Essential role of surface-bound complement factor H in controlling immune complex-induced arthritis

Area of Science:

• Immunology
• Rheumatology

Background:

• The alternative pathway (AP) of the complement system is crucial for developing collagen antibody-induced arthritis (CAIA).
• Factor H (fH) is a key regulator of the AP, primarily acting in circulation but also binding to tissues.
• The precise role of tissue-bound fH in controlling AP-driven joint inflammation remains unclear.

Purpose of the Study:

• To investigate the role of tissue-bound Factor H in regulating the alternative pathway during collagen antibody-induced arthritis (CAIA).
• To determine if blocking fH's tissue-binding capacity exacerbates joint inflammation and complement deposition in a murine CAIA model.

Main Methods:

• Utilized a recombinant inhibitor (rfH19-20) to block the carboxyl-terminal binding domain of fH to tissues.
• Administered rfH19-20 or a control (rfH3-5) to wild-type and fH(+/-) mice with CAIA.
• Assessed clinical disease activity, histopathological joint injury, and C3 complement fragment deposition in synovium and cartilage.

Main Results:

• Administration of rfH19-20 significantly worsened clinical scores and histopathological damage in the joints of mice with CAIA.
• Blocking fH's tissue binding led to increased C3 deposition in the synovium and cartilage.
• In vitro experiments confirmed that rfH19-20 enhances complement activation on cartilage extracts and synoviocytes.

Conclusions:

• Endogenous Factor H significantly inhibits the alternative pathway in CAIA by binding to sites of immune complex formation and complement activation within the joint.
• Targeting fH's tissue-binding capacity represents a potential therapeutic strategy to exacerbate joint inflammation, highlighting its protective role.