Anti-Factor B Antibodies and Acute Postinfectious GN in Children

Abstract

BackgroundThe 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.MethodsThis 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.ResultsAll children with acute postinfectious GN had activation of the alternative pathway of the complement 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.ConclusionsThese 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 glomerulopathy, and to help determine therapy.

Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties

“…PIGN is actually a form of acute C3GN, linked to transient CAP dysregulation that results from the transient presence of a C3 nephritic factor (C3Nef), an autoantibody that stabilizes the alternative C3 convertase, 35 and more frequently from the presence of anti-factor B autoantibodies detected in >90% of cases. 36 PIGN remains self-limited and reversible, with supportive treatment or short corticosteroid regimen, in the vast majority of cases. This explains the requirement of at least 3-month follow-up to exclude PIGN before C3G diagnosis is made.…”

“…The second part of complement workup relates to the detection of autoantibodies that target activators or regulators of the alternative C3 and/or C5 convertase (summarized in Figure 1 and Table 2 [3][4][5][27][28][29]36,40,41,[44][45][46] ). The best documented autoantibodies are C3Nef, a heterogeneous group of IgGs that bind and directly stabilize the C3bBb convertases.…”

Factors Affecting the Progression of Infection-Related Glomerulonephritis to Chronic Kidney Disease

“…There have also been reports of lupus-like symptoms in patients with some viral IRGN, such as parvovirus B19 [ 18 , 19 ] and CMV IRGN [ 20 ], with the appearance of ANA and anti-dsDNA antibodies. Furthermore, the presence of anti-factor B autoantibodies has recently been reported in patients with acute PIGN [ 21 ]. However, these were mostly reports of a small number of cases, and analyses of a large number of cases or prospective studies have not been reported to date.…”

“…Histological staining for NAPlr and plasmin activity [11] Use of antimicrobial agents Removal of indwelling device 2. Genetic background of the host's complement system [12] Serum complement levels, histological deposition of complement components, genetic testing Use of complement-regulating medications (in the future) Some autoantibodies, such as the anti-neutrophil cytoplasmic antibody (ANCA), anti-nuclear antibody (ANA), anti-dsDNA antibody, and anti-factor B antibody have been reported to be detected in patients with IRGN [14][15][16][17][18][19][20][21]. Although these antibodies may contribute to the progression of IRGN, at present there is little data regarding their significance on the prognosis of IRGN, and as their involvement remains controversial, we touched on this point but did not list the antibodies as possible factors associated with IRGN.…”

“…Some autoantibodies, such as the anti-neutrophil cytoplasmic antibody (ANCA), anti-nuclear antibody (ANA), anti-dsDNA antibody, and anti-factor B antibody have been reported to be detected in patients with IRGN [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Although these antibodies may contribute to the progression of IRGN, at present there is little data regarding their significance on the prognosis of IRGN, and as their involvement remains controversial, we touched on this point but did not list the antibodies as possible factors associated with IRGN.…”