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Anti-Factor B Antibodies and Acute Postinfectious GN in Children

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Anti-Factor B Antibodies and Acute Postinfectious GN in Children CLINICAL RESEARCH www.jasn.org Anti-Factor B Antibodies and Acute Postinfectious GN in Children Sophie Chauvet,1,2,3 Romain Berthaud,3,4 Magali Devriese,5 Morgane Mignotet,5 Paula Vieira Martins,5 Tania Robe-Rybkine,1 Maria A. Miteva,3,6 Aram Gyulkhandanyan,7 Amélie Ryckewaert,8 Ferielle Louillet,9 Elodie Merieau,10 Guillaume Mestrallet,11 Caroline Rousset-Rouvière,12 Eric Thervet,2,3 Julien Hogan,13 Tim Ulinski,14 Bruno O. Villoutreix,3,15 Lubka Roumenina,1 Olivia Boyer,3,4,16 and Véronique Frémeaux-Bacchi1,5,3 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background The pathophysiology of the leading cause of pediatric acute nephritis, acute postinfectious GN, including mechanisms of the pathognomonic transient complement activation, remains uncertain. It shares clinicopathologic features with C3 glomerulopathy, a complement-mediated glomerulopathy that, unlike acute postinfectious GN, has a poor prognosis. Methods This retrospective study investigated mechanisms of complement activation in 34 children with acute postinfectious GN and low C3 level at onset. We screened a panel of anticomplement protein autoantibodies, carried out related functional characterization, and compared results with those of 60 children from the National French Registry who had C3 glomerulopathy and persistent hypocomplementemia. Results All children with acute postinfectious GN had activation of the alternative pathway of the com- plement system. At onset, autoantibodies targeting factor B (a component of the alternative pathway C3 convertase) were found in a significantly higher proportion of children with the disorder versus children with hypocomplementemic C3 glomerulopathy (31 of 34 [91%] versus 4 of 28 [14%], respectively). In acute postinfectious GN, anti-factor B autoantibodies were transient and correlated with plasma C3 and soluble C5b-9 levels. We demonstrated that anti-factor B antibodies enhance alternative pathway convertase activity in vitro,confirming their pathogenic effect. We also identified crucial antibody binding sites on factor B, including one correlated to disease severity. Conclusions These findings elucidate the pathophysiologic mechanisms underlying acute postinfectious GN by identifying anti-factor B autoantibodies as contributing factors in alternative complement pathway activation. At onset of a nephritic syndrome with low C3 level, screening for anti-factor B antibodies might help guide indications for kidney biopsy to avoid misdiagnosed chronic glomerulopathy, such as C3 glo- merulopathy, and to help determine therapy. JASN 31: ccc–ccc, 2020. doi: https://doi.org/10.1681/ASN.2019080851 Acute postinfectious GN (APIGN) is the leading Received August 28, 2019. Accepted December 26, 2019. 1,2 cause of acute nephritis in children. Streptococcal Published online ahead of print. Publication date available at skin or throat infections are still the main triggers of www.jasn.org. the disease in children. After a latency period after Correspondence: Veronique Frémeaux-Bacchi, Department infection, the typical presentation is an acute ne- of Immunology, European Hospital Georges Pompidou, 20 rue phritic syndrome with low C3 levels sometimes Leblanc 75015 Paris, France. Email: veronique.fremeaux-bacchi@ associated to a nephrotic syndrome, and rarely to aphp.fr a rapidly progressive GN. The diagnosis is mainly Copyright © 2020 by the American Society of Nephrology JASN 31: ccc–ccc,2020 ISSN : 1046-6673/3104-ccc 1 CLINICAL RESEARCH www.jasn.org based on clinical and biologic features and confirmed by nor- Significance Statement malization of C3 levels within a few days or weeks and by the resolution of nephritic syndrome either with supportive care Acute postinfectious GN, the leading cause of acute nephritis in only, or with a short corticosteroid therapy.3 Kidney biopsy is children, associates with transient complement activation of un- notrequiredinmostchildren.3 It is only indicated in case of determined mechanism. Its clinical features overlap considerably i.e. with those of C3 glomerulopathy, a severe chronic condition. In this atypical presentation or course ( , persistent hypocomple- retrospective study, the authors demonstrated that in more than mentemia beyond 3 months) to rule out differential diagnosis 90% of children with acute postinfectious GN, complement over- or to assess prognosis in severe forms. Using light micros- activation results from activation of the alternative pathway of the copy, APIGN is characterized by glomerular cell proliferation complement system, driven by transient presence of autoanti- bodies targeting factor B, a component of the alternative C3 con- with