingredients and gut microbiota metabolites in order to control local immunoreactivity. Notably, ILC3 secrete IL-17 and GM-CSF that activate immune cells in combating potentially pathogenic microorganisms. ILC3 also produce IL-22 that potentiates the strength and integrity of epithelial tight junctions, production of mucus and antimicrobial peptides thus enabling the proper function of the intestinal barrier. The newly discovered function of small intestine ILC3 is the secretion of IL-2 and the promotion of regulatory T cell (Treg) generation and function. Since the intestinal barrier dysfunction, together with the reduction in small intestine ILC3 and Treg numbers are associated with the pathogenesis of type 1 diabetes (T1D), the focus of this article is intestinal ILC3 modulation for the therapy of T1D. Of particular interest is free fatty acids receptor 2 (FFAR2), predominantly expressed on intestinal ILC3, that can be stimulated by available selective synthetic agonists. Thus, we propose that FFAR2-based interventions by boosting ILC3 beneficial functions may attenuate autoimmune response against pancreatic β cells during T1D. Also, it is our opinion that treatments based on ILC3 stimulation by functional foods can be used as prophylaxis in individuals that are genetically predisposed to develop T1D.

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.

It is well known that enteric bacterial antigens drive the development of chronic colitis in a variety of different mouse models of the inflammatory bowel diseases (IBD). The objective of this study was to evaluate the role of gut-associated lymphoid tissue (GALT; Peyer's patches, isolated lymphoid follicles), mesenteric lymph nodes (MLNs) and spleen in the pathogenesis of chronic colitis in mice.MethodsSurgical as well as genetic approaches were used to generate lymphopenic mice devoid of one or more of these lymphoid tissues. For the first series of studies, we subjected recombinase activating gene-1-deficient mice (RAG−/−) to sham surgery (Sham), mesenteric lymphadenectomy (MLNx), splenectomy (Splx) or both (MLNx/Splx). In a second series of studies we intercrossed lymphotoxinβ-deficient (LTβ−/−) mice with RAG−/− animals to generate LTβ−/− x RAG−/− offspring that were anticipated to contain functional MLNs but be devoid of GALT and most peripheral lymph nodes. Flow purified naïve (CD4+CD45RBhigh) T-cells were adoptively transferred into the different groups of RAG−/− recipients to induce chronic colitis.ResultsWe found that at 3-5 wks following T-cell transfer, all four of the surgically-manipulated RAG−/− groups (Sham, MLNx, Splx and MLNx/Splx) developed chronic colitis that was similar in onset and severity. Flow cytometric analysis revealed no differences among the different groups with respect to surface expression of different gut-homing markers nor were there any differences noted in IFN-γ and IL-17 generation by mononuclear cells isolated among these surgically-manipulated mice. Although we anticipated that LTβ−/− x RAG−/− mice would contain functional MLNs but be devoid of GALT and peripheral lymph nodes (PLNs), we found that LTβ−/− x RAG−/−mice were in fact devoid of MLNs as well as GALT and PLNs. Adoptive transfer of CD45RBhigh T-cells into LTβ−/− x RAG−/− mice or their littermate controls (LTβ+/+ x RAG−/−) induced rapid and severe colitis in both groups.ConclusionsTaken together, our data demonstrate that: a) neither the GALT, MLNs nor PLNs are required for induction of chronic gut inflammation in this model of IBD and b) T-and/or B-cells may be required for the development of MLNs in LTβ−/− mice. (Inflamm Bowel Dis 2011;)

Red hybrid tilapia were fed a formalin-killed oral Streptococcus iniae vaccine (FKV) in the present study was assessed. Three hundred Red hybrid tilapia 80 ± 10 g were divided into five groups (1A, 1B, 2A, 2B, and Cx), each consisting of 60 fish. Fish from Groups 1A, 1B, 2A, and 2B were fed with FKV over different periods of administration, while Group 2B was the only group of fish to receive an oral booster vaccination on day 14- and 21-days post-vaccination (dpv). Group Cx was fed with normal pellets containing no vaccine as a control group. At four weeks post-vaccination (wpv), all fish were experimentally infected with S. iniae. Groups 2A and 2B had the lowest level of mortalities following vaccination (45% and 30%, respectively) compared to Groups 1A and 1B (80% and 55%, respectively), while the level of mortalities in Group Cx was 100%. All vaccinated groups showed a significant increase in anti-S. iniae IgM levels (p < 0.05) in serum, mucus, and gut-lavage, while Group Cx did not (p > 0.05) and all fish in this group died by five weeks post-infection. In conclusion, fish fed with the S. iniae FKV had a greater level of protection against S. iniae, with increased specific antibody response to the vaccine and there was also evidence of GALT stimulation by the vaccine.

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.

The intestine and the gut-associated lymphoid tissue (GALT) are essential components of whole body immune defense, protecting the body from foreign antigens and pathogens, while allowing tolerance to commensal bacteria and dietary antigens. The requirement for protein to support the immune system is well established. Less is known regarding the immune modifying properties of individual amino acids, particularly on the GALT. Both oral and parenteral feeding studies have established convincing evidence that not only the total protein intake, but the availability of specific dietary amino acids (in particular glutamine, glutamate, and arginine, and perhaps methionine, cysteine and threonine) are essential to optimizing the immune functions of the intestine and the proximal resident immune cells. These amino acids each have unique properties that include, maintaining the integrity, growth and function of the intestine, as well as normalizing inflammatory cytokine secretion and improving T-lymphocyte numbers, specific T cell functions, and the secretion of IgA by lamina propria cells. Our understanding of this area has come from studies that have supplemented single amino acids to a mixed protein diet and measuring the effect on specific immune parameters. Future studies should be designed using amino acid mixtures that target a number of specific functions of GALT in order to optimize immune function in domestic animals and humans during critical periods of development and various disease states.