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The same systemic autoimmune disease provokes arthritis and endocarditis via distinct mechanisms.

ABSTRACT: The immune mechanisms that provoke concomitant inflammation of synovial joints and cardiac valves in disorders such as rheumatic fever and systemic lupus erythematosus remain poorly defined. Here, we report the discovery of spontaneous endocarditis-in addition to their well-studied autoimmune arthritis-in K/BxN T cell receptor (TCR) transgenic mice. The same adaptive immune system elements were required for initiation of arthritis and endocarditis, and both diseases were dependent on autoantibodies. In contrast, the participation of key innate immune system molecules and perhaps T cells as effectors of inflammation differed between the 2 target tissues. Arthritis in K/BxN TCR transgenic mice depended primarily on complement C5 and not FcRgamma-using receptors; conversely, endocarditis depended essentially on FcRgamma receptors and not C5. Elucidating how a single systemic autoimmune disease engages distinct immune effector pathways to damage different target tissues is essential for optimizing the treatment of such disorders.

SUBMITTER: Binstadt BA

PROVIDER: S-EPMC2757808 | biostudies-other | 2009 Sep

REPOSITORIES: biostudies-other

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The same systemic autoimmune disease provokes arthritis and endocarditis via distinct mechanisms.

Binstadt Bryce A BA Hebert Jennifer L JL Ortiz-Lopez Adriana A Bronson Roderick R Benoist Christophe C Mathis Diane D

Proceedings of the National Academy of Sciences of the United States of America 20090915 39

The immune mechanisms that provoke concomitant inflammation of synovial joints and cardiac valves in disorders such as rheumatic fever and systemic lupus erythematosus remain poorly defined. Here, we report the discovery of spontaneous endocarditis-in addition to their well-studied autoimmune arthritis-in K/BxN T cell receptor (TCR) transgenic mice. The same adaptive immune system elements were required for initiation of arthritis and endocarditis, and both diseases were dependent on autoantibod ...[more]

PMID: 19805369

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Project description:Systemic autoimmune diseases are characterized by hyperactive effector T cells (Teffs), aberrant cytokines and chemokines, and dysfunctional regulatory T cells (Tregs). We previously uncovered new roles for serine/arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in T cell signaling and cytokine production in human T cells. SRSF1 levels are decreased in T cells from patients with systemic lupus erythematosus (SLE), and low levels correlate with severe disease. Moreover, T cell-conditional Srsf1-deficient mice recapitulate the autoimmune phenotype, exhibiting CD4 T cell hyperactivity, dysfunctional Tregs, systemic autoimmunity, and tissue inflammation. However, the role of SRSF1 in controlling molecular programs in Teffs and Tregs and how these pathways are implicated in autoimmunity is not known. Here, by comparative bioinformatics analysis, we demonstrate that SRSF1 controls largely distinct gene programs in Tregs and Teffs in vivo. SRSF1 regulates 189 differentially expressed genes (DEGs) unique to Tregs, 582 DEGs unique to Teffs, and 29 DEGs shared between both. Shared genes included IL-17A, IL-17F, CSF1, CXCL10, and CXCR4, and were highly enriched for inflammatory response and cytokine-cytokine receptor interaction pathways. SRSF1 controls distinct pathways in Tregs, which include chemokine signaling and immune cell differentiation, compared with pathways in Teffs, which include cytokine production, T cell homeostasis, and activation. We identified putative mRNA binding targets of SRSF1 which include CSF1, CXCL10, and IL-17F. Finally, comparisons with transcriptomics profiles from lupus-prone MRL/lpr mice reveal that SRSF1 controls genes and pathways implicated in autoimmune disease. The target genes of SRSF1 and putative binding targets we discovered, have known roles in systemic autoimmunity. Our findings suggest that SRSF1 controls distinct molecular pathways in Tregs and Teffs and aberrant SRSF1 levels may contribute to their dysfunction and immunopathogenesis of systemic autoimmune disease.

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The same systemic autoimmune disease provokes arthritis and endocarditis via distinct mechanisms.

Publications

The same systemic autoimmune disease provokes arthritis and endocarditis via distinct mechanisms.

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