Anaphylatoxins spark the flame in early autoimmunity

Abstract

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.

Keywords: C3a; C5a; anaphylatoxins; break of tolerance; complement; early autoimmunity.

Figure 1

Impact of the anaphylatoxins on DC-mediated and intrinsic T cell activation. (A) The genetic absence or pharmacological targeting of C5aR1 on DCs leads to attenuated T helper type 1 (T_H1) immunity and an increased frequency of Regulatory T cells (Tregs). (B) C5aR1 signaling on naïve mucosal conventional DC2 (cDC2) controls the expression of CD40 and MHC-II which determines the threshold of naïve CD4⁺ T cell activation. Mucosal antigen exposure is associated with decreased C5aR1 expression; the lack of C5aR1 expression in cDC2s releases the break on CD40 and MHC-II expression resulting in strong CD4⁺ T cell proliferation and the break of mucosal tolerance. (C) T cell activation triggers the secretion of preformed C3 and C5 into the extracellular space, which can be cleaved into C3a, C3b, C5a, and C5b by canonical and non-canonical mechanisms. Binding of these complement fragments to their respective receptors on the T cell induces CD4⁺ T_H1 and CD8⁺ effector T cell functions. C3 and C5 are also processed intracellularly by proteases such as cathepsin L (CTSL) in the case of C3 and an unknown protease in the case of C5, respectively. Intracellular C3a is critical to maintain low-level mechanistic target of rapamycin (mTOR) activity by binding to C3aR on lysosomes, thereby contributing to the homeostatic survival of CD4⁺ T cells. The cleavage of intracellular C5 into C5a and C5b is enhanced by CD46-mediated signaling. C5a engages C5aR1 triggering NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome assembly, eventually driving T_H1 differentiation of CD4⁺ T cells and CD8⁺ effector T cell functions. Importantly, autocrine engagement of surface-expressed C5aR2 by C5a-desArg can control intracellular C5aR1 activity. Created in BioRender.com.

Figure 2

Anaphylatoxin receptor activation on TFH cells and GC B cells controls the production of IgG (auto)antibodies (A) C5aR1 signaling on CD4+ T cells facilitates the expansion of TFH cells and their subsequent production of IL-4 and IL-21, which are crucial for the germinal center reaction. The absence of C5aR1 signaling leads to an attenuated TFH cell expansion and reduced GC reaction. (B) During the GC reaction, C3a and C5a engage their receptors, C3aR and C5aR1 respectively, on GC B cells, driving B cell proliferation and differentiation into memory B cells (B_mem) as well as long-lived plasma cells (PC). When complement activation is inhibited (bottom) either by decay-accelerating factor (DAF, CD55) over-expression or deletion of C3aR/C5aR1 on GC B cells, (1) GCs collapse prematurely due to impaired dark zone re-entry and affinity maturation (2), resulting in decreased generation of Bmem and long-lived PCs (3). Created in BioRender.com.