Loss of self-control in the complement system and innate autoreactivity

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The complement system is vital for immunity and tissue homeostasis, involving numerous components that require strict regulation to prevent self-attack.
• Factor H (FH) is a major regulator of the complement system, protecting host cells and controlling its amplification.
• Dysfunctions and defects in FH are linked to autoimmune diseases characterized by inflammation and damage to self-tissues, termed innate autoreactivity.

Purpose of the Study:

• To investigate the specific roles of different domains of factor H (FH) in regulating the complement system.
• To elucidate the pathogenetic mechanisms by which FH defects and polymorphisms lead to specific diseases, including MPGN II, PLD, aHUS, and AMD.
• To understand how FH dysfunction contributes to autoreactivity and tissue damage in various conditions.

Main Methods:

• Analysis of mutations and polymorphisms in the factor H (FH) gene.
• Functional studies assessing complement regulatory activities (cofactor activity, decay accelerating activity, C3b binding).
• Correlation of specific FH defects with clinical manifestations and disease predispositions (MPGN II, PLD, aHUS, AMD).

Main Results:

• Loss of N-terminal regulatory activity in FH causes partial lipodystrophy (PLD) and membranoproliferative glomerulonephritis type II (MPGN II), with C3b and MAC deposition in kidneys.
• A polymorphism in the FH SCR7-domain is associated with age-related macular degeneration (AMD), affecting FH binding to C-reactive protein (CRP) and debris clearance.
• Impaired C-terminal recognition of C3b on self-structures by FH leads to atypical hemolytic uremic syndrome (aHUS), causing complement attacks on blood cells and endothelial cells.

Conclusions:

• Specific domains and functions of factor H (FH) are critical for preventing complement-mediated damage to self-tissues.
• FH defects and polymorphisms are directly implicated in the pathogenesis of MPGN II, PLD, aHUS, and AMD.
• Increased understanding of FH's role in innate autoreactivity provides a basis for future therapeutic strategies targeting complement dysregulation.