With complements from ANCA mice.

ANCA is found in the vast majority of patients with active smallvessel vasculitis.Thisdiseasegroup includeswhat isnowknownas granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and a renal-limited disease form featuring necrotizing crescentic pauci-immune GN (NCGN).1 ANCA is directed against neutrophils and monocytes and was initially considered a helpful clinical diagnostic and disease activity-monitoring tool.2Over the last 3 decades, numerous ANCA-induced inflammatory responses mediated by ANCAantigen expressing neutrophils and monocytes were described.3 However, a pioneering step was taken when a murine disease model for antimyeloperoxidase (MPO) antibody-induced NCGNwas established, allowing the explorationof 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 ANCAdisease 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 lackof 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 ANCA-induced NCGN and could be specifically targeted. Using a murine disease model and bone marrow from genedeficient mice, our group established that ANCA-activated neutrophils promote C5a generation and that the C5a–C5a receptor (CD88) interaction on myeloid cells was pivotal for NCGN.8 These data implicated C5a receptor (CD88) blockade as a potential therapeutic strategy in ANCA vasculitis. Despite these advances, we still faced several unresolved issues at this point. We did not know what the roles of the MAC and the C5L2 receptor were, nor did we have the tools to actually pharmacologically block the C5a (CD88) receptor. Xiao et al. rose to the challenge and now report the results of their study in this issue of JASN.9 Using passive transfer of antibodies to mouse MPO, the investigators induced pauciimmune NCGN. Anti-MPO IgG transfer into a C6 deficiency background showed no protection. These data answered our first question, namely the assumption thatMAC had no role in the disease and thus MAC depletion was not a therapeutic goal. In fact, undisturbed C5, C5b, and thus MAC formation, would enable patients with vasculitis to fight infections under immune-compromising treatment protocols. The next question was to determine the role of the C5L2 receptor. Mice deficient in this receptor more than doubled the percentage of glomerular crescents with anti-MPO–antibody transfer, establishing that C5L indeed had an inhibitory function in ANCAvasculitis. These data indicate that preventing C5a generation by inhibiting C5 would unnecessarily abolish an important protective C5a effect mediated by the C5L2 receptor. How did the investigators tackle the issue of C5a receptor (CD88) blockade? They replaced the murine receptor by its human analog and were still able to induce NCGN by anti-MPO Published online ahead of print. Publication date available at www.jasn.org.