Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

Tsantikos, E; Oracki, SA; Quilici, C; Anderson, GP; Tarlinton, DM; Hibbs, ML

Author(s): Tsantikos, E; Oracki, SA; Quilici, C; Anderson, GP; Tarlinton, DM; Hibbs, ML;
Details: Publication Year 2010-02-01,Volume 184,Issue #3,Page 1348-1360
Journal Title: JOURNAL OF IMMUNOLOGY
Publication Type: Journal Article
Abstract: Lyn-deficient mice develop Ab-mediated autoimmune disease resembling systemic lupus erythematosus where hyperactive B cells are major contributors to pathology. In this study, we show that an inflammatory environment is established in Lyn(-/-) mice that perturbs several immune cell compartments and drives autoimmune disease. Lyn(-/-) leukocytes, notably B cells, are able to produce IL-6, which facilitates hyperactivation of B and T cells, enhanced myelopoiesis, splenomegaly, and, ultimately, generation of pathogenic autoreactive Abs. Lyn(-/-) dendritic cells show increased maturation, but this phenotype is independent of autoimmunity as it is reiterated in B cell-deficient Lyn(-/-) mice. Genetic deletion of IL-6 on a Lyn-deficient background does not alter B cell development, plasma cell accumulation, or dendritic cell hypermaturation, suggesting that these characteristics are intrinsic to the loss of Lyn. However, hyperactivation of B and T cell compartments, extramedullary hematopoiesis, expansion of the myeloid lineage and autoimmune disease are all ameliorated in Lyn(-/-)IL-6(-/-) mice. Importantly, our studies show that although Lyn(-/-) B cells may be autoreactive, it is the IL-6-dependent inflammatory environment they engender that dictates their disease-causing potential. These findings improve our understanding of the mode of action of anti-IL-6 and B cell-directed therapies in autoimmune and inflammatory disease treatment. The Journal of Immunology, 2010, 184: 1348-1360.
Publisher: AMER ASSOC IMMUNOLOGISTS
Keywords: SYSTEMIC-LUPUS-ERYTHEMATOSUS; ANTI-INTERLEUKIN-6 RECEPTOR ANTIBODY; GERMINAL CENTER DEVELOPMENT; B-CELL DIFFERENTIATION; ACUTE-PHASE RESPONSES; VIRUS TYPE-I; RHEUMATOID-ARTHRITIS; MOLECULAR MIMICRY; TYROSINE KINASE; DOUBLE-BLIND
Publisher's Version: https://doi.org/10.4049/jimmunol.0901878
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2010-02-01 12:00:00