Targeting classical complement pathway to treat complement mediated autoimmune diseases.
Mice deficient for classical complement pathway (CCP) factor C4 are resistant to antibody and complement mediated experimental autoimmune myasthenia gravis (EAMG). Anti-C1q antibody administration before or following acetylcholine receptor immunization suppresses EAMG development by reducing lymph node cell IL-6 production and neuromuscular junction IgG, C3 and C5b-C9 deposition. This effect is achieved by treating mice with 10 microg of anti-C1q antibody, twice weekly for 4 weeks. Treatment with a higher amount of anti-C1q antibody gives rise to increased serum anti-acetylcholine receptor antibody, immune complex and C3 levels, facilitates kidney C3 and IgG deposits and thus reduces the treatment efficacy. C4 KO and anti-C1q antibody treated mice display normal immune system functions and intact antibody production capacity. Furthermore, CCP inhibition preserves alternative complement pathway activation, which is required for host defense against microorganisms. Therefore, CCP inhibition might constitute a specific treatment approach for not only myasthenia gravis but also other complement mediated autoimmune diseases.
Tüzün
Erdem
E
Department of Neurology, University of Istanbul, Istanbul, Turkey. drerdem@yahoo.com
Li
Jing
J
Saini
Shamsher S
SS
Yang
Huan
H
Christadoss
Premkumar
P
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism; D003181:Complement C4 / Q000172:deficiency / Q000235:genetics*; D003171:Complement Pathway, Classical / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D000906:Antibodies; D003181:Complement C4; D015850:Interleukin-6; D015922:Complement C1q