Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

Integration of Th17- and Lymphotoxin-Derived Signals Initiates Meningeal-Resident Stromal Cell Remodeling to Propagate Neuroinflammation.

Tertiary lymphoid tissues (TLTs) have been observed in the meninges of multiple sclerosis (MS) patients, but the stromal cells and molecular signals that support TLTs remain unclear. Here, we show that T helper 17 (Th17) cells induced robust TLTs within the brain meninges that were associated with local demyelination during experimental autoimmune encephalitis (EAE). Th17-cell-induced TLTs were underpinned by a network of stromal cells producing extracellular matrix proteins and chemokines, enabling leukocytes to reside within, rather than simply transit through, the meninges. Within the CNS, interactions between lymphotoxin αß (LTαß) on Th17 cells and LTßR on meningeal radio-resistant cells were necessary for the propagation of de novo interleukin-17 responses, and activated T cells from MS patients expressed elevated levels of LTßR ligands. Therefore, input from both Th17 cells and the lymphotoxin pathway induce the formation of an immune-competent stromal cell niche in the meninges.

B Cells and Microbiota in Autoimmunity.

Trillions of microorganisms inhabit the mucosal membranes maintaining a symbiotic relationship with the host's immune system. B cells are key players in this relationship because activated and differentiated B cells produce secretory immunoglobulin A (sIgA), which binds commensals to preserve a healthy microbial ecosystem. Mounting evidence shows that changes in the function and composition of the gut microbiota are associated with several autoimmune diseases suggesting that an imbalanced or dysbiotic microbiota contributes to autoimmune inflammation. Bacteria within the gut mucosa may modulate autoimmune inflammation through different mechanisms from commensals ability to induce B-cell clones that cross-react with host antigens or through regulation of B-cell subsets' capacity to produce cytokines. Commensal signals in the gut instigate the differentiation of IL-10 producing B cells and IL-10 producing IgA+ plasma cells that recirculate and exert regulatory functions. While the origin of the dysbiosis in autoimmunity is unclear, compelling evidence shows that specific species have a remarkable influence in shaping the inflammatory immune response. Further insight is necessary to dissect the complex interaction between microorganisms, genes, and the immune system. In this review, we will discuss the bidirectional interaction between commensals and B-cell responses in the context of autoimmune inflammation.

Isotype-Switched Autoantibodies Are Necessary To Facilitate Central Nervous System Autoimmune Disease in Aicda-/- and Ung-/- Mice.

B cell-depleting therapies have been shown to ameliorate symptoms in multiple sclerosis (MS) patients; however, the mechanism of action remains unclear. Following priming with Ag, B cells undergo secondary diversification of their BCR, including BCR class-switch recombination (CSR) and somatic hypermutation (SHM), with both processes requiring the enzyme activation-induced (cytidine) deaminase. We previously reported that activation-induced (cytidine) deaminase is required for full clinical manifestation of disease in an animal model of MS (experimental autoimmune encephalomyelitis; EAE) provoked by immunization with the extracellular domain of recombinant human myelin oligodendrocyte glycoprotein (hMOG). In this study, we investigated the role of CSR versus SHM in the pathogenesis of EAE. We found that passive transfer of class-switched anti-MOG IgG1 Abs into hMOG-primed Aicda-/- mice is sufficient to fully rescue EAE disease. In addition, we found that the nature of the Ag is an important determinant of EAE severity in Aicda-/- mice because the lack of a diversified BCR does not affect the induction of EAE when immunized with the extracellular domain of rat MOG. To discriminate the effect of either CSR or SHM, we induced EAE in uracil DNA glycosylase-deficient mice (Ung-/-) that exhibit a defect primarily in CSR. We observed that Ung-/- mice exhibit milder clinical disease compared with control mice, concomitant with a reduced amount of anti-MOG IgG1 class-switched Abs that preserved normal affinity. Collectively, these results indicate that CSR plays an important role in governing the incidence and severity of EAE induced with hMOG but not rat MOG.

Plasmacytoid dendritic cells and autoimmune inflammation.

Plasmacytoid dendritic cells (pDC) are a sub-population of dendritic cells (DC) that produce large amounts of type I interferon (IFN) in response to nucleic acids that bind and activate toll-like-receptor (TLR)9 and TLR7. Type I IFN can regulate the function of B, T, DC, and natural killer (NK) cells and can also alter the residence time of leukocytes within lymph nodes. Activated pDC can also function as antigen presenting cells (APC) and have the potential to prime and differentiate T cells into regulatory or inflammatory effector cells, depending on the context. In this review we discuss pDC ontogeny, function, trafficking, and activation. We will also examine how pDC can potentially be involved in regulating immune responses in the periphery as well as within the central nervous system (CNS) during multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE).

Gut epithelial barrier dysfunction in lupus triggers a differential humoral response against gut commensals.

