Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis

Erdem Tüzün, Benjamin G. Scott, Elzbieta Goluszko, Stephen Higgs, Premkumar Christadoss

Research output: Contribution to journalArticle

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Abstract

Abs to acetylcholine receptor (AChR) and complement are the major constituents of pathogenic events causing neuromuscular junction destruction in both myasthenia gravis (MG) and experimental autoimmune MG (EAMG). To analyze the differential roles of the classical vs alternative complement pathways in EAMG induction, we immunized C3-/-, C4-/-, C3 +/-, and C4+/- mice and their control littermates (C3 +/+ and C4+/+ mice) with AChR in CFA. C3-/- and C4-/- mice were resistant to disease, whereas mice heterozygous for C3 or C4 displayed intermediate susceptibility. Although C3-/- and C4-/- mice had anti-AChR Abs in their sera, anti-AChR IgG production by C3-/- mice was significantly suppressed. Both C3 -/- and C4-/- mice had reduced levels of B cells and increased expression of apoptotis inducers (Fas ligand, CD69) and apoptotic cells in lymph nodes. Immunofluorescence studies showed that the neuromuscular junction of C3-/- and C4-/- mice lacked C3 or membrane attack complex deposits, despite having IgG deposits, thus providing in vivo evidence for the incapacity of anti-AChR IgGs to induce full-blown EAMG without the aid of complements. The data provide the first direct genetic evidence for the classical complement pathway in the induction of EAMG induced by AChR immunization. Accordingly, severe MG and other Ab- and complement-mediated diseases could be effectively treated by inhibiting C4, thus leaving the alternative complement pathway intact.

Original languageEnglish (US)
Pages (from-to)3847-3854
Number of pages8
JournalJournal of Immunology
Volume171
Issue number7
StatePublished - Oct 1 2003

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Autoimmune Experimental Myasthenia Gravis
Classical Complement Pathway
Cholinergic Receptors
Alternative Complement Pathway
Neuromuscular Junction
Immunoglobulin G
Complement Membrane Attack Complex
Fas Ligand Protein
Myasthenia Gravis
Fluorescent Antibody Technique
Immunization
B-Lymphocytes
Lymph Nodes

ASJC Scopus subject areas

  • Immunology

Cite this

Tüzün, E., Scott, B. G., Goluszko, E., Higgs, S., & Christadoss, P. (2003). Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis. Journal of Immunology, 171(7), 3847-3854.

Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis. / Tüzün, Erdem; Scott, Benjamin G.; Goluszko, Elzbieta; Higgs, Stephen; Christadoss, Premkumar.

In: Journal of Immunology, Vol. 171, No. 7, 01.10.2003, p. 3847-3854.

Research output: Contribution to journalArticle

Tüzün, E, Scott, BG, Goluszko, E, Higgs, S & Christadoss, P 2003, 'Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis', Journal of Immunology, vol. 171, no. 7, pp. 3847-3854.
Tüzün, Erdem ; Scott, Benjamin G. ; Goluszko, Elzbieta ; Higgs, Stephen ; Christadoss, Premkumar. / Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis. In: Journal of Immunology. 2003 ; Vol. 171, No. 7. pp. 3847-3854.
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