Control of autoimmune responses through bidirectional cross-talk between the C5a/C5aR1 axis and IgG Fc receptors
- The regulation of the complement cascade at different stages of canonical activation through soluble and receptor-bound complement regulatory proteins such as factor H, CD46, CD55 and CD59 is well appreciated. Less is known about the control of anaphylatoxin receptors. This is surprising given their powerful proinflammatory and immunoregulatory properties in allergic, autoimmune and infectious diseases and their impact on cell homeostasis, metabolism and repair.
Previously it has been shown that the C5a/C5aR1 axis controls FcγR expression thereby modulating IC-mediated inflammation (Karsten and Köhl 2012). More specifically, C5a upregulates the expression of activating FcgRIIII but downregulates the expression of FcgRIIB. Importantly, this cross-talk between the C5a/C5aR1 axis and FcgRs is bidirectional and builds the framework for IgG1-mediated control of C5aR1-mediated activation of innate immune cells (Figure 2). In fact, some IgG1-IC can block C5aR1-induced recruitment and actvation of neutrophils and macrophages. Key to the inhibitory properties of IgG1 antibodies is is their Fc-glycan composition. IgG molecules are N-glycosylated in their CH2 domain at Asn297. The attached sugars can be mannose, N-acetyl-glucosamine (GlcNAc), bisecting GlcNAc, galactose or sialic acid. When IgG1 antibodies harbor an Fc-glycan structure that terminate with galactose, they gain the ability to aggregate FcgRIIB and Dectin-1. This heterodimerization induces a signaling cascade which inhibits C5aR1-mediated ERK1/2 phosphorylation thus blocking C5a-induced cell migration and activation (Karsten et al. Nat. Med. 2012). Thus, the adaptive B cell response and the production of antigen-specific IgG1 may attenuate C3aR/C5aR1-mediated activation of innate effector cells (neutrophils, eosinophils, mast cells) or amplify it, depending on the Fc-glycan composition. In a proof of concept approach, highly-galactosylated IgG1-IC attenuated the formation of blister formation in a model of autoimmune bullous dermatoses (AIBD).
Figure 1: Bidirectional cross-talk between C5a receptor and IgG Fc receptor signaling. (A) In the mouse system, IgG2a or IgG2b ICs activate complement, resulting in the generation of C5a. (B) Activation of the C5aR on macrophages results in the upregulation of activating FcgRs and downregulation of the inhibitory FcgRIIB, thereby reducing the threshold for FcgR-mediated stimulation of macrophages. (C) IC-triggered ligation of activating FcgRs promotes the production of C5 and activates proteases that cleave C5 into C5a, thereby amplifying the C5a-induced inflammation. (D) Highly galactosylated IgG1 IC bind to FcgRIIB and associate FcgRIIB with Dectin-1. This heterodimer formation induces an anti-inflammatory pathway blocking C5aR-mediated effector functions.
This project aims to further delineate the complex cross-talk of the C5aR1 and IgG Fc receptors and its impact on both, the sensitization and effector phases of autoimmune responses.
Figure 1: Bidirectional cross-talk between C5a receptor and IgG Fc receptor signaling. (A) In the mouse system, IgG2a or IgG2b ICs activate complement, resulting in the generation of C5a. (B) Activation of the C5aR on macrophages results in the upregulation of activating FcγRs and downregulation of the inhibitory FcγRIIB, thereby reducing the threshold for FcR-mediated stimulation of macrophages. (C) IC-triggered ligation of activating FcγRs promotes the production of C5 and activates proteases that cleave C5 into C5a, thereby amplifying the C5a-induced inflammation. (D) Highly galactosylated IgG1 IC bind to FcγRIIB and associate FcγRIIB with Dectin-1. This heterodimer formation induces an anti-inflammatory pathway blocking C5aR-mediated effector functions.
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- Ludwig R.J., Kalies K., Köhl J., Schmidt E., Zillikens D. Emerging treatments for pemphigoid disease. Trends Mol. Med. 2013 19:501-512.
- Iwata H., Bieber K., Tiburzy B., Chrobok N., Kalies L., Shimizu A., Leineweber S., Ishiko A., Vorobyev A., Zillikens D., Köhl J., Westermann J., Seeger K., Manz R., Ludwig R.J.. B cells, dendritic cells, and macrophages are requried to induce an autoreactive CD4 helper T cell response in experimental epidermolysis bullosa acquisita. 2013 J. Immunol. 191:2978-2988.
- Schulze F.S., Beckmann T., Nimmerjahn F., Ishiko A., Collin M., Köhl J., Goletz S., Zillikens D., Ludwig R., Schmidt E.. FcgRIIB, FcgRIII and FcgRIV mediate tissue destruction in experimental bullous pemphigoid. 2014 Am. J. Pathol. 184:2185-2196.
- Kemmer A., Bieber K., Abadpour A., Yu X., Mitschker N., Roth A., Kauderer C., Ludwig R.J., Seeger K., Köhl J., Zillikens D., Recke A. A recombinant fusion protein derived from dog hookworm inhibits autoantibody-induced dermal-epidermal separation ex vivo. 2015 Exp. Dermatol. 24:872-878.
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RTG 1727 Project A5 The relevance of the C5a/C5aR1-axis for induction of autoantibody response in EBA
CRU 303 Project 3 The C5a/C5aR1 axis as a regulator of autoreactive IgG glycosylation in pemphigoid diseases