Preferential production of IgG1, IL-4 and IL-10 in MuSK-immunized mice

Canan Ulusoy, Eunmi Kim, Erdem Tüzün, Ruksana Huda, Vuslat Yilmaz, Konstantinos Poulas, Nikos Trakas, Lamprini Skriapa, Athanasios Niarchos, Richard T. Strait, Fred D. Finkelman, Selin Turan, Paraskevi Zisimopoulou, Socrates Tzartos, Güher Saruhan-Direskeneli, Premkumar Christadoss

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)155-163
Number of pages9
JournalClinical Immunology
Volume151
Issue number2
DOIs
StatePublished - 2014

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Interleukin-4
Interleukin-10
Phosphotransferases
Immunoglobulin G
Muscles
Autoimmune Experimental Myasthenia Gravis
Freund's Adjuvant
Antibodies
Myasthenia Gravis
Mouse MuSK protein
Serum
Immunity
LDL-Receptor Related Proteins
Th2 Cells
Immunoglobulin Isotypes
Neuromuscular Junction
LDL Receptors
Incidence
Muscle Weakness
Cholinergic Receptors

Keywords

  • Anti-MuSK IgG1
  • Experimental autoimmune myasthenia gravis
  • IL-10
  • IL-4
  • Muscle specific kinase
  • Myasthenia gravis

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Ulusoy, C., Kim, E., Tüzün, E., Huda, R., Yilmaz, V., Poulas, K., ... Christadoss, P. (2014). Preferential production of IgG1, IL-4 and IL-10 in MuSK-immunized mice. Clinical Immunology, 151(2), 155-163. https://doi.org/10.1016/j.clim.2014.02.012

Preferential production of IgG1, IL-4 and IL-10 in MuSK-immunized mice. / Ulusoy, Canan; Kim, Eunmi; Tüzün, Erdem; Huda, Ruksana; Yilmaz, Vuslat; Poulas, Konstantinos; Trakas, Nikos; Skriapa, Lamprini; Niarchos, Athanasios; Strait, Richard T.; Finkelman, Fred D.; Turan, Selin; Zisimopoulou, Paraskevi; Tzartos, Socrates; Saruhan-Direskeneli, Güher; Christadoss, Premkumar.

In: Clinical Immunology, Vol. 151, No. 2, 2014, p. 155-163.

Research output: Contribution to journalArticle

Ulusoy, C, Kim, E, Tüzün, E, Huda, R, Yilmaz, V, Poulas, K, Trakas, N, Skriapa, L, Niarchos, A, Strait, RT, Finkelman, FD, Turan, S, Zisimopoulou, P, Tzartos, S, Saruhan-Direskeneli, G & Christadoss, P 2014, 'Preferential production of IgG1, IL-4 and IL-10 in MuSK-immunized mice', Clinical Immunology, vol. 151, no. 2, pp. 155-163. https://doi.org/10.1016/j.clim.2014.02.012
Ulusoy, Canan ; Kim, Eunmi ; Tüzün, Erdem ; Huda, Ruksana ; Yilmaz, Vuslat ; Poulas, Konstantinos ; Trakas, Nikos ; Skriapa, Lamprini ; Niarchos, Athanasios ; Strait, Richard T. ; Finkelman, Fred D. ; Turan, Selin ; Zisimopoulou, Paraskevi ; Tzartos, Socrates ; Saruhan-Direskeneli, Güher ; Christadoss, Premkumar. / Preferential production of IgG1, IL-4 and IL-10 in MuSK-immunized mice. In: Clinical Immunology. 2014 ; Vol. 151, No. 2. pp. 155-163.
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abstract = "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.",
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