ReviewThe role of Fc receptors and complement in autoimmunity
Introduction
Immunoglobulin G (IgG) molecules are a family of glycoproteins essential for defending the body against invading pathogens. The antibody constant domain is very efficient in initiating pro-inflammatory pathways such as the activation of innate immune effector cells via cellular receptors specific for the antibody constant region (Fcγ receptors; FcγRs) and the activation of the complement system, with the generation of further pro-inflammatory mediators. IgG antibodies consist of four different subclasses in mice (IgG1, IgG2a, IgG2b, and IgG3) and vary greatly in their capacity to recruit different effector pathways. Murine IgG1 antibodies, for example, cannot activate the complement system efficiently, whereas IgG2a, IgG2b and IgG3 do. Similarly, murine IgG3 binds only very weakly if at all to FcγRs but can efficiently activate the classical pathway of complement activation [1].
The family of the murine FcγRs consists of three activating (FcγRI, III, IV) and one inhibitory (FcγRIIB) member. Importantly, all inflammatory cell types (such as mast cells, monocytes, macrophages, eosinophils and neutrophils) express activating and inhibitory FcγRs simultaneously, thereby setting a threshold for cell activation by IgG [2]. Low affinity FcγRIII can be engaged by IgG1 and IgG2, whereas FcγRIV can be engaged by IgG2 antibodies only [1].
The activation of complement can occur by three different pathways, the classical (CP), the lectin (LP), and the alternative pathway (AP). The CP is activated primarily by antigen-antibody complexes binding to C1q, the LP is initiated by ficolins and mannan binding lectin (MBL) binding to certain carbohydrates, and the AP can be activated by spontaneous C3 hydrolysis or via properdin, generating C3(H2O), which can bind factor B (fB). Activation of each of these pathways generates C3-convertases resulting in activation of the common terminal pathway and initiating several effector responses, such as chemotaxis by C3a and C5a, opsonization by C3b, and cell lysis by the membrane attack complex (MAC) [3].
Occasionally, in the setting of an autoimmune disease, IgG antibodies to autologous structures may develop and cause different forms of tissue damage. Many informative animal models are available in which autoantibodies play a clear role, providing opportunities for detailed analysis of similar disease pathways operating in human autoimmune diseases. In this review we have focused on effector pathways involved in murine models of rheumatoid arthritis, glomerulonephritis and autoimmune subepidermal blistering diseases.
Section snippets
Murine models of arthritis
Several autoantibody-mediated mouse models are available to study rheumatoid arthritis (RA). The KxB/N serum transfer-induced arthritis (STIA), mediated by anti-glucose 6 phosphoisomerase antibodies, and the anti-collagen II (anti-CII) antibody-induced arthritis (CAIA) are two models which have been extensively used to study end-stage effector mechanisms in RA [4]. The use of C5−/− and FcγR−/− mice first showed that both effector mechanisms are necessary in STIA. Importantly, the AP and not the
Murine models of anti-glomerular basement membrane nephritis
Anti-glomerular basement membrane (GBM)-mediated glomerulonephritis plays an essential role in autoimmune diseases such as Goodpasture's syndrome, and is characterized by rapidly progressive glomerulonephritis and linear deposition of antibodies along the GBM [13]. Nephrotoxic serum nephritis is a widely used model of anti-GBM disease, in which anti-GBM antibodies are passively transferred into rodents. These antibodies cause acute glomerular injury, also referred to as the heterologous phase
Murine models of autoimmune subepidermal blistering diseases
Epidermolysis bullosa acquisita (EBA) is a severe chronic blistering disease of skin and mucous membranes characterized by tissue-bound and circulating IgG antibodies to type VII collagen (COL7), a major constituent of the dermal–epidermal junction [21]. The pathogenic relevance of anti-COL7 autoantibodies has been demonstrated in vivo by transferring antibodies against COL7 into adult mice [22], [23] and by immunizing mice with autologous COL7 [24]. Blister formation is dependent on the Fc
Integration of the FcγR and complement network influences
Autoantibodies interact with FcγRs and the complement network, inducing tissue injury. It was suggested that only one or the other effector arm may usually dominate an inflammatory response [31]. However, a growing body of evidence (summarized in Table 1) suggests that both FcγRs and the complement network can be equally indispensable for immune complex-mediated tissue injury. It is commonly accepted that low affinity FcγRs are critically involved in a wide range of antibody-complex diseases,
Take-home messages
- •
Both FcγRs and complement are necessary in certain autoimmune conditions.
- •
The critical role of the FcγRs is mediated by FcγRIII and/or the newly discovered FcγRIV.