endocapillary hypercellularity due to varying degrees of fi fl vertase. They also identi ed crucial antibody binding sites on factor neutrophil recruitment. Characterization by immuno uo- B, including one correlated to disease severity at onset. The pres- rescence microscopy involves bright glomerular C3 staining ence of anti-factor B antibodies was highly specific to acute post- with typical subepithelial deposits associated or not with Ig infectious GN, suggesting that screening for these antibodies might staining. Mechanisms underlying the glomerular lesions re- help clinicians distinguish the disorder during its acute phase from main unclear. It was first suggested that the formation of C3 glomerulopathy. immune complexes, containing specificantigens(i.e., streptococcal antigens), and their deposition within the glo- Methods). For comparison, we used clinical and biologic merular tuft drive complement activation and immune cell data of 60 children from the National French Registry with infiltration.4 Later, it was proposed that the alternative pathway biopsy-proven C3G and persistent hypocomplementemia of the complement system has a major contribution in APIGN defined by low C3 levels for at least 1 year. In this group, as assessed by decreased plasma C3 and normal plasma C4 only plasma samples collected at the acute phase, available in levels in a large majority of patients and the demonstration 28 of 60 hypocomplementemic C3G (H-C3G) patients, were that streptococcal antigens were able to directly activate the used for antibody screening (Supplemental Figure 1). His- complement alternative pathway.5 The main differential diag- tologic criteria used for diagnosis of APIGN and C3G are nosis in a child with postinfectious acute nephritic syndrome provided in the Supplemental Methods. The local ethical and low C3 levels is C3 glomerulopathy (C3G), a glomerul- committee approved the study and written informed consent opathy of poor prognosis that warrants prompt specific was obtained from all patients’ legal guardians for genetic treatment.6,7 C3Gismediatedbyacquiredorinheriteddys- analysis. regulation of the complement alternative pathway, resulting in prolonged low plasma C3 levels in half of the patients and Assays for Complement Component and Complement predominant C3 deposition in glomeruli.8,9 Considerable Gene Analysis overlapping in the clinical, biologic, and histopathologic C3, C4, and soluble C5b-9 (sC5b-9) were measured in patients’ features of APIGN with C3G hampers appropriate EDTA plasma samples. Screening for anti-factor H, anti-C3b, management.7 anti-C3bBb, anti-FB autoantibodies in patients’ plasma This study was designed to investigate the mechanism of and study of antibody isotype specificity were performed complement pathway activation in a cohort of patients with by ELISA (Supplemental Methods).10–12 Genetic variation APIGN. We discovered pathogenic anti-factor B (anti-FB) screening of complement factor H (CFH), complement factor I, autoantibodies that drive complement overactivation in C3, complement FB (CFB), and complement factor H related APIGN in contrast to C3G. The screening of anti-FB anti- 5 (CFHR5) genes and complex rearrangement between bodies may become a useful tool for guiding diagnosis and CFH/CFHRs were performed as previously described.12 Results therapeutic strategies in patients with nephritic syndrome of genetic analysis were compared with that of 45 of 60 patients and low C3 levels. with H-C3G with available DNA, 80 French volunteers who were healthy,13 and European individuals from the 1000 Genomes Project.14 METHODS Epitope Mapping and Functional Characterization of Study Population Anti-FB Antibodies We conducted a multicentric, retrospective study on 34 chil- By ELISA, we tested the ability of anti-FB autoantibodies to dren diagnosed with APIGN between April 2008 and August bind to 32 linear peptides of FB or 15 recombinant FB proteins 2017. The children’s plasma was sent to the French Reference carrying selected amino acid changes generated by site- Laboratory in the Georges Pompidou European Hospital directed mutagenesis as previously described (Supplemental (Paris) for complement analyses. Patients were eligible if Methods).15 Peptides and amino acid changes were mapped they were ,18 years of age, with clinical and/or biopsy- on the structure of FB, C3bB, and C3bBb using the Pymol proven diagnosis of APIGN with low plasma C3 levels followed software and the atomic coordinates of FB,16 C3bBD,17 and by C3 normalization within 90 days (Figure 1, Supplemental C3bBb18 (Supplemental Methods). 2 JASN JASN 31: ccc–ccc,2020 www.jasn.org CLINICAL RESEARCH To determine the functional consequences of anti-FB au- Suspected APIGN toantibodies on complement activation, total IgG purified N=62 from EDTA plasma of patients with APIGN were tested for their
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