BACKGROUND: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. RESULTS: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF. CONCLUSIONS: In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10-15% of IC-MPGN/C3G patients.
- MeSH
- autoprotilátky imunologie metabolismus MeSH
- dospělí MeSH
- komplement C3 nefritický faktor metabolismus MeSH
- komplement metabolismus MeSH
- lidé MeSH
- membranoproliferativní glomerulonefritida imunologie metabolismus MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nemoci ledvin imunologie metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
SLE je onemocnění charakterizované nadprodukcí různých typů autoprotilátek. Za jistých okolností lze zjistit přítomnost autoprotilátek rovněž proti neoepitopům komplementového systému. Neoepitopy nejsou přítomny v nativních proteinech, ale objevují se při jejich strukturálních změnách. Mezi známé antikomplementové autoprotilátky patří: C3 nefritický faktor, protilátka proti C1 inhibitoru či protilátky proti C1R (C1 receptor). Bezesporu nejvýznamnější autoprotilátkou proti komplementu jsou anti-C1q protilátky. Jsou přítomny asi u třetiny nemocných se SLE, korelují s klinickou aktivitou a s přítomností lupusové glomerulonefritidy. Vysoké titry anti C1q protilátek jsou doprovázeny sníženými hladinami C1 ale také C3 a zejména C4 složky komplementu. Přítomnost anti-C1q protilátek není omezena či specifická pouze pro lupus. Poprvé byly popsány v případě syndromu HUVS (Hypocomplementemic Urticar Vasculitis Sydrome), později také při Feltyho syndromu, revmatoidní vaskulitidě, u hepatitidy C a ve stárnoucí populaci. Asociace mezi přítomností protilátek anti C1q, spotřebou komplementu a přítomností renálního postižení v případě SLE vzbuzuje otázku, zda a jak se tyto autoprotilátky podílejí na patogenezi orgánového postižení. Jak ukazují zvířecí modely choroby, pro vznik lupusové nefritidy je potřebná přítomnost jak anti-dsDNA, tak anti-C1q protilátek, jejichž vzájemná interakce spouští mechanizmy rozvoje imunokomplexového renálního postižení.
SLE is a disease characterized by overproduction of various types of autoantibodies. Under certain circumstances, it is possible to detect the presence of autoantibodies directed against neoepitopes of complement system, as well. Neoepitopes are not present in native proteins, but develop with their structural alterations. The following antibodies come under known anticomplement auoantibodies: C3 nephritic factor, antibody directed against C1 inhibitor or antibodies directed against C1R (C1 receptor). Anti-C1q antibodies are concededly the most significant autoantibodies directed against complement system. They are present in about one third of patients with SLE and there is a correlation with clinical activity and the presence of lupus glomerulonephritis. High titers of anti-C1q antibodies are accompanied by decreased levels of C1, as well as C3 and especially C4 complement component. The presence of anti-C1q antibodies is not limited or specific for lupus only. They were described for the first time in case of HUVS (Hypocomplementemic Urticarial Vasculitis Sydrome), later in Felty’s syndrome, rheumatoid vasculitis, hepatitis C and in senescent population, as well. The association of anti-C1q antibodies, complement consumption and presence of renal affection in case of SLE calls into question, whether and how do these autoantibodies participate in organ affection pathogenesis. As shown in animal models of disease, the presence of both anti-dsDNA and anti-C1q antibodies is necessary for the genesis of lupus nephritis. Their mutual interaction triggers the mechanisms of development of renal affection mediated by immune complexes.
