Rather, our results suggest that pathogenic antibodies produced by the adaptive immune system participate activating FcRs on innate immune effector cells to drive valvular carditis. In this study, we found that no single activating FcR (FcRI, III or IV) was solely responsible for Dimesna (BNP7787) the development of valvular carditis in K/BxN mice. FcRIII and FcRIV acted redundantly to promote valvular carditis in the K/BxN mouse model of systemic autoantibody-associated arthritis. Macrophage depletion reduced the severity of valve swelling. These findings suggest that pathogenic autoantibodies participate FcRs on macrophages to drive valvular carditis and provide new insight into the pathogenesis of cardiovascular swelling in the establishing of autoantibody-associated chronic inflammatory diseases. Several systemic autoimmune diseases characterized by autoantibody production impact both the synovial joints and the heart, including systemic lupus erythematosus (SLE), anti-phospholipid syndrome, acute rheumatic fever, and rheumatoid arthritis (RA) (1-3). Most notable is the improved cardiovascular morbidity and mortality among individuals with SLE and RA due to atherosclerotic coronary artery disease. This improved risk is not fully explained by traditional risk factors, Rabbit Polyclonal to Histone H2B strongly suggesting the chronic inflammatory diseases themselves contribute to poor cardiovascular results (4-6). Cardiac manifestations of these diseases also include valvular carditis (2). The immune mechanisms by which these diseases provoke swelling of the joints and also the cardiovascular system remain poorly recognized. T cell receptor (TCR) transgenic K/BxN mice develop spontaneous, fully penetrant, autoantibody-associated arthritis and valvular carditis (7, 8). The valve swelling in these mice shares several pathologic features with the valvular carditis found in rheumatic conditions. Specifically, it affects left-sided valves, is definitely characterized by immunoglobulin G (IgG) and match C3 binding to the valves and a cellular infiltrate comprising mainly T cells and mononuclear myeloid cells (2, 7, 9, 10). Neutrophils are not found in the inflamed valve in these mice (7). This model system is consequently well-suited to address how systemic autoimmune inflammatory diseases travel cardiac pathology. Autoimmunity in K/BxN mice is initiated by a breach of immunological self-tolerance when T lymphocytes bearing Dimesna (BNP7787) the transgene-encoded KRN TCR identify peptides derived from the ubiquitously indicated antigen glucose-6-phosphate isomerase (GPI) offered by the major histocompatibility complex (MHC) class II molecule I-Ag7 (8, 11). This ultimately prospects to the sustained production of anti-GPI IgG autoantibodies. Transfer of anti-GPI autoantibodies causes arthritis in recipient mice (12). Interruption of any of Dimesna (BNP7787) the events leading to the production of autoantibodies abrogates the development of both arthritis and valvular carditis (7). However, the downstream immune effector mechanisms responsible for arthritis and carditis with this model differ. Specifically, arthritis requires complement component C5 but not the common Fc receptor gamma signaling chain (FcR). Conversely, valvular carditis requires FcR but not C5 (7). FcR is an immunoreceptor tyrosine-based activation motif (ITAM)-comprising signaling molecule that pairs with activating Fc gamma receptors (FcRs) and several other types of receptors; it is required for cell surface expression of the receptors and for transmission transduction (13-15). FcRs bind the Fc portion of IgG (13, 15). You will find two general categories of FcRs: activating and inhibitory. In mice, the activating FcRs are FcRI, III and IV. These receptors have unique IgG-binding alpha chains, but share the common gamma signaling chain, FcR. The inhibitory receptor, FcRII, does not associate with FcR. The activating FcRs have distinct cellular expression patterns, predominantly on myeloid cells. They bind the different IgG subtypes with varying affinities: FcRI and IV mainly bind IgG2a/c and IgG2b, whereas FcRIII binds IgG1 more strongly than it binds IgG2a/c and IgG2b (13, 15). The knowledge that the common gamma signaling chain FcR is required for valvular carditis in K/BxN mice led to two hypotheses: 1) that one or more of the activating Fc gamma receptors is required or 2) that a different FcR-associated receptor is at work. Here we used a genetic approach to dissect these options and also explored what FcR-expressing cells are the important drivers of valvular carditis in K/BxN mice. Materials and Methods Mice KRN TCR transgenic mice within the C57BL/6 (B6) background and B6 mice congenic for H-2g7 (B6.g7) were gifts from Diane Mathis and Christophe Benoist (Harvard Medical School, Boston, MA, USA and the Institut de Gntique et de Biologie Molculaire et Cellulaire, Strasbourg, France) (7, 8). C5-deficient B6 mice congenic for the non-obese diabetic (NOD)-derived allele (encoding non-functional C5) were also a gift from Drs. Mathis and Benoist (7, 16). C3-deficient mice within the B6 background were a gift from Michael Carroll (Harvard Medical School, Boston, MA, USA) (17). FcR (have been previously explained (19). Mice with the targeted deletion.
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