TY - JOUR
T1 - Preferential production of IgG1, IL-4 and IL-10 in MuSK-immunized mice
AU - Ulusoy, Canan
AU - Kim, Eunmi
AU - Tüzün, Erdem
AU - Huda, Ruksana
AU - Yilmaz, Vuslat
AU - Poulas, Konstantinos
AU - Trakas, Nikos
AU - Skriapa, Lamprini
AU - Niarchos, Athanasios
AU - Strait, Richard T.
AU - Finkelman, Fred D.
AU - Turan, Selin
AU - Zisimopoulou, Paraskevi
AU - Tzartos, Socrates
AU - Saruhan-Direskeneli, Güher
AU - Christadoss, Premkumar
N1 - Funding Information:
This study was supported by the Myasthenia Gravis Foundation of America , Association Francaise contre les Myopathies , Muscular Dystrophy Association and Hellas–Turkey Bilateral Project ( 109S353 ) supported by the Scientific and Technological Research Council of Turkey (TÜBİTAK) and the NSRF “Thalis” Autoimmunity Grant of Greece .
PY - 2014/4
Y1 - 2014/4
N2 - Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness associated with acetylcholine receptor (AChR), muscle-specific receptor kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4)-antibodies. MuSK-antibodies are predominantly of the non-complement fixing IgG4 isotype. The MuSK associated experimental autoimmune myasthenia gravis (EAMG) model was established in mice to investigate immunoglobulin (Ig) and cytokine responses related with MuSK immunity. C57BL/6 (B6) mice immunized with 30. μg of recombinant human MuSK in incomplete or complete Freund's adjuvant (CFA) showed significant EAMG susceptibility (>. 80% incidence). Although mice immunized with 10. μg of MuSK had lower EAMG incidence (14.3%), serum MuSK-antibody levels were comparable to mice immunized with 30. μg MuSK. While MuSK immunization stimulated production of all antibody isotypes, non-complement fixing IgG1 was the dominant anti-MuSK Ig isotype in both sera and neuromuscular junctions. Moreover, MuSK immunized IgG1 knockout mice showed very low serum MuSK-antibody levels. Sera and MuSK-stimulated lymph node cell supernatants of MuSK immunized mice showed significantly higher levels of IL-4 and IL-10 (but not IFN-γ and IL-12), than those of CFA immunized mice. Our results suggest that through activation of Th2-type cells, anti-MuSK immunity promotes production of IL-4, which in turn activates anti-MuSK IgG1, the mouse analog of human IgG4. These findings might provide clues for the pathogenesis of other IgG4-related diseases as well as development of disease specific treatment methods (e.g. specific IgG4 inhibitors) for MuSK-related MG.
AB - Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness associated with acetylcholine receptor (AChR), muscle-specific receptor kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4)-antibodies. MuSK-antibodies are predominantly of the non-complement fixing IgG4 isotype. The MuSK associated experimental autoimmune myasthenia gravis (EAMG) model was established in mice to investigate immunoglobulin (Ig) and cytokine responses related with MuSK immunity. C57BL/6 (B6) mice immunized with 30. μg of recombinant human MuSK in incomplete or complete Freund's adjuvant (CFA) showed significant EAMG susceptibility (>. 80% incidence). Although mice immunized with 10. μg of MuSK had lower EAMG incidence (14.3%), serum MuSK-antibody levels were comparable to mice immunized with 30. μg MuSK. While MuSK immunization stimulated production of all antibody isotypes, non-complement fixing IgG1 was the dominant anti-MuSK Ig isotype in both sera and neuromuscular junctions. Moreover, MuSK immunized IgG1 knockout mice showed very low serum MuSK-antibody levels. Sera and MuSK-stimulated lymph node cell supernatants of MuSK immunized mice showed significantly higher levels of IL-4 and IL-10 (but not IFN-γ and IL-12), than those of CFA immunized mice. Our results suggest that through activation of Th2-type cells, anti-MuSK immunity promotes production of IL-4, which in turn activates anti-MuSK IgG1, the mouse analog of human IgG4. These findings might provide clues for the pathogenesis of other IgG4-related diseases as well as development of disease specific treatment methods (e.g. specific IgG4 inhibitors) for MuSK-related MG.
KW - Anti-MuSK IgG1
KW - Experimental autoimmune myasthenia gravis
KW - IL-10
KW - IL-4
KW - Muscle specific kinase
KW - Myasthenia gravis
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U2 - 10.1016/j.clim.2014.02.012
DO - 10.1016/j.clim.2014.02.012
M3 - Article
C2 - 24589747
AN - SCOPUS:84896056386
SN - 1521-6616
VL - 151
SP - 155
EP - 163
JO - Clinical Immunology
JF - Clinical Immunology
IS - 2
ER -