Introduction: Systemic lupus erythematosus is an autoimmune disease with multisystemic involvement including intestinal inflammation. Lupus-associated intestinal inflammation may alter the mucosal barrier where millions of commensals have a dynamic and selective interaction with the host immune system. Here, we investigated the consequences of the intestinal inflammation in a TLR7-mediated lupus model. Methods: IgA humoral and cellular response in the gut was measured. The barrier function of the gut epithelial layer was characterised. Also, microbiota composition in the fecal matter was analysed as well as the systemic humoral response to differential commensals. Results: The lupus-associated intestinal inflammation modifies the IgA+ B cell response in the gut-associated lymphoid tissue in association with dysbiosis. Intestinal inflammation alters the tight junction protein distribution in the epithelial barrier, which correlated with increased permeability of the intestinal barrier and changes in the microbiota composition. This permeability resulted in a differential humoral response against intestinal commensals. Discussion: Lupus development can cause alterations in microbiota composition, allowing specific species to colonize only the lupus gut. Eventually, these alterations and the changes in gut permeability induced by intestinal inflammation could lead to bacterial translocation.

Traditional Fermented Foods and Beverages from around the World and Their Health Benefits.

Traditional fermented foods and beverages play an important role in a range of human diets, and several experimental studies have shown their potential positive effects on human health. Studies from different continents have revealed strong associations between the microorganisms present in certain fermented foods (e.g., agave fructans, kefir, yeats, kombucha, chungkookjang, cheeses and vegetables, among others) and weight maintenance, reductions in the risk of cardiovascular disease, antidiabetic and constipation benefits, improvement of glucose and lipids levels, stimulation of the immunological system, anticarcinogenic effects and, most importantly, reduced mortality. Accordingly, the aim of this review is to corroborate information reported in experimental studies that comprised interventions involving the consumption of traditional fermented foods or beverages and their association with human health. This work focuses on studies that used fermented food from 2014 to the present. In conclusion, traditional fermented foods or beverages could be important in the promotion of human health. Further studies are needed to understand the mechanisms involved in inflammatory, immune, chronic and gastrointestinal diseases and the roles of fermented traditional foods and beverages in terms of preventing or managing those diseases.

Haptoglobin deficiency facilitates the development of autoimmune inflammation.

Haptoglobin (HP) is an acute phase protein synthesized by liver cells in response to IL-6. HP has been demonstrated to modulate the immune response and to have anti-inflammatory activities. To analyze HP's effect on autoimmune inflammation, we here studied the course of EAE induced by immunization of Hp knockout (Hp(-/-)) and syngeneic WT mice with myelin oligodendrocyte glycoprotein peptide (MOG(35-55)). Hp(-/-)mice suffered from a more severe disease that was associated with increased expression of IL-17A, IL-6, and IFN-gamma mRNA in the CNS and with a denser cellular infiltrate in the spinal cord. During the recovery phase, a significantly higher number of myeloid DC, CD8+ cells, IL-17+ CD4+ and IFN-gamma+ CD4+ cells persisted in the CNS of Hp(-/-) mice. Absence of HP affected the priming and differentiation of T cells after MOG(35-55) immunization, as levels of Th2 cytokines produced in response to MOG stimulation by Hp(-/-) T cells were reduced. These results suggest that HP plays a modulatory and protective role on autoimmune inflammation of the CNS.

Contribution of regulatory T cells and effector T cell deletion in tolerance induction by costimulation blockade.

Blocking of costimulatory signals for T cell activation leads to tolerance in several transplantation models, but the underlying mechanisms are incompletely understood. We analyzed the involvement of regulatory T cells (Treg) and deletion of alloreactive cells in the induction and maintenance of tolerance after costimulation blockade in a mouse model of graft-vs-host reaction. Injection of splenocytes from the C57BL/6 parent strain into a sublethally irradiated F(1) offspring (C57BL/6 x C3H) induced a GVHR characterized by severe pancytopenia. Treatment with anti-CD40L mAb and CTLA4-Ig every 3 days during 3 wk after splenocyte injection prevented disease development and induced a long-lasting state of stable mixed chimerism (>120 days). In parallel, host-specific tolerance was achieved as demonstrated by lack of host-directed alloreactivity of donor-type T cells in vitro and in vivo. Chimerism and tolerance were also obtained after CD25(+) cell-depleted splenocyte transfer, showing that CD25(+) natural Treg are not essential for tolerance induction. We further show that costimulation blockade results in enhanced Treg cell activity at early time points (days 6-30) after splenocyte transfer. This was demonstrated by the presence of a high percentage of Foxp3(+) cells among donor CD4(+) cells in the spleen of treated animals, and our finding that isolated donor-type T cells at an early time point (day 30) after splenocyte transfer displayed suppressive capacity in vitro. At later time points (>30 days after splenocyte transfer), clonal deletion of host-reactive T cells was found to be a major mechanism responsible for tolerance.

ICOS deficiency results in exacerbated IL-17 mediated experimental autoimmune encephalomyelitis.

