The yin and the yang of early classical pathway complement disorders

Abstract

The classical pathway of the complement cascade has been recognized as a key activation arm, partnering with the lectin activation arm and the alternative pathway to cleave C3 and initiate the assembly of the terminal components. While deficiencies of classical pathway components have been recognized since 1966, only recently have gain-of-function variants been described for some of these proteins. Loss-of-function variants in C1, C4, and C2 are most often associated with lupus and systemic infections with encapsulated bacteria. C3 deficiency varies slightly from this phenotypic class with membranoproliferative glomerulonephritis and infection as the dominant phenotypes. The gain-of-function variants recently described for C1r and C1s lead to periodontal Ehlers Danlos syndrome, a surprisingly structural phenotype. Gain-of-function in C3 and C2 are associated with endothelial manifestations including hemolytic uremic syndrome and vasculitis with C2 gain-of-function variants thus far having been reported in patients with a C3 glomerulopathy. This review will discuss the loss-of-function and gain-of-function phenotypes and place them within the larger context of complement deficiencies.

Keywords: HUS; gingival detachment; glomerulopathy; lupus; periodontal disease; sepsis.

Graphical Abstract

Figure 1

the classical pathway of the complement cascade is displayed. C1q, C1r, C1s, C4, and C2 comprise the activation pathway for C3, ultimately generating the classical pathway C3 convertase of C4b2a and the C5 convertase of C4b2a3b. The tulip shaped structure of C1q is formed from six heterotrimers of C1qA, C1qB, and C1qC. It is integrated with two each of the enzymes C1r and C1s, forming the C1 complex. Once activated through binding of the globular heads to the Fc region of IgG or IgM (or other activators via the stalk region), the conformational change allows C1r to cleave the other C1r and then both C1s molecules, thereby activating C1s for cleavage of first C4 and then C2. C4b covalently binds the surface of the pathogen, nucleating the assembly of the C3 and C5 convertases. Once C5 is cleaved, the membrane attack complex self assembles, stabilized by C9. The early stages of complement deposition facilitate engulfment by neutrophils (i.e., opsonization) through recognition of C3b and iC3b (inactivated C3b) by the CR1 receptor on neutrophils, also known as CD35, which augments phagocytosis mediated by Fc receptors. CR3 receptors (CD11bCD18) are upregulated on neutrophils in inflammatory states and also bind iC3b and can mediate phagocytosis. C1q receptors play a limited role for pathogen uptake but are important for the clearance of apoptotic cells. (Produced in Biorender).

Figure 2

soluble cleavage products of classical pathway activation are biologically active in a variety of roles. C3a and C5a have sequence and structural similarity but bind distinct G-protein coupled receptors. The C3aR is expressed on cells of myeloid origin, endothelial cells, epithelial cells and smooth muscle cells. C5aR is also highly expressed on myeloid cells, with expression on endothelial cells, neurons, microglia, astrocytes, and some specific tissues. Both C3a and C5a can trigger an oxidative burst, histamine release from mast cells and basophils and activation of eosinophils. They have additionally been implicated in tissue repair and T cell responses. C4a is structurally similar to C3a and C5a and has been found to induce comparable vascular responses but at very high doses. A receptor for C4a has been contentiously debated although some data suggest that it may bind to protease activated receptors 1 and 4, however, there is as yet little consensus on the mechanism of action of C4a and the biological role is similarly debated. (Produced in Biorender).