R Eisenberg

..56R and B6.56R.TLR9(-/-) postinduction of cGVH disease. Taken together, these results suggested that TLR9 may worsen some aspects of systemic autoimmunity while alleviating others...

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..We propose that a pathological autoimmune process can use receptor editing to induce the de novo creation and activation of B cells with autoreactive receptors in the peripheral immune system...

..We need to be persistent and imaginative in identifying these effective agents and proving their efficacy so that they may be widely used in our lupus populations...

..Two large ongoing randomized controlled trials will determine the efficacy of rituximab in SLE, both renal and extra-renal, and will inform us better about the biology of the B cell in this disease and the effects of B-cell depletion...

..Further understanding of the role of TLRs in pathological autoreactivity of the adaptive immune system will likely lead to important insights into the etiopathogenesis of SLE and potential targets for novel therapies...

..We can reasonably expect important advances in the understanding and treatment of RA and SLE in the next 5-10 years, as B-cell targeting methods become more widespread and sophisticated...

..A randomized controlled trial is currently active to test this possibility...

..Here I discuss the overall paradigm of autoimmunity, and what kinds of mechanisms might play a role. It is likely that multiple different pathways are critical in various diseases, and even in a single condition...

..Future investigations will target the biochemistry of the loss of tolerance and the specificity of autoreactive T cells that provide help for autoantibody production...

..Controlled trials in SLE will be necessary to determine whether rituximab is useful therapy in this disease, and will teach us more about the roles of B cells in its pathogenesis...

..We find that the B cell plays a key central role in this process and represents an attractive target for therapeutic intervention...

..This permits the examination of the role of somatic immunoglobulin genetics and B-cell tolerance in a model of systemic lupus erythematosus...

..The increased use of rituximab, other anti-CD20 agents, and other B-cell targeting therapies holds great promise for substantial clinical benefits, as well as providing special opportunities to understand better disease pathogenesis...

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..Thus, our study indicates that alloreactive T cell help can break tolerance in a complex manner, involving several events...

..These results reveal a protective function of DAF in the development of a systemic autoimmune syndrome and suggest that dysfunction or down-regulation of DAF may contribute to autoimmune disease pathogenesis and manifestation...

..Anti-CD79 mAbs show promise as a potential treatment for systemic lupus erythematosus and as a model for B cell depletion in vivo...

..These findings indicate that Mer serves an important role in the activation of self-reactive B cells in systemic autoimmunity...

..These observations define a connection between induction of lupus-like symptoms and development of severe atherosclerosis in ApoE deficient lupus mouse models...

..Further refinement of these potential biomarkers may lead to a better understanding of the role of B cells in disease pathogenesis and a more rational use of B cell depletion therapies...

..Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE...

..This observation underscores the critical role of marginal zone B cells in activation and production of autoantibodies...

..Thus, the autoimmunity induced by chronic GVH may ultimately result from the failure of B cell tolerance at multiple checkpoints...

..These studies clearly indicate that B cells need to coexist with CD4 T cells early in their development to develop full susceptibility to alloactivation signals...

..Genetic analysis associated this response with the generation of anti-dsDNA B cells through secondary rearrangements that replaced the site-directed transgene (sd-tg) with endogenous VH genes...

..Together, these results reveal multiple mechanisms of action for DAF in ameliorating systemic autoimmunity...

..Since this process of tolerance loss is central to the pathogenesis of SLE, the results will help clarify some of the fundamental underlying mechanisms of this disease. ..

..Such insights should be readily translatable to human autoimmune diseases. ..

..Such insights should be readily translatable to human autoimmune diseases. ..

..Such understanding will, eventually, lead to more rational therapy for this disease and other autoimmune diseases. ..

..Is the pace of MRL/lpr disease dictated by events that occur after the early lymphocyte stage of ontogeny? 4. Does the genotype of the B cell control the lymphoproliferation of T cells? ..

..The knowledge gained will improve of our understanding of the pathogenesis of systemic lupus erythematosus and how we can target the B lymphocytes in treatment. ..