Monoclonal immunoglobulin mediates complement activation in monoclonal gammopathy associated-C3 glomerulonephritis.

BACKGROUND: C3 glomerulonephritis (C3GN) is a rare disease caused by inherited or acquired complement alternative pathway (CAP) dysregulation, which could also be secondary to monoclonal gammopathy of undetermined significance (MGUS). Herein, we described a patient presenting with C3GN and monoclonal gammopathy, and the pathogenic association between the two diseases was further explored in vitro. CASE PRESENTATION: A 76-year-old Chinese man presented with low serum C3 level, haematuria and nephrotic syndrome, and experienced rapid worsening of renal function over a period of 10 months. His serum and urine immunofixation electrophoresis both revealed a monoclonal IgGλ. A bone marrow puncture showed plasma cell dyscrasias with the highest plasma cell count of 5.25%. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence, a membranoproliferative pattern on light microscopy and electron dense deposits in sub-epithelial, intramembranous, sub-endothelial and mesangial regions by electron microscopy. The patient was positive for C3 nephritic factor (C3NeF) activity and anti-CFH autoantibodies, and all became negative during disease remission. The anti-CFH autoantibodies purified from the patient's plasma exchange fluids were proven to be a monoclonal IgGλ, and could inhibit CFH binding to C3b and accelerate the formation of C3 convertase indirectly by interfering with the formation-impeding activity of CFH. No deficiency of candidate genes, especially variants in CFH, was detected in our patient. Based on the pathological and laboratory findings, the diagnosis of monoclonal gammopathy of renal significance (MGRS)-associated C3GN was finally made. CONCLUSIONS: This is the first demonstration that intact monoclonal immunoglobulin (IgGλ) could act as an anti-CFH antibody and lead to MGRS-associated C3GN by activating the CAP.

Anti-complement factor H (CFH) autoantibodies could delay pristane-induced lupus nephritis.

PURPOSE: Anti-complement factor H (CFH) autoantibodies could be detected in lupus and its significance remained to be elucidated. Herein, we aimed to explore the roles of anti-CFH autoantibodies based on pristane-induced lupus mice. METHODS: Twenty-four female Balb/c mice were randomly divided into four groups, with one group injected with pristane (pristane group), one group with pristane and then human CFH (hCFH) (pristane-CFH group) 3 times, and the other two as vertical controls, PBS group and PBS-CFH group. Histopathological analysis was performed six months after pristane administration. Levels of hCFH, anti-CFH autoantibodies and anti-dsDNA antibody were detected. Murine IgG (mIgG) were purified and cross-reactivity, epitopes, subclasses and functional analysis were further evaluated in vitro. RESULTS: Immunization with hCFH and subsequent development of anti-CFH autoantibodies significantly attenuated nephritis of pristane-induced lupus, including lower levels of urinary protein and serum creatinine, decreased levels of serum anti-dsDNA antibody, greatly ameliorated renal histopathologic damage, decreased IgG, complements (C1q, C3) deposits and lower inflammatory factor (IL-6) expression in glomerulus. Furthermore, the purified mIgG (contained anti-CFH autoantibodies) could recognize both hCFH and murine CFH, and the epitopes were predominantly located in hCFH short consensus repeats (SCRs) 1-4, 7 and 11-14. The IgG subclasses were predominant IgG1. The autoantibodies could enhance the binding between hCFH and C3b, and increase factor I mediated-C3b lysis in vitro. CONCLUSION: Our results suggested that anti-CFH autoantibodies could attenuate pristane-induced lupus nephritis by increasing bio-functions of CFH on regulating complement activation and controlling inflammation.

Patient-specific iPSC-derived endothelial cells reveal aberrant p38 MAPK signaling in atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease associated with high morbidity and mortality. Existing evidence suggests that the central pathogenesis to aHUS might be endothelial cell damage. Nevertheless, the role of endothelial cell alterations in aHUS has not been well characterized and the underlying mechanisms remain unclear. Utilizing an induced pluripotent stem cell-derived endothelial cell (iPSC-EC) model, we showed that anti-complement factor H autoantibody-associated aHUS patient-specific iPSC-ECs exhibited an intrinsic defect in endothelial functions. Stimulation using aHUS serums exacerbated endothelial dysfunctions, leading to cell apoptosis in iPSC-ECs. Importantly, we identified p38 as a novel signaling pathway contributing to endothelial dysfunctions in aHUS. These results illustrate that iPSC-ECs can be a reliable model to recapitulate EC pathological features, thus providing a unique platform for gaining mechanistic insights into EC injury in aHUS. Our findings highlight that the p38 MAPK signaling pathway can be a therapeutic target for treatment of aHUS.

Anti-complement factor H autoantibodies may be protective in lupus nephritis.

BACKGROUND: This study aimed to investigate the role of anti-CFH autoantibodies in lupus nephritis based on a well-defined cohort. METHODS: One hundred twenty patients with biopsy-proven active lupus nephritis were collected as the discovery cohort, sixty patients served as the validation cohort, thirty-four patients with SLE without renal involvement (NR-SLE) were as disease controls, and thirty healthy donors were also included. The anti-CFH autoantibodies and IgG subclasses were detected by ELISA, and epitopes were evaluated by western blot. Anti-CFH autoantibodies were purified by affinity chromatography column, and the interference on the biofunctions of CFH was further studied by the C3b binding assay and cofactor activity assay in vitro. RESULTS: The prevalence of anti-CFH autoantibodies in lupus nephritis was significantly higher than that in healthy controls (8.3% (10/120) vs. 0% (0/30), P = 0.017), and no significant difference was found between the discovery and the validation group (8.3% (10/120) vs. 11.7% (7/60), P = 0.268) or the discovery and the NR-SLE group (8.3% (10/120) vs. 11.8% (4/34), P = 0.231). The subclass was mainly IgG2 (7/10), and major epitopes were in the middle (8/10 in SCRs 11-14) and N-terminal (7/10 in SCRs 1-4) regions of CFH. Patients with anti-CFH autoantibodies had a significantly lower prevalence of acute kidney injury (0% (0/10) vs. 40.0%(4/10), P = 0.025), lower serum creatinine levels (0.76 (0.40, 1.06) vs. 1.43 (0.46, 11.15), mg/dL, P = 0.023), and higher hemoglobin levels (113.8 ± 24.63 vs. 90.0 ± 22.53, g/L, P = 0.037) than those who were negative after further stratified analysis. A functional study showed that anti-CFH autoantibodies purified from patients with lupus nephritis could improve the binding between CFH and C3b, and also enhance the cofactor activity of CFH in vitro. CONCLUSIONS: Anti-CFH autoantibodies were detected in patients with lupus nephritis in approximately 10% of patients with polyepitopes and IgG2 subclass predominance. Patients with anti-CFH autoantibodies presented with milder renal damage, and the purified autoantibodies could enhance the C3b binding and CFI cofactor activity of CFH in vitro, which suggested a protective role in the lupus nephritis.

A case of adult atypical haemolytic uraemic syndrome related to anti-factor H autoantibodies successfully treated by plasma exchange, corticosteroids and rituximab.

Complement factor H auto-antibodies (CFH-ab) are a rare cause (6-10%) of atypical haemolytic uraemic syndrome (aHUS). All observations previously described were retrospective and occurred in children or teenagers. We report the first case of aHUS associated with anti-CFH antibodies in an adult patient who was successfully treated by plasma exchange, corticosteroids and rituximab.