Loss of self-control in the complement system and innate autoreactivity.
The complement system performs effective antimicrobial and clean-up functions to keep the body clear from invading microbes and accumulating debris. From its about 35 components many regulate complement activity to prevent self-attack. Our work has focused on regulator defects and dysfunctions that cause autoreactivity, that is, inflammation and damage against self-tissues ("innate autoreactivity"). The major complement regulator, factor H (FH), protects host cells and keeps excessive amplification under control. Mutations and polymorphisms in FH predispose to four different diseases: membranoproliferative glomerulonephritis type II (MPGN II), partial lipodystrophy (PLD), recurrent atypical hemolytic uremic syndrome (aHUS), and age-related macular degeneration (AMD). Loss of the complement regulatory activity (cofactor activity for C3b inactivation and decay accelerating activity) in the N terminus of FH leads to PLD and MPGN II, the latter of which is characterized by C3b and MAC deposition on the glomerular basement membranes of kidneys. Polymorphism in the SCR7-domain in the middle part of FH predisposes to AMD, which is the most common cause of vision loss in elderly people. This polymorphism influences the ability of FH to bind to C-reactive protein (CRP) and to target phagocytic clearance of debris (e.g., eye pigment) and control local inflammation. Finally, the loss of the ability of the FH C terminus to recognize C3b molecules deposited on self-structures predisposes to aHUS, where blood cells, platelets, and endothelial cells, particularly in kidneys, become targets for repeated complement attacks and increased procoagulant activity. The pathogenetic mechanisms of these diseases are being increasingly understood, which in the future will help in designing new therapies.
Meri
Seppo
S
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland. seppo.meri@helsinki.fi
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D016923:Cell Death; D003165:Complement System Proteins / Q000276:immunology*; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D018448:Models, Immunological; D051193:Toll-Like Receptors / Q000276:immunology