The human factor H protein family - an update

Abstract

Complement is an ancient and complex network of the immune system and, as such, it plays vital physiological roles, but it is also involved in numerous pathological processes. The proper regulation of the complement system is important to allow its sufficient and targeted activity without deleterious side-effects. Factor H is a major complement regulator, and together with its splice variant factor H-like protein 1 and the five human factor H-related (FHR) proteins, they have been linked to various diseases. The role of factor H in inhibiting complement activation is well studied, but the function of the FHRs is less characterized. Current evidence supports the main role of the FHRs as enhancers of complement activation and opsonization, i.e., counter-balancing the inhibitory effect of factor H. FHRs emerge as soluble pattern recognition molecules and positive regulators of the complement system. In addition, factor H and some of the FHR proteins were shown to modulate the activity of immune cells, a non-canonical function outside the complement cascade. Recent efforts have intensified to study factor H and the FHRs and develop new tools for the distinction, quantification and functional characterization of members of this protein family. Here, we provide an update and overview on the versatile roles of factor H family proteins, what we know about their biological functions in healthy conditions and in diseases.

Keywords: Factor H; age-related macular degeneration; cancer; complement alternative pathway; factor H-related proteins; infection; inflammation; kidney disease.

Figure 1

Schematic representation of the human FH protein family. Members of the human FH protein family are exclusively composed of 4 to 20 CCP domains, represented as circles. The numbers indicate the individual domains, and coloring indicates domains responsible for binding to ligands and/or mediating functions. Domains of the FHR proteins display varying degree of amino acid sequence identity to the corresponding FH domains and are vertically aligned accordingly (5). Please note that the existence of FHR-4B is controversial (6). Figure modified after .

Figure 2

Overview of ligands and functions of the FH family proteins. The figure shows major ligands (in purple background) and cells/surfaces (in green background) to which binding of individual FH family members was shown. The interactions are represented by colored dots; the different colors code for the various FH family proteins as indicated in the middle of the figure. Note that non-canonical roles include effects also on non-immune cells, as discussed in the text.

Figure 3

Roles of FH family proteins in the regulation of complement activation. The schematic drawing indicates the main funtions of FH and FHL-1 in inhibiting complement activation in body fluids and also when bound to certain surfaces, such as endothelial cells (ECs) and extracellular matrices (ECM; e.g. the glomerular basement membrane and the Bruch’s membrane). FHR proteins in turn may compete with the binding of FH (and FHL-1) to ligands and surfaces, thereby indirectly enhancing complement activation, but may also directly activate complement when bound to surfaces and – by binding C3, C3(H₂O) or C3b – recruiting a functional C3 convertase. In addition, some FHRs were reported to inhibit C5 conversion and the terminal pathway.

Figure 4

FH family proteins can balance between pro-inflammatory and anti-inflammatory conditions. (A) Immobilized FH and FHR-1 downregulate DNA / extracellular trap release from neutrophil granulocytes, contributing to reduced host damage caused by an inflammatory environment and the presence of autoantigens. (B) FH can bind directly to DNA or apoptotic and necrotic cells; together they induce an anti-inflammatory cytokine profile in monocytes and macrophages, while FHR-1 under the same conditions shifts processes into an inflammatory direction. (C) FH family proteins can influence complement activation and, therefore, the opsonisation pattern on dead cell surfaces. The actively internalized FH can promote C3 cleavage intracellularly in early apoptotic cells, resulting in cell surface accumulation of iC3b. Recruitment of FH by mCRP and PTX3 limits complement activation and facilitates removal of apoptotic cells in an anti-inflammatory manner. FHR-1 and FHR-5 can recruit both mCRP and PTX3 to necrotic cell surface and vice versa, and rather enhance complement activation (25).

Figure 5

Role of FH family proteins in complement regulation. The state of balance between the inhibitor (FH) – and possibly that of FHL-1 – and the activator FHRs determines susceptibility to complement-mediated diseases. When inhibiton and activation are in an optimal balance (left panel), opsonization supported by the FHRs can proceed without the deleterious inflammatory and potential lytic activity of the terminal pathway. When levels or function of the proteins are altered in such a way that the balance is shifted towards overactivation (right panel), e.g. due to mutations or autoantibodies, the deleterious effects are enhanced and increase susceptibility to certain diseases.