Autoimmunity: Twenty Years in the Fas Lane

Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.
The Journal of Immunology (Impact Factor: 4.92). 12/2012; 189(11):5097-100. DOI: 10.4049/jimmunol.1202833
Source: PubMed
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    ABSTRACT: The initiation and perpetuation of autoimmunity recognize numerous checkpoints, from the genomic susceptibility to the breakdown of tolerance. This latter phenomenon includes the loss of B cell anergy and T regulatory cell failure, as well as the production of autoantibodies and autoreactive T cells. These mechanisms ultimately lead to tissue injury via different mechanisms that span from the production of proinflammatory cytokines to the chemotaxis of immune cells to the target sites. The pathways to autoimmunity have been widely investigated over the past year and resulted in a number of articles in peer-reviewed journals that has increased by nearly 10 % compared to 2011. We herein follow on the attempt to provide a brief discussion of the majority of articles on autoimmune diseases that were published in the major immunology journals in the previous solar year. The selection is necessarily arbitrary and may thus not be seen as comprehensive but reflects current research trends. Indeed, 2012 articles were mostly dedicated to define new and old mechanisms with potential therapeutic implications in autoimmunity in general, though based on specific clinical conditions or animal models. As paradigmatic examples, the environmental influence on autoimmunity, Th17 changes modulating the autoimmune response, serum autoantibodies and B cell changes as biomarkers and therapeutic targets were major issues addressed by experimental articles in 2012. Further, a growing number of studies investigated the sex bias of autoimmunity and supported different working hypotheses to explain the female predominance, including sex chromosome changes and reproductive life factors. In conclusion, the resulting scenario illustrates that common factors may underlie different autoimmune diseases and this is well represented by the observed alterations in interferon-α and TGFβ or by the shared signaling pathways.
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    ABSTRACT: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that interacts with advanced glycation end products, but also with C3a, CpG DNA oligonucleotides, and alarmin molecules such as HMGB1 to initiate a proinflammatory reaction. Systemic lupus erythematosus is an autoimmune disorder associated with the accumulation of RAGE ligands. We generated mice invalidated for RAGE in the lupus-prone B6-MRL Fas lpr/j background to determine the role of RAGE in the pathogenesis of systemic lupus erythematosus. We compared the phenotype of these mice with that of their wild-type and B6-MRL Fas lpr/j littermates. Lymphoproliferative syndrome, production of anti-dsDNA Abs, lupus nephritis, and accumulation of CD3(+)B220(+)CD4(-)CD8(-) autoreactive T cells (in the peripheral blood and the spleen) were significantly increased in B6-MRL Fas lpr/j RAGE(-/-) mice compared with B6-MRL Fas lpr/j mice (respectively p < 0.005, p < 0.05, p < 0.001, and p < 0.001). A large proportion of autoreactive T cells from B6-MRL Fas lpr/j mice expressed RAGE at their surface. Time course studies of annexin V expression revealed that autoreactive T cells in the spleen of B6-MRL Fas lpr/j-RAGE(-/-) mice exhibited a delay in apoptosis and expressed significantly less activated caspase 3 (39.5 ± 4.3%) than T cells in B6-MRL Fas lpr/j mice (65.5 ± 5.2%) or wild-type mice (75.3 ± 2.64%) (p = 0.02). We conclude that the deletion of RAGE in B6-MRL Fas lpr/j mice promotes the accumulation of autoreactive CD3(+)B220(+)CD4(-)CD8(-) T cells, therefore exacerbating lymphoproliferative syndrome, autoimmunity, and organ injury. This suggests that RAGE rescues the apoptosis of T lymphocytes when the death receptor Fas/CD95 is dysfunctional. Copyright © 2015 by The American Association of Immunologists, Inc.
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