Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin–Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H–Related Protein-5 (FHR5) Deposition

Abstract

IntroductionIgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury.MethodsTo elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN.ResultsM-ficolin, L-ficolin, mannan-binding lectin (MBL)–associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H–related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN.ConclusionOur data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity.

Complement lectin pathway protein levels reflect disease activity in juvenile idiopathic arthritis: a longitudinal study of the Nordic JIA cohort

“…The pathophysiology and etiology are multi-factorial and not fully understood. There is an increasing body of evidence that inadequately controlled activation of complement factors leading to either overactivity or deficiency may be involved in the pathogenesis of some autoimmune diseases [3–6]. However, the role of the complement system in JIA is still not fully elucidated [7–11].…”

Glomerular Complement Factor H–Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment

“…Antigen staining intensities were graded as previously described 27 . Because nonspecific staining was seen in sclerosed glomeruli in previous 20 and our studies, only nonsclerosed glomeruli were included in statistical analyses.…”

“…In addition to the associations between FHR5 variants and familial C3G,13, 15, 22 evidence that glomerular FHR5 might increase glomerular injury includes in vitro studies demonstrating FHR5 can (i) bind extracellular matrix components and support assembly of the alternative pathway C3 convertase formation, thereby promoting further C3b generation, and (ii) antagonize the ability of fH to limit amplification of C3b (a process termed fH deregulation) 21, 23, 24. Furthermore, both circulating FHR5 levels25, 26 and the intensity of glomerular FHR5 deposition 27 associate with IgA nephropathy severity.…”

A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease

“…However, familial cases of C3 GP have been observed in the presence of CFHR3-1 protein abnormalities [39] or the internal duplication of CFHR1 [40] or CFHR5, specifically in members of a Cypriot family [41].…”