The Complement System
Complement mediated aHUS is the prototypical of disease occurring as a consequence of complement dysregulation.
The complement system comprises around 50 plasma and cell-surface proteins operating in a regulated network of signalling and amplification central to the normal physiological functioning of both the innate and adaptive immune system. In addition to opsonisation and lysis of pathogens and modulation of the adaptive immune system, it also facilitates the disposal of damaged host cells and potentially damaging immune complexes.
Complement activation is initiated by three pathways: the classical pathway is activated by immune complexes and other molecules (e.g. C-reactive protein), and activation of the lectin pathway results from protein interactions with pathogens .
The alternative pathway may also be initiated by pattern recognition molecules, but crucially it is is a positive feedback loop which is constitutively active due to spontaneous hydrolysis (tick-over) of C3, and is recruited by the classical and lectin pathways; this enables a rapid response against pathogens, but leaves the host vulnerable to bystander damage if the amplification loop is unchecked.
The system is therefore tightly regulated by plasma proteins including factor H (FH) and factor I (FI), and cell surface proteins such as membrane co-factor protein (MCP, CD46). Defects in these regulators or in the alternative pathway components can lead to complement dysregulation, with activation of the terminal complement pathway and generation of the anaphylatoxin C5a and the membrane attack complex (MAC, C5b-9), resulting in a complement mediated aHUS. The relative roles of these effector molecules in causing disease remains to be established.
Endothelial cell damage and swelling
In complement mediated aHUS dysregulated complement activation primarily occurs on endothelial cell surfaces, and whilst abnormal serum levels of complement components such as C3 may be observed, normal levels do not exclude complement mediated disease. There is evidence of complement activation (plasma levels and tissue staining) in many other TMAs, but whether this is a primary event, a disease modifier, or an inconsequential bystander phenomenon has not yet been definitively established.
Genetic mutations in complement mediated aHUS
Molecular evidence that CFH mutations were associated with aHUS was first described in genetic research published in 1998 by the NRCTC, and since then a multitude of studies have determined heterozygous pathogenic activating mutations in the genes encoding the alternative pathway components C3 and factor B, and loss of function mutations in the genes encoding the regulators FH (including CFH/CFHR fusions ), FI and CD46.
These genetic mutations are not causative but are instead predisposing, with penetrance incomplete. Penetrance of disease is age related and has been reported to be as high as 64% by the age of 70 for individuals carrying a single genetic mutation. This suggests that additional disease risk modifiers are important.Around 3% of patients have one or more mutation, with increased penetrance per additional mutation. Haplotypes (particular combinations of single nucleotide polymorphisms (SNPs)) in CFH and CD46 also modify penetrance . Together, these still do not answer the question of why some individuals do not develop disease until later in life. This is best explained by the need for an environmental trigger such as infection or pregnancy, events that involve complement activation, thus unmasking a latent complement defect.