Role of Bruton’s Tyrosine Kinase and Interleukin-6 in Plasma Cell Accumulation and Autoantibody Production in Lyn-Deficient Mice, A Model of Lupus




Gutierrez, Maria Antonietta

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Systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nuclear antigens such as DNA and chromatin, resulting in autoantibody production, immune complex deposition, inflammation, and end organ damage such as glomerulonephritis (GN). Currently, only non-specific, immunosuppressive therapies are approved for use in lupus patients. These have undesirable side effects and risks. The development of more targeted therapies is necessary and requires a better understanding of the mechanisms that contribute to the production of autoantibodies. Mice deficient in Lyn, a gene associated with human lupus, develop several features characteristic of SLE, including peripheral plasma cell accumulation, anti-dsDNA antibodies, and GN. Lyn is a Src-family tyrosine kinase that, in general, inhibits B cell and myeloid cell activity. Loss of Lyn results in cellular hyperactivity associated with autoantibody production. Bruton’s tyrosine kinase (Btk), which is critical to B cell receptor (BCR) signaling, mediates BCR hypersensitivity and autoantibody production in lyn-/- mice. B cell hyperresponsiveness is not, however, sufficient for the autoimmune phenotype; additional Btk-dependent events are required. Btk also contributes to myeloid cell function, and generally opposes Lyn action in these cells as in B cells. However, the relative contribution of myeloid hyperactivity to autoantibody production in lyn-/- mice is unknown. Lyn-deficient mice expressing reduced Btk dosage in B cells and no Btk in myeloid cells were utilized to better define how Lyn and Btk regulate and mediate, respectively, the progression from tolerance to autoimmunity. Two major checkpoints regulating autoantibody production were identified and found to be breached in lyn-/- mice. The first checkpoint regulates Btk-mediated accumulation of long-lived plasma cells co-incident with polyclonal IgM autoreactivity. This is due in part to impaired migration of lyn-/- plasma cells towards SDF-1 and involves a B cell intrinsic effect of Lyn-deficiency. The second checkpoint regulates the class-switching of B cells with lupus-associated autoantigen specificities and the production of pathogenic autoantibodies. This step requires IL-6, which is produced in excess by lyn-/- myeloid cells in a Btk-dependent manner.
These results suggest that both B and myeloid defects contribute to autoimmunity in lyn-/- mice and identify Btk and IL-6 as potential therapeutic targets for SLE.

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