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Clinical trials have shown that BAFF inhibitors do not reduce memory B cell levels but can reduce the number of mature B cells. It remains uncertain whether BAFF affects memory-maintaining cytokines such as IL-15. We found that BAFF suppressed IL-15 expression in B cells from lupus-like or experimental allergic encephalomyelitis mice. When BAFF was blocked with atacicept-IgG, IL-15 expression was upregulated in lupus-like or experimental allergic encephalomyelitis mice. Finally, we showed that BAFF suppressed IL-15 expression in transitional 2 B cells by reducing Foxo1 expression and inducing Foxo1 phosphorylation. This study suggests that BAFF suppresses IL-15 expression in autoimmune diseases, and this opens up the possible opportunity for the clinical application of BAFF- and IL-15-specific therapeutic agents.

Purpose: To determine the involvement of retinal astrocytes (RACs) in T cell-mediated experimental autoimmune uveitis (EAU)., Methods: Frozen sections of eyes from naive mice or mice with EAU were stained for glial fibrillary acidic protein (GFAP) or major histocompatibility complex (MHC) class II molecules and were examined by confocal microscopy. RACs were isolated and cocultured with interphotoreceptor retinoid-binding protein (IRBP) peptide-specific T cells. The proliferation and cytokine production of responder T cells were determined by [(3)H]-thymidine incorporation and ELISA, respectively., Results: The development of intraocular inflammation was associated with increased GFAP-positive cells in the retina. RACs from EAU-prone mice (B10RIII) activated uveitogenic T cells in vitro, enhanced T-cell proliferation and the production of proinflammatory cytokines, and increased the numbers of IL-17(+) IRBP T cells in the inflamed eye. The interaction between local RACs and IRBP-specific T cells was regulated by a distinct pattern of costimulatory molecules. In addition, the ability of IRBP-specific T cells to interact with RACs was dependent on whether the latter were derived from EAU-prone (B10RIII) or EAU-low susceptible (C57Bl/6) strains of mice., Conclusions: This study suggests that the RACs in EAU-prone mice contribute to the reactivation of pathogenic T cells in the eye, leading to intraocular inflammation and tissue damage.

Purpose: The aims of this study were to determine whether IL-17(+) T cells were present in CD4 and CD8 interphotoreceptor retinoid-binding protein (IRBP)-specific T cells and to determine the role of antigen-specific and nonspecific IL-17(+) T cells in the pathogenesis of experimental autoimmune uveitis (EAU)., Methods: B6 mice were immunized with uveitogenic peptide IRBP1-20. In vivo-primed T cells were separated and stimulated with the immunizing peptide. Intracellular expression of IFN-gamma and IL-17 by the T cells was assessed, and the pathogenic activity of the activated T cells was determined., Results: A subset of autoreactive IRBP-specific CD8 T cells expressed IL-17. IRBP-specific T cells preferentially expressed IL-17 when expanded by IL-23, whereas IFN-gamma-expressing cells were dominant when the T cells were cultured with IL-2. Importantly, both expanded T-cell populations were uveitogenic. In addition, IL-23 promoted the expansion of antigen-specific and non-antigen-specific IL-17(+) T cells, whereas TGF-beta and IL-6 acted only on non-antigen-specific IL-17(+) T cells. Only the antigen-specific IL-17(+) T cells were uveitogenic. The activation of autoreactive IL-17(+) T cells was markedly increased in vivo by the mycobacterial component of CFA and pertussis toxin (PTX) and in vitro by the ligation of Toll-like receptors., Conclusions: IL-17(+) T cells can be readily detected among activated autoreactive and bystander T cells and may play a major role in the pathogenesis of EAU.

To determine whether decreased regulatory T cell activity contributes to the pathogenesis of recurrent experimental autoimmune uveitis (EAU), we compared the immunoregulatory activity of CD8+CD45RClow T cells isolated from rats that had recovered from acute EAU with those from rats with the progressive, recurrent disease. Our results showed that CD8+CD45RClow T cells isolated from the recovered rats showed suppressive activity in vitro, whereas those from rats with progressive, recurrent EAU do not. Depletion of CD8+CD45RClow T cells from T cells used for adoptive transfer of EAU increased the pathogenic activity of the T cells. Co-transfer of CD8+CD45RClow T cells with uveitogenic T cells prevented the relapse of disease in the recipient rats. The suppressive CD8+CD45RClow T cells expressed increased levels of Foxp3 after stimulation in vitro with the autoantigen, and inhibited the production of IFN-gamma by autoreactive T cells. Our data indicate that the decreased suppressive activity of CD8+CD45RClow T cells is correlated with disease development in this autoimmune disease. Further studies on the biology of this T cell population should provide much needed insights into disease pathogenesis.

