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The ultraviolet (UV) radiation contained in sunlight is a powerful immune suppressant. While exposure to UV is associated with protection from the development of autoimmune diseases, particularly multiple sclerosis, the precise mechanism by which UV achieves this protection is not currently well understood. Regulatory B cells play an important role in preventing autoimmunity and activation of B cells is a major way in which UV suppresses adaptive immune responses. Whether UV-protection from autoimmunity is mediated by the activation of regulatory B cells has never been considered before. When C57BL/6 mice were exposed to low, physiologically relevant doses of UV, a unique population of B cells was activated in the skin draining lymph nodes. As determined by flow cytometry, CD1d low CD5 – MHC-II hi B220 hi UV-activated B cells expressed significantly higher levels of CD19, CD21/35, CD25, CD210 and CD268 as well as the co-stimulatory molecules CD80, CD86, CD274 and CD275. Experimental autoimmune encephalomyelitis (EAE) in mice immunized with MOG/CFA was reduced by exposure to UV. UV significantly inhibited demyelination and infiltration of inflammatory cells into the spinal cord. Consequently, UV-exposed groups showed elevated IL-10 levels in secondary lymphoid organs, delayed EAE onset, reduced peak EAE score and significantly suppressed overall disease incidence and burden. Importantly, protection from EAE could be adoptively transferred using B cells isolated from UV-exposed, but not unirradiated hosts. Indeed, UV-protection from EAE was dependent on UV activation of lymph node B cells because UV could not protect mice from EAE who were pharmacologically depleted of B cells using antibodies. Thus, UV maintenance of a pool of unique regulatory B cells in peripheral lymph nodes appears to be essential to prevent an autoimmune attack on the central nervous system. [ABSTRACT FROM AUTHOR]

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the pancreatic infiltration of immune cells resulting in T cell-mediated destruction of the insulin-producing beta cells. The successes of the Non-Obese Diabetic (NOD) mouse model have come in multiple forms including identifying key genetic and environmental risk factors e.g. Idd loci and effects of microorganisms including the gut microbiota, respectively, and how they may contribute to disease susceptibility and pathogenesis. Furthermore, the NOD model also provides insights into the roles of the innate immune cells as well as the B cells in contributing to the T cell-mediated disease. Unlike many autoimmune disease models, the NOD mouse develops spontaneous disease and has many similarities to human T1D. Through exploiting these similarities many targets have been identified for immune-intervention strategies. Although many of these immunotherapies did not have a significant impact on human T1D, they have been shown to be effective in the NOD mouse in early stage disease, which is not equivalent to trials in newly-diagnosed patients with diabetes. However, the continued development of humanized NOD mice would enable further clinical developments, bringing T1D research to a new translational level. Therefore, it is the aim of this review to discuss the importance of the NOD model in identifying the roles of the innate immune system and the interaction with the gut microbiota in modifying diabetes susceptibility. In addition, the role of the B cells will also be discussed with new insights gained through B cell depletion experiments and the impact on translational developments. Finally, this review will also discuss the future of the NOD mouse and the development of humanized NOD mice, providing novel insights into human T1D. [ABSTRACT FROM AUTHOR]

A strong gender bias is seen in many autoimmune diseases including systemic lupus erythematosus (SLE). To investigate the basis for the female preponderance in SLE, we have been studying BALB/c mice in which B cells express the R4A heavy chain of an anti-DNA antibody in association with an endogenous light chain repertoire (R4Atg mice). In unmanipulated mice, approximately 5% of B cells express the R4A transgene. R4Atg mice do not spontaneously develop elevated serum titers of anti-DNA antibodies. Administration of either estradiol (E2) or prolactin (Pr) results in escape from tolerance of autoreactive B cells, expressed as an increase in transgene-expressing B cells and elevated serum titers of anti-DNA antibodies. We previously demonstrated that autoreactive B cells maturing in an estrogenic milieu develop as marginal zone (MZ) B cells; when these same B cells mature in the presence of increased prolactin, they develop as follicular (Fo) B cells. To determine the long term consequence of this differential maturation of DNA-reactive B cells, we treated R4Atg BALB/c mice with E2 or Pr for 6 weeks until serum titers of anti-DNA antibody were high, at which time hormonal exposure was discontinued. In E2-treated mice, the anti-DNA titers remained high even 3 months after discontinuation of hormone exposure. Nascent B cells underwent normal tolerance induction, but existing autoreactive MZ B cells persisted and continued to secrete autoantibody. In contrast, Pr caused only a short-term increase in anti-DNA antibody titers. By 3 months after cessation of hormone treatment, serum anti-DNA antibody titers and B cell subsets were indistinguishable from those in placebo (P) treated mice. These findings suggest that autoantibody responses are sustained for variable lengths of time depending on the B cell subset producing the autoantibodies. This observation may be relevant to understanding the heterogeneous presentation of patients with SLE and to the design of therapies targeting specific B-cell populations in autoimmune disease. [ABSTRACT FROM AUTHOR]

