Common polymorphisms in complement alternative pathway (AP) proteins C3 (C3_R102G), factor B (fB_R32Q), and factor H (fH_V62I) are associated with age-related macular degeneration (AMD) and other pathologies. Our published work showed that fB_R32Qinfluences C3 convertase formation, whereas fH_V62Iaffects factor I cofactor activity. Here we show how C3_R102G(C3S/F) influences AP activity. In hemolysis assays, C3_102Gactivated AP more efficiently (EC₅₀C3_102G: 157 nM; C3_102R: 191 nM;P< 0.0001). fB binding kinetics and convertase stability were identical, but native and recombinant fH bound more strongly to C3b_102R(K_DC3b_102R: 1.0 μM; C3b_102G: 1.4 μM;P< 0.0001). Accelerated decay was unaltered, but fH cofactor activity was reduced for C3b_102G, favoring AP amplification. Combining disease “risk” variants (C3_102G, fB_32R, and fH_62V) in add-back assays yielded sixfold higher hemolytic activity compared with “protective” variants (C3_102R, fB_32Q, and fH_62I;P< 0.0001). These data introduce the concept of a functional complotype (combination of polymorphisms) defining complement activity in an individual, thereby influencing susceptibility to AP-driven disease.

Dense deposit disease (DDD) is a severe renal disease characterized by accumulation of electron-dense material in the mesangium and glomerular basement membrane. Previously, DDD has been associated with deficiency of factor H (fH), a plasma regulator of the alternative pathway (AP) of complement activation, and studies in animal models have linked pathogenesis to the massive complement factor 3 (C3) activation caused by this deficiency. Here, we identified a unique DDD pedigree that associates disease with a mutation in the C3 gene. Mutant C3_923ΔDG, which lacks 2 amino acids, could not be cleaved to C3b by the AP C3-convertase and was therefore the predominant circulating C3 protein in the patients. However, upon activation to C3b by proteases, or to C3(H₂O) by spontaneous thioester hydrolysis, C3_923ΔDG generated an active AP C3-convertase that was regulated normally by decay accelerating factor (DAF) but was resistant to decay by fH. Moreover, activated C3b_923ΔDG and C3(H₂O)_923ΔDG were resistant to proteolysis by factor I (fI) in the presence of fH, but were efficiently inactivated in the presence of membrane cofactor protein (MCP). These characteristics cause a fluid phase–restricted AP dysregulation in the patients that continuously activated and consumed C3 produced by the normal C3 allele. These findings expose structural requirements in C3 that are critical for recognition of the substrate C3 by the AP C3-convertase and for the regulatory activities of fH, DAF, and MCP, all of which have implications for therapeutic developments.

We observe previously unknown interactions between clinically important adenovirus vector capsids, platelet factor 4, and CAR.

Complement is a key component of immune defence against infection; it potently drives inflammation at sites of pathology and is essential for killing of pathogens. Genetic linkage of common complement polymorphisms to disease has advanced the concept that subtle changes in complement activity significantly affect disease risk. Functional analyses of disease-linked polymorphic variants demonstrate that, although individual polymorphisms cause only small changes in activity, when combined, the aggregate effects are large. The inherited set of common variants, the complotype, thus has a major impact on susceptibility to inflammatory and infectious diseases. Assessing the complotype of an individual will aid prediction of disease risk and inform intervention to reduce or eliminate risk.

Early identification and treatment significantly improve clinical outcomes of psychotic disorders. Recent studies identified protein components of the complement and coagulation systems as key pathways implicated in psychosis. These specific protein alterations are integral to the inflammatory response and can begin years before the onset of clinical symptoms of psychotic disorder. Critically, they have recently been shown to predict the transition from clinical high risk to first-episode psychosis, enabling stratification of individuals who are most likely to transition to psychotic disorder from those who are not. This reinforces the concept that the psychosis spectrum is likely a central nervous system manifestation of systemic changes and highlights the need to investigate plasma proteins as diagnostic or prognostic biomarkers and pathophysiological mediators. In this review, we integrate evidence of alterations in proteins belonging to the complement and coagulation protein systems, including the coagulation, anticoagulation, and fibrinolytic pathways and their dysregulation in psychosis, into a consolidated mechanism that could be integral to the progression and manifestation of psychosis. We consolidate the findings of altered blood proteins relevant for progression to psychotic disorders, using data from longitudinal studies of the general population in addition to clinical high-risk (CHR) individuals transitioning to psychotic disorder. These are compared to markers identified from first-episode psychosis and schizophrenia as well as other psychosis spectrum disorders. We propose the novel hypothesis that altered complement and coagulation plasma levels enhance their pathways’ activating capacities, while low levels observed in key regulatory components contribute to excessive activation observed in patients. This hypothesis will require future testing through a range of experimental paradigms, and if upheld, complement and coagulation pathways or specific proteins could be useful diagnostic or prognostic tools and targets for early intervention and preventive strategies.