With Complements from ANCA Mice

Abstract

ANCA is found in the vast majority of patients with active smallvessel vasculitis. This disease group includes what is now known as granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and a renallimited disease form featuring necrotizing crescentic pauciimmune GN (NCGN). 1 ANCA is directed against neutrophils and monocytes and was initially considered a helpful clinical diagnostic and disease activity-monitoring tool. 2 Over the last 3 decades, numerous ANCA-induced inflammatory responses mediated by ANCA-antigen expressing neutrophils and monocytes were described. 3 However, a pioneering step was taken when a murine disease model for antimyeloperoxidase (MPO) antibody-induced NCGN was established, allowing the exploration of novel avenues. 4 The role of complement provides an ample example for such a novel and, for most clinicians, unexpected disease mechanism.A hallmark of ANCA disease is the scantly deposited Igs and complement components. In fact, this finding distinguishes ANCA NCGN from other NCGN entities that manifest with similar glomerular fibrinoid necrosis and crescents but with either granular or linear Ig as well as complement deposits. Moreover, until recently, the lack of complement consumption in ANCA-patient plasma by routine tests (e.g., C3 and C4) led clinicians to believe that complement is of no or, at most, trivial significance in this condition. Consequently, complement was not rigorously pursued in clinical and basic research on ANCA. However, not considering complement mechanistically may also have resulted in a missed chance for therapeutic intervention because promising complement-targeted strategies are emerging in clinical nephrology and beyond.Xiao et al. were the first to take advantage of a murine ANCA model by demonstrating that the alternative pathway, but not the classic or the lectin-binding complement pathways, was needed to induce NCGN. 5 The complement system consists of .30 plasma and membrane-bound proteins and the next steps were aimed at narrowing down the suspects. Huugen et al. identified C5 as a pivotal complement component that was essential in mediating NCGN in mice. They also showed that a C5-inhibiting antibody protected from NCGN. 6 Neutralizing C5 could be achieved with eculizumab, a humanized mAb that is already successfully used in patients with another C5-mediated renal disease, namely atypical hemolytic uremic syndrome. However, could the culprit be further delineated? C5 is processed by the C5 convertase (C3bBbC3b) yielding C5a and C5b. Together with C6, C7, C8, and C9, C5b forms the C5b-9 membrane attack complex (MAC). 7 The MAC is instrumental in pathogen recognition and elimination and should therefore be preserved if possible. Another aspect is that C5a not only activates the C5a receptor CD88 but also engages the inhibitory C5a-like receptor (C5L2). Thus, neutralizing C5 might have unnecessary drawbacks that could be avoided if C5a receptor (CD88) engagement by C5a was of utmost importance for AN...

Association of Serum C3 Concentration and Histologic Signs of Thrombotic Microangiopathy with Outcomes among Patients with ANCA-Associated Renal Vasculitis

“…Until recently, it was commonly accepted that serum C3 (sC3) and C4 (sC4) levels are normal in patients with AAV, which probably led to underestimate the pathogenic importance of the complement system in AAV (2). However, previous studies showed that most patients have at least focal complement tissue deposition (3), but the relevance of this observation was underpinned by the important ANCA discovery and the subsequent "pauci-immune/pauci-complement paradigm."…”

Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis

“…11 C5a and C5a receptor (C5aR, or CD88) play a central role in the pathogenesis of AAV. [12][13][14] C5a can prime and activate neutrophils, 15 which release C5a when stimulated by inflammatory cytokines such as TNFa. 16 C5a, acting on C5aR, is a potent neutrophil chemoattractant and agonist 17 and can decrease neutrophil deformability, slowing their ability to traverse small blood vessels, particularly in the presence of ANCA.…”

The rise of complement in ANCA-associated vasculitis: from marginal player to target of modern therapy

“…This was considered to result from negligible complement activation. Moreover, hypocomplementaemia is uncommon in AAV patients [2].…”