The interleukin (IL).12 family cytokines have been examined as therapeutic targets in the treatment of several autoimmune diseases. Our previous study showed that a novel IL.12 family cytokine, IL.39 (IL.23p19/Ebi3) mediates inflammation in lupus.like mice. In the present study, the effect of anti.mouse IL.39 polyclonal antibodies on autoimmune symptoms in lupus.like mice was investigated. Rabbit anti.mouse IL.39 polyclonal antibodies were produced by immunization with recombinant mouse IL.39, and purified using protein A chromatography. These antibodies were subsequently used to treat lupus.like mice. Flow cytometry, captured images, ELISA and H&E staining were used to determine the effect of anti.IL.39 polyclonal antibodies on inflammatory cells, autoantibody titers, proteinuria, infiltrating inflammatory cells and the structure of the glomerular region. The anti.IL.39 polyclonal antibodies effectively reduced the numbers of inflammatory cells, splenomegaly, autoantibody titers, proteinuria, infiltrating inflammatory cells, and restored the structure of the glomerular region in MRL/lpr mice. Taken together, these results suggested that anti.IL.39 polyclonal antibodies ameliorated autoimmune symptoms in lupus.like mice. Therefore, IL.39 may be used as a possible target for the treatment of systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

B cell activating factor (BAFF) regulates B cell maturation, survival, function, and plays a critical pathogenic role in autoimmune diseases. It remains unclear how BAFF affects IL-10 − B cells versus regulatory B cells (Bregs) in inflammatory responses. In this study, we found that IL-10-expressing Bregs decreased in lupus-prone MRL/lpr mice and experimental allergic encephalomyelitis (EAE) mice. On blockade of the effects of BAFF with TACI-IgG, IL-10 + Bregs were upregulated in MRL/lpr and EAE mice. In addition, BAFF expanded IL-10 + B cells over IL-10 − B cells under noninflammatory conditions in vitro , whereas it expanded IL-10 − B cells over IL-10 + B cells during inflammatory responses, such as stimulation with autoantigen and LPS. Finally, the selection of IL-10 − B cells over IL-10 + B cells by BAFF was dependent on BAFF receptors (BAFFR, TACI, and BCMA) that were upregulated by inflammatory responses. This study suggests that BAFF selects IL-10 − B cells over IL-10 + regulatory B cells via BAFF receptors in inflammatory responses. [ABSTRACT FROM AUTHOR]

Interleukin 10 (IL-10)-producing regulatory B-cells (Bregs) suppress inflammatory responses that mediate autoimmune diseases. However, it is unknown whether Bregs derive from a pre-existing dedicated B-cell lineage or if any B-cell can differentiate into Bregs in response to BCR or TLR activation. GL7 + B-cells are antigen-experienced differentiated B-cells while GL7 −/lo are at an early stage of B-cell differentiation. While both GL7 −/lo and GL7 + B cells can produce IL-10, differentiation of GL7 − B-cells into Bregs does not require CD19- or Bcl6-induced signals, suggesting that BCR-induced proliferation or Ig class-switching is not necessary for generation of Breg cells. Of particular importance, we show that GL7 − Breg cells are dramatically expanded in lupus-like mice and GL7 − Bregs suppressed inflammatory responses in lupus-like mice by inducing expansion of Foxp3 + Treg cells. Taken together, these results suggest that pre-existing GL7 − IL-10 + cells are expanded during inflammation, differentiate into GL7 + Bregs and contribute to immune-regulation in lupus-like mice. [ABSTRACT FROM AUTHOR]

Recently B-cell activating factor (BAFF) was identified by our group and others as a novel therapeutic target for the treatment of autoimmune diseases. To expand upon this, we utilized microarrays to screen for molecules upregulated in B cells from BAFF-inhibited mice with lupus-like disease and identified metabotropic glutamate receptor 3 (Grm3). In addition to confirming the expression of this receptor in B cells, a synthetic agonist of Grm3 was found to downregulate B cells and ameliorate autoimmune symptoms in mice. Conversely, a Grm3 antagonist increased B-cell numbers and further aggravated disease. Thus, these results suggest that activation of Grm3 ameliorates lupus-like disease in mice by reducing B cell numbers. Not only do the findings presented in this study increase our understanding of the inhibitory signals initiated on the surface of B cells, but they also identify a novel potential target for the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]