The complement system contributes to the pathology of experimental autoimmune encephalomyelitis by triggering demyelination and modifying the antigen-specific T and B cell response

• Published in: Clinical immunology (Orlando, Fla.) Vol. 146; no. 3; pp. 155 - 164
• Main Authors: Hundgeburth, Lorenz C, Wunsch, Marie, Rovituso, Damiano, Recks, Mascha S, Addicks, Klaus, Lehmann, Paul V, Kuerten, Stefanie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2013
• Subjects: Allergy and Immunology; Animals; Antigens - immunology; B cells; B-Lymphocytes - immunology; Complement; Complement Activation - drug effects; Complement Inactivating Agents - pharmacology; Complement System Proteins - immunology; Demyelination; EAE/MS; Elapid Venoms - pharmacology; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Female; Mice; Mice, Inbred C57BL; MP4; Myelin Basic Protein - immunology; Myelin Proteolipid Protein - immunology; Myelin Sheath - pathology; Myelin Sheath - ultrastructure; Recombinant Fusion Proteins - immunology; Spinal Cord - pathology; Spinal Cord - ultrastructure; T cells; T-Lymphocytes - immunology; Multiple sclerosis; Complement receptor 2; Central nervous system; Experimental autoimmune encephalomyelitis; CNS; Complement; T cells; C57BL/6; Myelin basic protein; Cobra venom factor; Myelin oligodendrocyte glycoprotein; Antigen presenting cell; C3a receptor; PLP; Demyelination; MBP; WT; Ovalbumin; CR2; MOG; C5a receptor; MS; DAF; EAE; C1qRP; B cells; Wild-type; MP4; CVF; APC; B6; Decay-accelerating factor; Proteolipid protein; C1q receptor P; OVA; C5aR; C3aR; MBP–PLP fusion protein; EAE/MS
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2012.12.007

Abstract So far, studies of the human autoimmune disease multiple sclerosis (MS) have largely been hampered by the absence of a pathogenic B cell component in its animal model, experimental autoimmune encephalomyelitis (EAE). To overcome this shortcoming, we have previously introduced the myelin basic protein (MBP)–proteolipid protein (PLP) MP4-induced EAE, which is B cell and autoantibody-dependent. Here we show that MP4-immunized wild-type C57BL/6 mice displayed a significantly lower disease incidence when their complement system was transiently depleted by a single injection of cobra venom factor (CVF) prior to immunization. Considering the underlying pathomechanism, our data suggest that the complement system is crucial for MP4-specific antibodies to trigger CNS pathology. Demyelinated lesions in the CNS were colocalized with complement depositions. In addition, B cell deficient JH T mice reconstituted with MP4-reactive serum showed significantly attenuated clinical and histological EAE after depletion of complement by CVF. The complement system was also critically involved in the generation of the MP4-specific T and B cell response: in MP4-immunized wild-type mice treated with CVF the MP4-specific cytokine and antibody response was significantly attenuated compared to untreated wild-type mice. Taken together, we propose two independent mechanisms by which the complement system can contribute to the pathology of autoimmune encephalomyelitis. Our data corroborate the role of complement in triggering antibody-dependent demyelination and antigen-specific T cell immunity and also provide first evidence that the complement system can modify the antigen-specific B cell response in EAE and possibly MS.