Complement factor H in host defense and immune evasion

Abstract

Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.

IDK1 is a rat monoclonal antibody against hypoglycosylated bone sialoprotein with application as biomarker and therapeutic agent in breast cancer skeletal metastasis

“…Although this could be different in vivo because of the increased expression of BSP, the lack of any anti‐proliferative activity of IDK1, even in experiments using FBS without heat inactivation, lowers the probability that complement activation is a decisive factor in the mechanism of action of IDK1. Moreover, the abundant presence of cfH on MDA‐MB‐231 cells (Figure A) could be interpreted as part of their immune evasion strategy and further add to the lack of complement activation.…”

A Novel Choroidal Endothelial Cell Line Has a Decreased Affinity for the Age-Related Macular Degeneration–Associated Complement Factor H Variant 402H

“…8 Unregulated activation of the complement system, particularly the alternative pathway, has been strongly implicated in the etiology of AMD. Drusen contain complement components, 9,10 while mutations and AMD-associated polymorphisms have been identified in several proteins of the complement system, including the alternative pathway inhibitor complement factor H. [11][12][13][14] In particular, a common factor H polymorphism (Y402H) confers an increased risk for developing AMD [15][16][17] and has been shown to impair the protein's interaction with Bruch's membrane and choroidal vessels. 18 Therefore, choroidal endothelial cells (chEnCs) likely play a central role in both the ''dry'' and ''wet'' form of AMD.…”

“…39 Since HS plays a central role in controlling complement activation in the cellular microenvironment by binding to the alternative pathway inhibitor complement factor H, 14,[40][41][42] the expression of GAGs in ciChEnCs was evaluated. After resolving extracted GAGs by agarose gel electrophoresis, two distinct GAG spots were observed, which comigrated with commercial standards for HS and chondroitin sulfate, and which were efficiently degraded by incubation with the GAG-specific glycosidases heparinase I, II, and III, and chondroitinase ABC (Fig.…”

Factor H–IgG Chimeric Proteins as a Therapeutic Approach against the Gram-Positive Bacterial PathogenStreptococcus pyogenes

“…One strategy, also used by S. pyogenes as discussed above, is to recruit the host’s complement regulatory proteins FH and C4BP to the bacterial surface (20, 21). Ideally, these two complement inhibitors should exclusively protect host cells, but not microbes from complement attack (22).…”