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Chapter 24 Complement and Immunoglobulin Biology Leading to Clinical Translation 267

FI cleaves C3b, producing iC3b, the inactive form of C3b. iC3b is function—results in disease pathology. In addition, gain-of-function
incapable of reacting with factor B to form the AP C3 convertase, variants of factor B have been described that either form the AP C3
thereby preventing uncontrolled AP activation. In the absence of FI, convertase more efficiently than wild-type factor B or are more
unrestrained C3 consumption occurs secondary to accelerated spon- resistant to decay-dissociation by FH or DAF. Finally, several C3
taneous AP turnover. Patients with FI deficiency have recurrent variants have been described in aHUS patients that are gain of func-
infections caused by pyogenic organisms, including meningococcal tion in the sense that as C3b there is decreased binding affinity for
meningitis. MCP and FH and thus AP C3 convertases formed with this C3b as
Likewise, mice deficient in the central protein FH exhibit unre- subunit would have a prolonged lifetime relative to wild-type C3b. 64,65
strained C3 activation via the AP, leading to near depletion of serum Because FH mutations account for at least 30% of reported aHUS
C3. An important outcome of the failure to regulate C3 activation cases and approximately 70% of these are caused by missense muta-
is glomerulonephritis. Strikingly, mice deficient in FH develop a tions in SCR domains 19 and 20, the molecular basis of this disease
disease resembling the human disorder membrane glomerulonephri- association has been intensively investigated, and the findings of these
tis. The phenotype of the mice confirms the general notion that the studies are best understood in the context of a structure-based domain
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AP is always “on” and that failure to regulate activated C3 results in model of FH bound to C3b on a nonactivator (i.e., host) surface
consumption of circulating C3 and tissue injury. (Fig. 24.3). FH consists of 20 SCR domains, where some domains
Another example of the importance of FH regulation are reports in the middle of the molecule appear to play mainly a structural role,
of genetic association between variant alleles of FH and the human likely allowing the molecule to bend back on itself, but domain
diseases age-related macular degeneration (AMD) and atypical clusters near the ends mediate specific functions. SCRs 1 to 4 bind
hemolytic uremic syndrome (aHUS). Whereas AMD is a fairly to C3b and mediate both decay-accelerating and FI-cofactor func-
common condition—indeed, it is the leading cause of blindness in tionalities. Indeed, FH(SCR1–4) on its own is able to regulate a
the Western world—it has been the elucidation of the etiology of the fluid-phase AP C3 convertase, but it cannot do so for surface-bound
much rarer aHUS condition (two cases per million) that has led to AP C3 convertases. For regulation of the latter, there are three
a fuller appreciation of the diverse ways through which dysregulation additional binding interactions that become relevant. Two of these
of the AP of complement can give rise to severe pathology. Classically, are located within SCRs 19 to 20, specifically, a site localized mainly
HUS is a clinical triad of microangiopathic hemolytic anemia, to SCR19 binds to the C3d/TED domain of the surface-bound C3b
thrombocytopenia, and acute renal failure. The disease is character- molecule, and a site within SCR20 binds to surface-associated
ized by a precipitating injury of endothelial cells. In contrast to the polyanions such as sulfated glycosaminoglycans or sialic acid arrays.
fairly common classical form of HUS, which is diarrhea-associated The aHUS-associated missense mutations found within SCRs 19 to
and is usually caused by a Shiga toxin–secreting pathogen, the atypi- 20 affect one or other of these two binding functions and lead to
cal form of HUS is nondiarrheal and is caused by genetic predisposi- dysregulation of the AP C3 convertase at the surface of host tissue.
