Role of complement in autoimmunity - lessons from models and man
Professor Marina Botto FMedSci
Complement has been shown to contribute to the immunopathology of several autoimmune diseases including systemic lupus erythematosus (SLE). Notwithstanding that, and somewhat paradoxically, complement also appears able to protect against autoimmunity since complement deficiencies, particularly of the early components of the classical pathway (C1q, C4, C1r and C1s) are associated with autoimmune disorders, particularly SLE. There are currently mainly two favoured mechanisms whereby deficiency or low levels of complement might lead to the autoimmune manifestations of SLE, and these are not mutually exclusive. One is the “waste-disposal” hypothesis whereby in the absence of complement apoptotic cells and immune complexes fail to be cleared effectively promoting further autoantibody production and inflammation. The second, “tolerance hypothesis”, relates to the role of complement in regulating both B and T cell immune responses. However, none of the current hypotheses can provide a unifying explanation of why C1q and not C3 deficiency predisposes to autoimmunity as both molecules play important roles in the clearance of apoptotic cells/immune complexes and exert analogous immunoregulatory roles. A possible explanation comes from our recent findings that C3 has an additional role: it can influence intracellular trafficking by inducing delayed lysosomal fusion of apoptotic cell cargo. C3 opsonisation can regulate the endocytic handling of apoptotic cells, a process that is essential for optimal T cell activation. In the absence of C3, the T cell proliferation in response to apoptotic cell-associated self-antigens is impaired and this may prevent the development of SLE. Hence C3 is uniquely required for both the generation of optimal T cell immune responses to self-antigens displayed on dying cells and their clearance. In the absence of C3, both arms of this process are impaired and autoimmunity is prevented.
The membrane attack complex as an inflammatory trigger
Professor Paul Morgan FMedSci
The final common pathway of all routes of complement activation involves the non-enzymatic assembly of a complex comprising newly formed C5b with the plasma proteins C6, C7, C8 and C9. When assembly occurs on target cell membrane the forming complex inserts into and through the bilayer to create a pore, the membrane attack complex (MAC). On some targets, pore formation causes rapid lytic destruction; however, most nucleated cell targets resist lysis through a combination of ion pumps, membrane regulators and active recovery processes. Cells survive but not without consequence. The MAC pore causes ion fluxes and directly or indirectly impacts several important signalling pathways that in turn activate a diverse series of events in the cell, many of which are highly pro-inflammatory. Although this non-lytic, pro-inflammatory role of MAC has been recognised for thirty years, no consensus signalling pathway has emerged. Recent work has implicated specific signalling routes and, in some cells, inflammasome involvement opening the door to novel approaches to therapy in complement-driven pathologies.
The amplification loop drives inflammation
Professor Sir Peter Lachmann FMedSci FRS
The C3b feedback cycle, or C3 amplification loop, lies at the very heart of the complement system. It is the basis of the alternative complement pathway but also amplifies the classical and lectin pathways. It is a highly unusual triggered enzyme cascade where the concentrations of two enzymes that do not require to be activated (Factor I and Factor D) nevertheless influence greatly the extent of amplification. The C3 amplification loop also gives rise, as a side product, to the breakdown fragment, iC3b, whose reaction with CR 3 on neutrophils is required for all complement mediated inflammation and synergises with the action of C5a in recruiting and activating neutrophils the cells which are the principal mediators of complement mediated inflammation.
The lectin activation pathway of complement in health and disease
Professor Hans-Wilhelm Schwaeble
Of the three initiation routes of complement activation, the lectin pathway appears to be the most complex and least understood sensor and effector of the innate humoral immune response. The sensors of this pathway are pattern recognition molecules that direct activation of three different effector enzymes. They drive complement activation through two independently operating effector arms. While deficiencies of specific lectin pathway components were shown to lead to defects during embryonic development and predispositions to infectious disease, the specific pathophysiological contributions of each of the two lectin pathway effector arms to inflammatory pathologies is subject of current research. So far, it has been shown that one of the lectin pathway effector arms is exclusively involved in the pathophysiology of an inflammatory condition called ischaemia/reperfusion injury. The other lectin pathway effector arm was shown to critically contribute to the pathophysiology of haemolytic disease and collagen-induced arthritis. The intricate ways in which all three complement activation pathways correspond and modulate inflammatory conditions requires a more detailed understanding to open new therapeutic avenues in the treatment of inflammatory disease.