TY - JOUR
T1 - Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis
AU - Tüzün, Erdem
AU - Scott, Benjamin G.
AU - Goluszko, Elzbieta
AU - Higgs, Stephen
AU - Christadoss, Premkumar
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2003/10/1
Y1 - 2003/10/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.171.7.3847
DO - 10.4049/jimmunol.171.7.3847
M3 - Article
C2 - 14500686
AN - SCOPUS:18844476082
SN - 0022-1767
VL - 171
SP - 3847
EP - 3854
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -