Factor h: a complement regulator in health and disease, and a mediator of cellular interactions

Abstract

Complement is an essential part of innate immunity as it participates in host defense against infections, disposal of cellular debris and apoptotic cells, inflammatory processes and modulation of adaptive immune responses. Several soluble and membrane-bound regulators protect the host from the potentially deleterious effects of uncontrolled and misdirected complement activation. Factor H is a major soluble regulator of the alternative complement pathway, but it can also bind to host cells and tissues, protecting them from complement attack. Interactions of factor H with various endogenous ligands, such as pentraxins, extracellular matrix proteins and DNA are important in limiting local complement-mediated inflammation. Impaired regulatory as well as ligand and cell recognition functions of factor H, caused by mutations or autoantibodies, are associated with the kidney diseases: atypical hemolytic uremic syndrome and dense deposit disease and the eye disorder: age-related macular degeneration. In addition, factor H binds to receptors on host cells and is involved in adhesion, phagocytosis and modulation of cell activation. In this review we discuss current concepts on the physiological and pathophysiological roles of factor H in light of new data and recent developments in our understanding of the versatile roles of factor H as an inhibitor of complement activation and inflammation, as well as a mediator of cellular interactions. A detailed knowledge of the functions of factor H in health and disease is expected to unravel novel therapeutic intervention possibilities and to facilitate the development or improvement of therapies.

Figure 1

Complement activation pathways and the regulatory role of factor H.Complement activation is initiated by the recognition molecules of the classical (C1q) and lectin (MBL, ficolins) pathways or by the hydrolysis of the C3 thioester bond (alternative pathway). All three activation cascades lead to the assembly of C3 convertase enzymes that cleave the central C3 molecule into C3a and C3b. C3b deposits to nearby surfaces and, if not inactivated, it forms additional C3 convertases (amplification loop). The binding of C3b to an existing C3 convertase results in a C5 convertase that cleaves C5 into C5a, a potent anaphylatoxin, and C5b. C5b binds to surfaces and by binding C6, C7, C8 and several C9 molecules a terminal membrane attack complex is formed that allows target cell lysis. The system is controlled by several fluid phase and membrane-bound regulators that act at various steps of the activation cascade. Factor H is the major fluid-phase regulator of the alternative pathway, as it prevents the formation of the C3 and C5 convertases, facilitates the disassembly of already formed convertases and acts as a cofactor for the inactivation (enzymatic cleavage) of C3b.

Figure 2

The schematic structure of factor H. (a) Factor H is composed of 20 short consensus repeat (SCR) domains. Two major functional regions are located at the N- and C-termini of the molecule. SCRs 1-4 mediate the complement regulatory activities of factor H; (b) The SCRs 19-20 allow the attachment of factor H to host cells so that it can also inhibit complement activation directly at the cell surface.

Figure 3

Overview of main factor H functions and their implication in pathological conditions. Factor H is a major soluble complement regulator that inhibits activation of the alternative complement pathway in body fluids. In addition, factor H is also able to control complement activation on self-surfaces and thereby protects host cells and tissues from complement attack. Factor H binds to host cells and basement membranes via interactions with glycosaminoglycans and deposited C3b. The binding of factor H to apoptotic cells and extracellular matrices is in part mediated by the pentraxins CRP and PTX3, and is of particular importance as these structures and cells are otherwise not well protected from complement. Furthermore, factor H interacts with host cells via specific receptors and thus modulates cellular functions, including adhesion and phagocytosis. Impaired functions of factor H are associated with several diseases such as DDD, aHUS and AMD. Mutations in the CFH gene (examples of affected domains are shown in red) or autoantibodies directed against factor H (“mini-autoantibody” in DDD and anti-factor H IgG in aHUS are shown in red) cause defective complement regulation and ligand recognition leading to improperly controlled inflammation and tissue damage. On the other hand, the regulatory functions of factor H are abused by several pathogens and tumor cells in order to protect themselves from complement attack and thus to evade the host immune response.