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Classical Complement Pathway in Experimental Autoimmune Myasthenia Gravis Pathogenesis
Author(s) -
Christadoss Premkumar,
Tüzün Erdem,
Li Jing,
Saini Shamsher S.,
Yang Huan
Publication year - 2008
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1405.009
Subject(s) - myasthenia gravis , classical complement pathway , immunology , complement system , immune system , acetylcholine receptor , antibody , medicine , pathogenesis , autoimmune disease , immunization , receptor
Mice deficient for complement factors C3, C4, or C5 are resistant to experimental autoimmune myasthenia gravis (EAMG). Acetylcholine receptor (AChR) immune lymph node cells (LNC) of C3 deficient mice produce less interleukin 6 (IL‐6), and EAMG‐resistant IL‐6 deficient mice have less serum C3. Increased serum C1q‐circulating immune complex (CIC) levels correlated with EAMG disease severity in RIIIS/J mice. The CIC promotes EAMG severity by stimulating the production of LNC IL‐6, serum C1q, and C3 via FCγR interaction. Therefore, EAMG/MG could be treated by blocking the activation of classical complement pathway (CCP) and/or IL‐6. Anti‐C1q antibody administration before and following AChR immunization suppressed EAMG by reducing LNC IL‐6 production and neuromuscular junction deposits of IgG, C3, and C5b‐C9 complexes. Treatment with low dose (10 μg) of anti‐C1q antibody twice a week for 4 weeks in mice with ongoing clinical EAMG reduced the clinical severity of disease and LNC IL‐6 production. Therefore, inhibitors of CCP factors C1q, C2, or C4 could treat MG and would preserve the alternate complement pathway activation. Our goal is to tailor MG therapy using anti‐C2/C4 reagents in combination, with or without anti‐cytokine (e.g., anti‐IL‐6) reagents.