- •
Pathologic activation of the complement system occurs mostly via the alternative pathway.
- •
Pro-inflammatory effects induced by C5a–C5a receptor binding are critical intermediates linking pathogenic antibodies to tissue damage.
- •
C5a can act as a general regulator of FcγR expression; similarly, FcγR signaling can be involved in the
Acknowledgments
This work was supported by grants MI1314/1-1 (to M.S.) and SFB643, FOR832, SPP1468 and GK1660 (to F.N.) from the German Research Foundation and by a grant from the Bavarian Genome Research Network (to F.N.). We apologize to all our colleagues whose important work could not be cited directly in this manuscript. These references can be found in the review articles cited in the paper.
References (43)
- et al.
Arthritis critically dependent on innate immune system players
Immunity
(2002) - et al.
Role of the complement system in rheumatoid arthritis and psoriatic arthritis: relationship with anti-TNF inhibitors
Autoimmun Rev
(2011) - et al.
Goodpasture's disease
Lancet
(2001) - et al.
Evidence that anti-type VII collagen antibodies are pathogenic and responsible for the clinical, histological, and immunological features of epidermolysis bullosa acquisita
J Invest Dermatol
(2005) - et al.
Fc receptors and their interaction with complement in autoimmunity
Immunol Lett
(2005) - et al.
Fcgamma receptors: old friends and new family members
Immunity
(2006) - et al.
The role of the anaphylatoxins in health and disease
Mol Immunol
(2009) - et al.
Phosphoinositide 3-kinases gamma and delta, linkers of coordinate C5a receptor-Fcgamma receptor activation and immune complex-induced inflammation
J Biol Chem
(2008) - et al.
Pathways: strategies for susceptibility genes in SLE
Autoimmun Rev
(2010) - et al.
Systemic lupus erythematosus and infections: clinical importance of conventional and upcoming biomarkers
Autoimmun Rev
(2012)
The pro and anti-inflammatory activities of immunoglobulin G
Ann Rheum Dis
Antibody-mediated modulation of immune responses
Immunol Rev
The spectrum of complement alternative pathway-mediated diseases
Immunol Rev
Antibody-induced arthritis: disease mechanisms and genes involved at the effector phase of arthritis
Arthritis Res Ther
FcgammaRIV deletion reveals its central role for IgG2a and IgG2b activity in vivo
Proc Natl Acad Sci U S A
Essential role of Fc gamma receptors in anti-type II collagen antibody-induced arthritis
J Immunol
Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis
J Immunol
Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis
Eur J Immunol
Passive transfer studies with type II collagen antibody in B10.D2/old and new line and C57Bl/6 normal and beige (Chediak–Higashi) strains: evidence of important roles for C5 and multiple inflammatory cell types in the development of erosive arthritis
Arthritis Rheum
Role of C3a receptors, C5a receptors, and complement protein C6 deficiency in collagen antibody-induced arthritis in mice
J Immunol
Protection and injury: the differing roles of complement in the development of glomerular injury
Eur J Immunol
Cited by (54)
Fc receptors gone wrong: A comprehensive review of their roles in autoimmune and inflammatory diseases
2022, Autoimmunity ReviewsPhytoestrogens protect joints in collagen induced arthritis by increasing IgG glycosylation and reducing osteoclast activation
2020, International ImmunopharmacologyCitation Excerpt :In addition, studies have found that galactosylated ICs bind to FcγRIIb more effectively and initiate an anti-inflammatory signaling cascade [56]. Similarly, galactosylation of ICs has been reported to inhibit the pro-inflammatory activity of complement component C5a [57]. It is also important to note that agalactosylation of IgG activates complement through alternative pathway [58] and plays a pro-inflammatory role through the lectin pathway after binding to mannose-binding lectin (MBL) [59].
IgG glycan patterns are associated with type 2 diabetes in independent European populations
2017, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :These associations are largely in line with previous reports on IgG glycosylation and total N-glycome in these traits [6–8,21,24]. The associations we found in type 2 diabetes are reflective of an overall pro-inflammatory state and biological aging [3,7,11,25–28]. In the most extensive model, the associations were in concordance with a decrease in galactosylation and sialylation, an increase in fucosylated structures with bisecting GlcNac, and a decrease in fucosylated structures without bisecting GlcNAc.
Effects of statins on the immunoglobulin G glycome
2017, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :FA2B is one of the IgG's agalactosylated glycans. Glycans that lack terminal galactose activate complement and make IgG pro-inflammatory [30–32]. Also, FA2B is one of three glycans that change considerably with age (along with FA2G2 and FA2BG2) and the combination of these three glycans can explain up to 58% of variance in chronological age [33].