Extravasations and emigration of neutrophils to the inflammatory site depend on the interaction of immune-complex with Fcγ receptors and can be effectively blocked by decoy Fcγ receptors

Abstract

IntroductionAutoimmune diseases are heterogeneous in nature and are the most frequent cause of disability in adults. 1 Many autoimmune diseases lead to vital organ damage, disability and are often fatal in humans. Both the cellular and humoral arms of the immune system are involved in the pathogenesis of autoimmune diseases. Abnormal activation of autoantigen specific T and B cells due to molecular mimicry, viral infections, or cytokine dysregulation are among the suggested mechanisms for the initiation of the disease. 2 In many autoimmune diseases the binding of autoantibodies to tissues causes tissue injury. The effector functions of the Fc domains of these tissue-antigen bound antibodies depend on their ability to interact with complement components and/or Fc gamma receptors (Fc␥Rs) expressed on inflammatory cells. The relative role and contribution of these 2 effector systems to the initiation and development of antibody mediated inflammatory diseases are still under intense investigation.Studies have shown that the accumulation of neutrophils at the site of IC deposition is pivotal to the development of antibodymediated autoimmune inflammation. 3 The ICs trigger complement activation and production of chemotactic peptides such as C5a, which directly attract neutrophils to the inflammatory site. 4,5 Apart from attracting neutrophils, C5a also induce degranulation of mast cells resulting in further recruitment of neutrophils to the site of IC deposition. [5][6][7] These studies were further supported by the fact that mice deficient in C5a receptor gene show attenuated autoantibodyinduced inflammation. 4,8 Thus the complement peptides produced by IC orchestrate accumulation of neutrophils and cause tissue damage. On the other hand, studies using Fc␥ knockout mice have demonstrated the pivotal role of Fc␥Rs in neutrophil recruitment 9,10 and antibody-mediated autoimmune diseases. The Fc␥ subunit is essential for cell-surface expression of activating Fc␥Rs such as CD64, Fc␥RIV, and CD16A. [11][12][13][14] These Fc␥ or CD16A gene knockout mice did not develop autoimmune diseases under experimental conditions that induced the diseases in wild type mice. [15][16][17][18] Although these knockout mice studies have demonstrated independent roles of complement and Fc␥Rs, recent observations suggest interdependency of these 2 pathways in the progression of inflammation. 19 At the inflammatory site, C5a increases the potency of the Fc␥R-dependent inflammatory pathway by up-regulating activating CD16A while downregulating inhibitory CD32B in inflammatory cells. 20 Furthermore, the interaction of IC with CD16A upregulates the production of cell-derived C5. 21 This suggests that the absence of the complement pathway might influence the effectiveness of the Fc␥R-mediated pathway of inflammation and vice versa. Because many of these studies used either gene knockout mice or mast cell deficient mice which might have adapted developmental compensatory mechanisms, the results and interpretations of the relative role of these fun...

Truncated and Full-Length Thioredoxin-1 Have Opposing Activating and Inhibitory Properties for Human Complement with Relevance to Endothelial Surfaces

“…Inflammation caused by RPA depends on FcR and complement-mediated mechanisms (42)(43)(44), with early involvement of mast cells (45,46) and later contribution of macrophages (45). Several studies in which the C5aR has been pharmacologically targeted or genetically deleted provide compelling evidence for a critical role of C5a in initiating the inflammatory cascade in immune complex peritonitis (26,47).…”

Hsp60 and Hsp10 increase in colon mucosa of Crohn’s disease and ulcerative colitis

“…Since we now know that Hsp60 and Hsp10 travel everywhere outside cells it is possible for the immune system and antibodies to encounter these molecules, including the autologous ones, and react against them. Accumulation of antigen-antibody complexes in the mucosa would trigger a series of pathological events leading to perpetuation of inflammation and tissue destruction (Clynes et al 1999;Shashidharamurthy et al 2008;Mayadas et al 2009). In this situation the two chaperonins would have a pathogenic effect, opposite to the cytoprotection mentioned in the alternative (1) describe above, namely a pathogenic effect typical of autoimmune diseases.…”

Immune Complex-Mediated Enhancement of Secondary Antibody Responses

“…To determine whether this action plays a role in the generation of secondary Ab responses, we blocked ICs from binding to FcgRs by using CD32-Ig, a recombinant soluble FcgR dimer that binds the Fc regions of ICs with higher avidity than do cell-surface FcgRs (21,22). We immunized cohorts of B6 mice i.p.…”