Abstract
The human complement factor H-related protein-3 (FHR-3) is a soluble regulator of the complement system. Homozygous cfhr3/1 deletion is a genetic risk factor for the autoimmune form of atypical hemolytic-uremic syndrome (aHUS), while also found to be protective in age-related macular degeneration (AMD). The precise function of FHR-3 remains to be fully characterized. We generated four mouse monoclonal antibodies (mAbs) for FHR-3 (RETC) without cross-reactivity to the complement factor H (FH)-family. These antibodies detected FHR-3 from human serum with a mean concentration of 1 μg/mL. FHR-3 levels in patients were significantly increased in sera from systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica but remained almost unchanged in samples from AMD or aHUS patients. Moreover, by immunostaining of an aged human donor retina, we discovered a local FHR-3 production by microglia/macrophages. The mAb RETC-2 modulated FHR-3 binding to C3b but not the binding of FHR-3 to heparin. Interestingly, FHR-3 competed with FH for binding C3b and the mAb RETC-2 reduced the interaction of FHR-3 and C3b, resulting in increased FH binding. Our results unveil a previously unknown systemic involvement of FHR-3 in rheumatoid diseases and a putative local role of FHR-3 mediated by microglia/macrophages in the damaged retina. We conclude that the local FHR-3/FH equilibrium in AMD is a potential therapeutic target, which can be modulated by our specific mAb RETC-2.
Highlights
The human complement factor H-related protein 3 (FHR-3) belongs to the complement factor H (FH)-family
We identified local production of FH-related protein (FHR)-3 by microglia/macrophages in an aged donor retina with RPE atrophy – the latter being a typical hallmark of dry age-related macular degeneration (AMD)
The isolated and purified four monoclonal antibody (mAb) regensburg therapy complement (RETC)-2, RETC-3, RETC-5, and RETC-7 were specific for the C-terminal, fifth short consensus repeat (SCR) (SCR5) domain of FHR-3
Summary
The human complement factor H-related protein 3 (FHR-3) belongs to the complement factor H (FH)-family. This family, consisting of seven proteins [FH, FH-like protein 1, FH-related protein (FHR) 1–5], are secreted plasma proteins and important regulators of the complement system [1]. The five cfhr genes are located on chromosome 1q31.3, downstream of the cfh gene [2], coding for FH-family members, which share high sequence identities within their short consensus repeat (SCR) domains. FHR-3 is composed of five SCR domains, which display similarities with SCR6–8 (91–62%) and SCR19–20 (64–37%) of FH [1, 3, 4]. Unambiguous identification and modulation of FHR-3 is challenging considering their high protein sequence similarity. The molecular function of FHR-3 is only partly clarified and controversially discussed in the literature [1, 8]
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