Attachment of the soluble complement regulator factor H to cell and tissue surfaces: relevance for pathology.
Complement is a central element of innate immunity and this vital defense system initiates and coordinates immediate immune reactions which attack and eliminate microbes, foreign particles and altered self cells. Newly generated activation products are extremely toxic and consequently, activation is highly restricted in terms of time and space. The initial activation of the alternative complement pathway occurs continuously and the early phase acts indiscriminatoryl and forms on any surface. However, the system discriminates between self and foreign, and therefore allows activation on foreign surfaces e.g. microbes, and restricts activation on host cells. Consequently, self cells and tissues are protected from the harmful activation products. This protection is mediated by specific regulators or inhibitors, which exist in the fluid phase and/or in membrane-bound forms. Here we review a novel mechanism, i.e. the attachment of the soluble complement regulator factor H to the surface of self cells. This attachment, which is demonstrated experimentally by means of immunofluorescense microscopy and by flow cytometry, increases the inhibitory potential at the cell surface and mediates protection by reducing the local formation of toxic inflammatory products. This attachment is highly relevant and has pathophysiological consequences in several human diseases, including Factor H-associated hemolytic uremic syndrome (FH-HUS), membrano-proliferative glomerulonephritis type II, recurrent microbial infections and chronic inflammation, e.g. rheumatoid arthritis and immune evasion of tumor cells. Defects of this safeguard activity have been recently understood in patients with FH-HUS. Point mutations in the Factor H gene occurring in the C-terminus of the protein result in impaired cell binding capacity of Factor H and, consequently, during an inflammatory insult endothelial cells are not properly protected and are damaged.
Józsi
M
M
Department of Biological Infection, Hans Knoell Institute for Natural Products Research, Jena, Germany.
Manuelian
T
T
Heinen
S
S
Oppermann
M
M
Zipfel
P F
PF
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003167:Complement Activation; D003179:Complement C3b / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism*; D003170:Complement Pathway, Alternative; D004730:Endothelium, Vascular / Q000378:metabolism*; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008954:Models, Biological; D010336:Pathology; D017354:Point Mutation; D012995:Solubility; D013499:Surface Properties; D014471:Umbilical Veins / Q000166:cytology
C493495:CFH protein, human; D003179:Complement C3b; D017242:Complement Factor H