Abstract: Regulatory functions for B lymphocytes have been reported in murine models of autoimmune diseases in which B-cell deficient mice were shown to exhibit exacerbated disease. The B cells responsible for the immune regulations were identified as a subpopulation of interleukin 10-secreting cells. However, the mechanism of induction and the characteristics of regulatory B cells in humans have been hardly studied. This study reports that regulation of T cell responses can be induced by B cells following CD40-dependent cognate interaction. T cell proliferation and cytokine production were differentially regulated. Thus, CD40-induced regulatory B cells partially inhibited T cell proliferation following CD40 interaction without requirement of soluble factor. In contrast, modulation of Th1 differentiation resulted from CD80- and CD86-dependent interactions and from IL-10 production. The suppressive effects were mediated by CD19highIgD+CD38highCD24highCD5high B cells and appeared to be indirect, through the induction of regulatory T cells as indicated by the appearance of Foxp3+CD4+CD25+T cells. These data suggest that activation signals from T cells initiate regulatory properties in B cells that modulate T cell responses involving regulatory T cells. Finally, studies in autoimmune patients revealed that regulation of T cell proliferation was defective in systemic lupus erythematosus but efficient in other diseases. Restoration of efficient B-cell regulatory activity could provide innovative B-cell based treatment of autoimmune diseases. [Copyright &y& Elsevier]

Cutaneous lupus erythematosus (CLE) is a relapsing autoimmune disease, but key elements that drive disease initiation and progression remain elusive. To date, the lack of ideal murine model which resemble human cutaneous lupus makes it extremely challenging for moving mechanistic discoveries and novel therapeutics. Here, we prompt a humanized murine model to develop an inducible rapid-onset murine that performs cutaneous rather than systemic lupus, depending on the successful human immune system reconstruction from active lupus patients and UVB irradiation as for essentially pathogenic triggers. In addition, we demonstrate a newly discovered population of B cell with a unique phenotype, that of the age-associated B cell (ABC, T-bet+ CD11b+), exhibits B cell clusters in humanized cutaneous lupus. In the response of IL-21 and TLR7/9 signals, recruitment of autoreactive B cells to the position of inflammation with subsequent localized antibody production of IgG2a, IgG2b, IgG3, has the potential to exacerbate ongoing inflammation and thus driving lupus-like autoimmunity in a B-cell-dominant fashion. Overall, our model provides a relevant system for exploring the pathophysiology of cutaneous lupus, a suitable model for drug development, as well as updating a potential role of IL-21 and TLR7/9 to be targeted by biologics. The regulation network of ABC development and its pathogenic role in this newly established humanized CLE model. Firstly, we established a novel humanized CLE mouse model through the successfully engraftment of human PBMCs from active lupus patients. These mice performed lupus-like cutaneous lesions under suitable UVB irradiation. In addition, cutaneous lupus skin exhibited highly expressed human IL-21. These human-derived IL-21 cytokines play an important role in driving ABCs differentiation, including facilitating the expression of CD11b and transcription factor T-bet. On the other hand, apoptotic KCs induced by external UVB irradiation led an accumulation of endogenous nucleic acid. These nuclear autoantigens of CpG DNA and ssRNA can be recognized at the surface of B cells by the B cell receptor (BCR), and then these signals can trigger TLR7/9 in endosomes, further accelerating ABC development and proliferation, thereby prompting ABC clusters infiltration in skin lesion. These vigorous ABC responses were found to cause autoantibody production, including IgG2a, IgG2b, IgG3, but not IgG1. Antibody/antigen binding results in immune complexes that may work as positive stimulatory signals in autoimmunity, further highlighting the pathogenic role of ABC in tissue damage and ongoing inflammation. [Display omitted] • A novel humanized cutaneous lupus model for pathogenesis and medicine research. • Aberrant distribution of IL-21 and age-associated B cells in this humanized model. • Age-associated B cell differentiation and IgG secretion under IL-21 and TLR signals. [ABSTRACT FROM AUTHOR]