Mechanisms of Immune Complex–Mediated Neutrophil Recruitment and Tissue Injury

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Deposition of antibody-antigen immune complexes (ICs) in tissues underlies the pathogenesis of a range of human autoimmune diseases from glomerulonephritis, systemic lupus erythematosus (SLE), arthritis, and transplantation rejection to rheumatic fever. Experimental and clinical evidence suggests that autoimmunity is a risk factor for cardiovascular disease (CVD). Here, we overview the literature that links autoimmune diseases and accelerated atherosclerosis and review our understanding of IC-induced inflammation. In particular, we discuss the contribution of the location and composition of ICs to the cellular and molecular mechanisms of disease that develop and detail the steps leading to IC-mediated leukocyte recruitment and tissue injury. The focus is on neutrophil-dependent tissue injury. Although these cells have not found a prominent place in discussions of chronic inflammatory conditions such as autoimmunity and atherosclerosis, recent literature discussed here indicates that neutrophils initiate IC-induced inflammation that in turn launches and informs the subsequent immune response. A fuller understanding of the mechanisms involved in the initiation and perpetuation of immunoglobulin G (IgG) antibody mediated inflammation may lead to the design of innovative therapeutic strategies to prevent cardiovascular complications in patients with autoimmune diseases. Well-controlled studies have demonstrated that autoimmunity is an independent risk factor for atherosclerotic lesions and premature myocardial infarction.1,2 Population-based studies in various countries have shown that CVD-associated mortality in patients with rheumatoid arthritis (RA) is 1.5 to 2.0 times higher than in control individuals.3–6 Similarly, increased rates of CVD have been reported in other forms of inflammatory arthritis, including giant cell arteritis7 and psoriatic arthritis.8 The risk for CVD and myocardial infarction is also pronounced in patients with SLE, a complex autoimmune disease affecting multiple organs. The Pittsburgh lupus cohort presented a 52-fold increase in cardiovascular events in young women with SLE.9 The Framingham Heart Study risk factors contribute to CVD …