The role of C5a receptors in autoimmunity.

The complement system is an essential component of the innate immune response and plays a vital role in host defense and inflammation. Dysregulation of the complement system, particularly involving the anaphylatoxin C5a and its receptors (C5aR1 and C5aR2), has been linked to several autoimmune diseases, indicating the potential for targeted therapies. C5aR1 and C5aR2 are seven-transmembrane receptors with distinct signaling mechanisms that play both partially overlapping and opposing roles in immunity. Both receptors are expressed on a broad spectrum of immune and non-immune cells and are involved in cellular functions and physiological processes during homeostasis and inflammation. Dysregulated C5a-mediated inflammation contributes to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, epidermolysis bullosa acquisita, antiphospholipid syndrome, and others. Therefore, targeting C5a or its receptors may yield therapeutic innovations in these autoimmune diseases by reducing the recruitment and activation of immune cells that lead to tissue inflammation and injury, thereby exacerbating the autoimmune response. Clinical trials focused on the inhibition of C5 cleavage or the C5a/C5aR1-axis using small molecules or monoclonal antibodies hold promise for bringing novel treatments for autoimmune diseases into practice. However, given the heterogeneous nature of (systemic) autoimmune diseases, there are still several challenges, such as patient selection, optimal dosing, and treatment duration, that require further investigation and development to realize the full therapeutic potential of C5a receptor inhibition, ideally in the context of a personalized medicine approach. Here, we aim to provide a brief overview of the current knowledge on the function of C5a receptors, the involvement of C5a receptors in autoimmune disorders, the molecular mechanisms underlying C5a receptor-mediated autoimmunity, and the potential for targeted therapies to modulate their activity.

Anaphylatoxins spark the flame in early autoimmunity.

The complement system (CS) is an ancient and highly conserved part of the innate immune system with important functions in immune defense. The multiple fragments bind to specific receptors on innate and adaptive immune cells, the activation of which translates the initial humoral innate immune response (IR) into cellular innate and adaptive immunity. Dysregulation of the CS has been associated with the development of several autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ANCA-associated vasculitis, and autoimmune bullous dermatoses (AIBDs), where complement drives the inflammatory response in the effector phase. The role of the CS in autoimmunity is complex. On the one hand, complement deficiencies were identified as risk factors to develop autoimmune disorders. On the other hand, activation of complement can drive autoimmune responses. The anaphylatoxins C3a and C5a are potent mediators and regulators of inflammation during the effector phase of autoimmunity through engagement of specific anaphylatoxin receptors, i.e., C3aR, C5aR1, and C5aR2 either on or in immune cells. In addition to their role in innate IRs, anaphylatoxins regulate humoral and cellular adaptive IRs including B-cell and T-cell activation, differentiation, and survival. They regulate B- and T-lymphocyte responses either directly or indirectly through the activation of anaphylatoxin receptors via dendritic cells that modulate lymphocyte function. Here, we will briefly review our current understanding of the complex roles of anaphylatoxins in the regulation of immunologic tolerance and the early events driving autoimmunity and the implications of such regulation for therapeutic approaches that target the CS.

C5aR2 Deficiency Ameliorates Inflammation in Murine Epidermolysis Bullosa Acquisita by Regulating Fcγ Receptor Expression on Neutrophils.

Epidermolysis bullosa acquisita (EBA) is a rare blistering skin disease induced by autoantibodies directed against type VII collagen. The transfer of antibodies against murine type VII collagen into mice mimics the effector phase of EBA and results in a subepidermal blistering phenotype. Activation of the complement system, and especially the C5a/C5aR1 axis driving neutrophil activation, is critical for EBA pathogenesis. However, the role of the alternative C5a receptor, C5aR2, which is commonly thought to be more immunosuppressive, in the pathogenesis of EBA is still elusive. Therefore, we sought to delineate the functional relevance of C5aR2 during the effector phase of EBA. Interestingly, C5ar2-/- mice showed an attenuated disease phenotype, suggesting a pathogenic contribution of C5aR2 in disease progression. In vitro, C5ar2-/- neutrophils exhibited significantly reduced intracellular calcium flux, ROS release, and migratory capacity when activated with immune complexes or exposed to C5a. These functions were completely absent when C5ar1-/- neutrophils were activated. Moreover, C5aR2 deficiency lowered the ratio of activating and inhibitory FcγRs, impeding the sustainment of inflammation. Collectively, we show here a proinflammatory contribution of C5aR2 in the pathogenesis of antibody-induced tissue damage in experimental EBA.