The critical role of C5a as an initiator of neutrophil-mediated autoimmune inflammation of the joint and skin

Abstract

The deposition of IgG autoantibodies in peripheral tissues and the subsequent activation of the complement system, which leads to the accumulation of the anaphylatoxin C5a in these tissues, is a common hallmark of diverse autoimmune diseases, including rheumatoid arthritis (RA) and pemphigoid diseases (PDs). C5a is a potent chemoattractant for granulocytes and mice deficient in its precursor C5 or its receptor C5aR1 are resistant to granulocyte recruitment and, consequently, to tissue inflammation in several models of autoimmune diseases. However, the mechanism whereby C5a/C5aR regulates granulocyte recruitment in these diseases has remained elusive. Mechanistic studies over the past five years into the role of C5a/C5aR1 in the K/BxN serum arthritis mouse model have provided novel insights into the mechanisms C5a/C5aR1 engages to initiate granulocyte recruitment into the joint. It is now established that the critical actions of C5a/C5aR1 do not proceed in the joint itself, but on the luminal endothelial surface of the joint vasculature, where C5a/C5aR1 mediate the arrest of neutrophils on the endothelium by activating β₂ integrin. Then, C5a/C5aR1 induces the release of leukotriene B₄ (LTB₄) from the arrested neutrophils. The latter, subsequently, initiates by autocrine/paracrine actions via its receptor BLT1 the egress of neutrophils from the blood vessel lumen into the interstitial. Compelling evidence suggests that this C5a/C5aR1-LTB₄/BLT1 axis driving granulocyte recruitment in arthritis may represent a more generalizable biological principle critically regulating effector cell recruitment in other IgG autoantibody-induced diseases, such as in pemphigoid diseases. Thus, dual inhibition of C5a and LTB₄, as implemented in nature by the lipocalin coversin in the soft-tick Ornithodoros moubata, may constitute a most effective therapeutic principle for the treatment of IgG autoantibody-driven diseases.

Keywords: Autoantibodies; Autoantibody-driven tissue inflammation; Autoimmune disease; BLT1; Bullous pemphigoid; C5a; C5a/LTB4 axis; C5aR1; C5aR2; Chemoattractants; Chemokines; Complement; Coversin; Epidermolysis bullosa acquisita; Extravasation; K/BxN model; Leukotriene B4; Lipid-cytokine-chemokine cascade; Neutrophil migration; Neutrophils; Pemphigoid diseases; Rheumatoid arthritis.