tion. Even haploinsufficiency of variants of FH, MCP, and FI resulting In particular, complement-mediated damage to the kidney basement
from either loss of expression—or more commonly, loss of regulatory membrane is often a hallmark of aHUS. As a tissue devoid of the
membrane-associated complement regulators MCP, DAF, or CR1,
but rich in sulfated glycosaminoglycans, the functionality of the
soluble AP regulator FH becomes even more crucial for host protec-
tion and likely explains the high incidence of missense mutations
FH within SCRs 19 to 20 in aHUS patients. Interestingly, missense
1 mutations in FH SCRs 19 to 20 do not result in systemic C3 con-
2 sumption, as would be the case for complete deficiencies of FH. This
C3b is because SCRs 1 to 4 of the mutant molecule are still capable of
3 regulating spontaneously formed AP C3 convertases in the fluid
4 Polyanions phase.
(e.g., GAGs)
7 19 20 In addition to the polyanion binding site in FH SCR 20, there is
– – – also one in SCR 7. This SCR is the site of an amino acid polymor-
– – phism in FH (tyrosine to histidine at residue 402, Y402H) that is a
– significant risk factor for AMD but interestingly does not correlate
with disease susceptibility for aHUS. Heterozygotes and homozygotes
Self-surface for H402 are respectively 2.7-fold and 7.4-fold more at risk for AMD
(nonactivator) than homozygous Y402 individuals, and this single polymorphism
Fig. 24.3 A STRUCTURE-BASED MODEL OF THE FACTOR H can account for up to 50% of the risk of AMD. 67,68 Two significant
(FH)–MEDIATED REGULATION OF THE ALTERNATIVE PATHWAY functional differences have been observed for the Y402 and H402
ON HOST CELLS BEARING ADVENTITIOUSLY DEPOSITED C3b. variants of FH. First, the affinity and specificity for a spectrum of
Whereas the depicted interaction of FH domains SCR(1–4) with C3b is sulfated glycosaminoglycans is different for the two variants of FH.
sufficient to prevent C3b in solution from becoming a subunit of an AP C3 Secondly, the affinity of the H402 variant of FH for C-reactive
convertase, for surface-bound C3b, at least two additional interactions are protein (CRP), an acute-phase protein that binds to damaged tissue,
necessary. The first is the interaction indicated between FH SCR19 and the is substantially lower than that of the Y402 variant. It is notable that
thioester domain (TED)/C3d domain of the C3b molecule. The second is the Bruch’s membrane of the macula, similar to the kidney basement
between FH SCR20 and cell surface–associated sulfated glycosaminoglycans membrane, is devoid of membrane-associated complement regulators
(GAGs) or arrays of sialic acid containing glycans, in both cases denoted by and so is highly dependent on FH for local AP regulation. Indeed,
pentagons with an internal minus sign. Mutations affecting either the C3d the spectrum of sulfated glycosaminoglycans found on the Bruch’s
binding site or the polyanion binding site within FH SCR(19–20) lead to membrane appear to be more dependent on the polyanionic binding
alternative pathway dysregulation and the disease atypical hemolytic uremic site in SCR 7 for the interaction than that in SCRs 19 to 20 because
syndrome (aHUS). There is an additional polyanion binding site in SCR7, even with non-AMD eye tissue, there is preferential binding of the
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which appears to be important for regulating the alternative pathway on some Y402 variant to the Bruch’s membrane. Thus the lower binding
host surfaces, most particularly Bruch’s membrane in the eye because the affinity of the H402 FH variant, coupled with a possible age-related
SCR7 Y402H polymorphism is a risk factor for AMD. (Adapted from Kajander change in the biosynthesized spectrum of sulfated glycosaminoglycans
T, Lehtinen MJ, Hyvärinen S, et al: Dual interaction of factor H with C3d and on Bruch membrane, could account for the dysregulation of the AP
glycosaminoglycans in host-nonhost discrimination by complement. Proc Nat Acad Sci in the macula with the ensuing inflammation of the macula seen in
U S A 108:2897, 2011; reproduced with permission of the National Academy of AMD patients. There may also be a contribution from the differential
Science.) binding of the FH variants to CRP present on the particulate debris