INTRODUCTION: Inducible costimulatory molecule (ICOS) is important for the effector function of T cells, especially for Th2 and T cell dependent B cell responses. However, it has been shown that ICOS is required for the differentiation of Th17 cells. Since IL-17 has been identified as a major cytokine involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the enhanced severity of EAE in ICOS-deficient mice (ICOS(-/-)) mice is unexpected. METHODS: To better understand the role of ICOS and of IL-17 in EAE, we induced EAE in ICOS(-/-) by immunization with myelin oligodendrocyte glycoprotein peptide (MOG(35-55)) in complete Freund's adjuvant. RESULTS: As previously reported, we found that ICOS(-/-) mice developed more severe EAE. Upon restimulation with MOG(35-55,) splenocytes from ICOS(-/-) mice with EAE produced higher amounts of IL-17 and ICOS(-/-) mice had a higher expression of IL-17, IL-6, and TGF-beta mRNA in the spinal cords at the onset of the disease. Finally, the blockade of IL-17 strongly inhibited disease even in ICOS(-/-) mice, showing that IL-17 is playing a major role in the pathogenesis of EAE both in WT and ICOS(-/-) mice. CONCLUSION: In conclusion, MOG immunization induces MOG-specific Th17 cells also in ICOS(-/-) mice, and a higher expression of IL-17 and of Th17-driving cytokines IL-6 and TGF-beta in the central nervous system at the onset of EAE that correlates with their more severe disease.

Sodium arsenite retards proliferation of PHA-activated T cells by delaying the production and secretion of IL-2.

Arsenic is a metalloid that commonly contaminates drinking water, and is a known human carcinogen. It has been shown that peripheral blood mononuclear cells (PBMCs) from healthy donors treated in vitro with NaAsO(2) and stimulated with phytohemagglutinin (PHA) show a lower proliferation than nontreated cells. We reported previously a reduction in the secretion of IL-2 in NaAsO(2)-treated PBMCs stimulated with PHA, an observation that might explain, in part, the reduction in proliferation. Since arsenic induces cytoskeleton alterations, which in turn may affect protein transport of the cell, we assumed that NaAsO(2) induced an accumulation of IL-2 inside the cells, and thus a reduction in the secretion of IL-2. In order to demonstrate this hypothesis, we assessed the intracellular IL-2 at the single cell level by flow cytometry, and unexpectedly found a reduction in the percentage of IL-2 producing T cells in the presence of NaAsO(2). We tracked the proliferation of T cells by using the 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) dye and found that NaAsO(2) slows down the entrance to cell division and delays the proliferation of cells that have already entered the cell cycle. Nevertheless, the expression of the activation molecules, CD25 and CD69, was unaltered. Assessment of the intracellular and secreted IL-2 in kinetic experiments showed that in fact, NaAsO(2) delays the production of IL-2, given that a recovery of both intracellular and secreted IL-2 was detected at 72 h. Evaluation of the cell cycle showed a higher proportion of cells in G(0)/G(1) and a lower proportion in G(2)/M in the presence of NaAsO(2). We thus conclude that NaAsO(2) reduces proliferation of T cells by delaying the production and secretion of IL-2, thus blocking T cells in G(1); as a consequence, the entry to cell cycle and the rounds of cell division are retarded, and a lower proliferation of T cells is hence observed.

Secondary B cell receptor diversification is necessary for T cell mediated neuro-inflammation during experimental autoimmune encephalomyelitis.

BACKGROUND: Clinical studies of B cell depletion in Multiple Sclerosis (MS) have revealed that B Lymphocytes are involved in the neuro-inflammatory process, yet it remains unclear how B cells can exert pro- and anti-inflammatory functions during MS. Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of MS whereby myelin-specific T cells become activated and subsequently migrate to the Central Nervous System (CNS) where they perform pro-inflammatory functions such as cytokine secretion. Typically EAE is induced by immunization of mice of a susceptible genetic background with peptide antigen emulsified in Complete Freund's Adjuvant. However, novel roles for B-lymphocytes in EAE may also be explored by immunization with full-length myelin oligodendrocyte glycoprotein (MOG) that contains the B cell conformational epitope. Here we show that full length MOG immunization promotes a chronic disease in mice that depends on antigen-driven secondary diversification of the B cell receptor. METHODS: Activation-Induced Deaminase (AID) is an enzyme that is essential for antigen-driven secondary diversification of the B cell receptor. We immunized AID(-/-) mice with the extracellular domain (amino acids 1-120) of recombinant human MOG protein (rhMOG) and examined the incidence and severity of disease in AID(-/-) versus wild type mice. Corresponding with these clinical measurements, we also evaluated parameters of T cell activation in the periphery and the CNS as well as the generation of anti-MOG antibodies (Ab). CONCLUSIONS: AID(-/-) mice exhibit reduced severity and incidence of EAE. This suggests that the secondary diversification of the B cell receptor is required for B cells to exert their full encephalogenic potential during rhMOG-induced EAE, and possibly also during MS.