Interrelation of Diet, Gut Microbiome, and Autoantibody Production

B cells possess a predominant role in adaptive immune responses via antibodydependent and -independent functions. The microbiome of the gastrointestinal tract is currently being intensively investigated due to its profound impact on various immune responses, including B cell maturation, activation, and IgA antibody responses. Recent findings have demonstrated the interplay between dietary components, gut microbiome, and autoantibody production. “Western” dietary patterns, such as high fat and high salt diets, can induce alterations in the gut microbiome that in turn affects IgA responses and the production of autoantibodies. This could contribute to multiple pathologies including autoimmune and inflammatory diseases. Here, we summarize current knowledge on the influence of various dietary components on B cell function and (auto)antibody production in relation to the gut microbiota, with a particular focus on the gut–brain axis in the pathogenesis of multiple sclerosis.MK was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (640116), by a SALK-grant from the government of Flanders, Belgium, and by an Odysseus grant of the Research Foundation Flanders, Belgium (FWO). JF is a postdoctoral fellow of the FWO.B cells; autoantibodies; diet; microbiome; multiple sclerosis; experimental autoimmune encephalomyeliti

Interrelation of Diet, Gut Microbiome, and Autoantibody Production

B cells possess a predominant role in adaptive immune responses via antibody-dependent and -independent functions. The microbiome of the gastrointestinal tract is currently being intensively investigated due to its profound impact on various immune responses, including B cell maturation, activation, and IgA antibody responses. Recent findings have demonstrated the interplay between dietary components, gut microbiome, and autoantibody production. “Western” dietary patterns, such as high fat and high salt diets, can induce alterations in the gut microbiome that in turn affects IgA responses and the production of autoantibodies. This could contribute to multiple pathologies including autoimmune and inflammatory diseases. Here, we summarize current knowledge on the influence of various dietary components on B cell function and (auto)antibody production in relation to the gut microbiota, with a particular focus on the gut–brain axis in the pathogenesis of multiple sclerosis

B cells of multiple sclerosis patients induce autoreactive proinflammatory T cell responses

Antibody-independent B cell functions play an important role in multiple sclerosis (MS) pathogenesis. In this study, B cell antigen presentation and costimulation in MS were studied. Peripheral blood B cells of MS patients showed increased expression of costimulatory CD86 and CD80 molecules compared with healthy controls (HC). In MS cerebrospinal fluid (CSF), 12-fold and 2-fold increases in CD86+ and CD80+ B cells, respectively, were evidenced compared with peripheral blood. Further, B cells from MS patients induced proinflammatory T cells in response to myelin basic protein (MBP). Immunomodulatory treatment restored B cell costimulatory molecule expression and caused significantly reduced B cell induced T cell responses. Together, these results demonstrate the potential of B cells from MS patients to induce autoreactive proinflammatory T cell responses. Immunomodulatory therapy abrogated this effect, emphasizing the importance of B cell antigen presentation and costimulation in MS pathology

Age-Associated B Cells with Proinflammatory Characteristics Are Expanded in a Proportion of Multiple Sclerosis Patients

Immune aging occurs in the elderly and in autoimmune diseases. Recently, IgD(-) CD27(-) (double negative, DN) and CD21(-) CD11c(+) (CD21(low)) B cells were described as age- associated B cells with proinflammatory characteristics. This study investigated the prevalence and functional characteristics of DN and CD21(low) B cells in multiple sclerosis (MS) patients. Using flow cytometry, we demonstrated a higher proportion of MS patients younger than 60 y with peripheral expansions of DN (8/41) and CD21(low) (9/41) B cells compared with age- matched healthy donors (1/33 and 2/33, respectively), which indicates an increase in age- associated B cells in MS patients. The majority of DN B cells had an IgG(+) memory phenotype, whereas CD21(low) B cells consisted of a mixed population of CD27(-) naive, CD27(+) memory, IgG(+), and IgM(+) cells. DN B cells showed similar (MS patients) or increased (healthy donors) MHC-II expression as class- switched memory B cells and intermediate costimulatory molecule expression between naive and class- switched memory B cells, indicating their potential to induce (proinflammatory) T cell responses. Further, DN B cells produced proinflammatory and cytotoxic cytokines following ex vivo stimulation. Increased frequencies of DN and CD21(low) B cells were found in the cerebrospinal fluid of MS patients compared with paired peripheral blood. In conclusion, a proportion of MS patients showed increased peripheral expansions of age- associated B cells. DN and CD21(low) B cell frequencies were further increased in MS cerebrospinal fluid. These cells could contribute to inflammation by induction of T cell responses and the production of proinflammatory cytokines

Compositional Changes of B and T Cell Subtypes during Fingolimod Treatment in Multiple Sclerosis Patients: A 12-Month Follow-Up Study

<div><p>Background and objective</p><p>The long term effects of fingolimod, an oral treatment for relapsing-remitting (RR) multiple sclerosis (MS), on blood circulating B and T cell subtypes in MS patients are not completely understood. This study describes for the first time the longitudinal effects of fingolimod treatment on B and T cell subtypes. Furthermore, expression of surface molecules involved in antigen presentation and costimulation during fingolimod treatment are assessed in MS patients in a 12 month follow-up study.</p><p>Methods</p><p>Using flow cytometry, B and T cell subtypes, and their expression of antigen presentation, costimulation and migration markers were measured during a 12 month follow-up in the peripheral blood of MS patients. Data of fingolimod-treated MS patients (n = 49) were compared to those from treatment-naive (n = 47) and interferon-treated (n = 27) MS patients.</p><p>Results</p><p>In the B cell population, we observed a decrease in the proportion of non class-switched and class-switched memory B cells (p<0.001), both implicated in MS pathogenesis, while the proportion of naive B cells was increased during fingolimod treatment in the peripheral blood (PB) of MS patients (p<0.05). The remaining T cell population, in contrast, showed elevated proportions of memory conventional and regulatory T cells (p<0.01) and declined proportions of naive conventional and regulatory cells (p<0.05). These naive T cell subtypes are main drivers of MS pathogenesis. B cell expression of CD80 and CD86 and programmed death (PD) -1 expression on circulating follicular helper T cells was increased during fingolimod follow-up (p<0.05) pointing to a potentially compensatory mechanism of the remaining circulating lymphocyte subtypes that could provide additional help during normal immune responses.</p><p>Conclusions</p><p>MS patients treated with fingolimod showed a change in PB lymphocyte subtype proportions and expression of functional molecules on T and B cells, suggesting an association with the therapeutic efficacy of fingolimod.</p></div