Consequences of Breaking B Cell Tolerance Autoimmune Diseases

In at least two major types of autoimmune diseases, autoantibodies, and B cells producing them, contribute to the pathophysiology of the disease. In both cases, somatically hypermutated autoantibodies have been identified, and some of them have been shown to possibly induce, but certainly propagate factors in the destruction of cells and tissues generating the disease phenotypes. A characteristic spectrum of autoantigens appears to be connected with the induction and/or propagation of these autoimmune diseases. In systemic lupus erythematosus (SLE), nuclear antigens, especially double-stranded DNA, histones, and nucleoprotein complexes such as the ss- and Rho-antigens, are recognized by the somatically mutated autoantibodies. In chronic inflammatory rheumatoid arthritis (RA) posttranslationally modified proteins of cells in the target tissues, e.g., citrullinated proteins of the tissues of the synovialis, characterize some of the autoantigens recognized by the autoantibodies. In SLE viral antigens, for example, those encoded by Epstein-Barr virus and antigens of other infectious agents have been implied in breaking T cell tolerance, thereby setting the stage for B cell activation,

V-region hypermutation, and selection of B cells with hypermutated, nuclear antigen-specific BcRs. In RA, breaking of tolerance may initially involve helper T cell activation by peptides containing posttranslationally modified peptides of autoantigens in MHC class II complexes, followed by activation of B cell-specific for the same, or similarly modified proteins, with the positive selection of hypermutated, high-avidity autoantibody-producing cells. Again, the autoantibodies can form immune complexes and can participate in the destruction of tissue, in this case in the synovialis.

For both diseases, secreted autoantibodies were long suspected to be major disease-propagating factors. However, recent evidence from clinical trials with a B cell-specific monoclonal antibody, i.e., against the B cell-associated surface marker CD20, have shifted the focus of interest to B cells and cells expressing the hypermutated, autoantigen-specific BcRs on their surface as major contributors to the acute disease manifestations. Within 2 weeks, two doses of the CD20-specific mAb nearly abolish major disease manifestations— in a time period in which the autoantibody detectable in the patient's blood stream are hardly reduced. The CD20-specific mAb that induces a strong B cell cytopenia in circulating blood might, therefore, remove the inflammation-inducing cooperators from the autoantigen-peptide-MHCII-specific helper T cells which normally produce inflammatory cytokines such as TNF in the autoimmune response.

Acknowledgements A.R.R. is supported by a grant from the Swiss National Funds No. 3100-066692, F.M. by a grant from the Swiss National Funds No. 3100-066682.

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