Serum properdin consumption as a biomarker of C5 convertase dysregulation in C3 glomerulopathy

Abstract

SummaryProperdin (P) stabilizes the alternative pathway (AP) convertases, being the only known positive regulator of the complement system. In addition, P is a pattern recognition molecule able to initiate directly the AP on non-self surfaces. Although P deficiencies have long been known to be associated with Neisseria infections and P is often found deposited at sites of AP activation and tissue injury, the potential role of P in the pathogenesis of complement dysregulation-associated disorders has not been studied extensively. Serum P levels were measured in 49 patients with histological and clinical evidence of C3 glomerulopathy (C3G). Patients were divided into two groups according to the presence or absence of C3 nephritic factor (C3NeF), an autoantibody that stabilizes the AP C3 convertase. The presence of this autoantibody results in a significant reduction in circulating C3 (P < 0Á001) and C5 levels (P < 0Á05), but does not alter factor B, P and sC5b-9 levels. Interestingly, in our cohort, serum P levels were low in 17 of the 32 C3NeF-negative patients. This group exhibited significant reduction of C3 (P < 0Á001) and C5 (P < 0Á001) and increase of sC5b-9 (P < 0Á001) plasma levels compared to the control group. Also, P consumption was correlated significantly with C3 (r 5 0Á798, P 5 0Á0001), C5 (r 5 0Á806, P < 0Á0001), sC5b-9 (r 5 20Á683, P 5 0Á043) and a higher degree of proteinuria (r 5 20Á862, P 5 0Á013). These results illustrate further the heterogeneity among C3G patients and suggest that P serum levels could be a reliable clinical biomarker to identify patients with underlying surface AP C5 convertase dysregulation.

Properdin: a tightly regulated critical inflammatory modulator

“…Ziegler et al . showed that higher levels of properdin were found in the urine of patients with renal disease vs healthy individuals, and Corvillo et al . proposed using serum properdin concentrations as a diagnostic marker for a subset of C3 glomerulopathy patients.…”

“…74 Mature neutrophils do not synthesize properdin but contain large stores of it in secondary granules, which are rapidly released upon stimulation with a variety of agonists, including C5a, fMLP, TNF-α, and IL-8. 75,76 A complete review of biological sources of properdin can be found in Cortes et al 71 Ziegler et al 78 showed that higher levels of properdin were found in the urine of patients with renal disease vs healthy individuals, and Corvillo et al 79 proposed using serum properdin concentrations as a diagnostic marker for a subset of C3 glomerulopathy patients. Studies are lacking, however, that shed light on the dynamics of properdin metabolism in the context of diseases that do not affect the kidney or that have excessive leukocyte activation or leukocyte dysfunction.…”

Immunological features of patients affected by Barraquer-Simons syndrome

“…FB levels may indeed be reduced in patients with C3NeF but this is not a constant finding. This issue has been debated in several works but there are heterogeneous results concerning FB levels in the published series [23][24][25]. During AP activation, in the absence of C3NeF, C3 and FB consumption are usually correlated; however, C3NeF breaks this correlation.…”

“…Serum C3 and C4 levels were measured by nephelometry (Siemens Healthcare, Erlangen, Germany). FB and P levels were measured using in-house ELISA assays, previously described by our group [23].…”

Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery

“…The correlation between high terminal pathway activity and low serum levels of the positive AP regulator properdin observed in some C3G patients implies that the consumption of this factor in the circulation and its likely increased binding to the injured glomeruli may favor the formation of C5 convertases, thus contributing to higher C5 turnover in a subset of C3G patients, typically those with a C3GN pattern of diffuse, mostly mesangial deposits on electron microscopy [41]. Whereas the efficacy of anti-C5 therapy in other renal pathologies such as aHUS has been consistently higher, the poor outcomes in C3G may also reflect the recruitment of distinctly different pathological mechanisms in these renal disorders.…”