ABSTRACT
Following immunization with acetylcholine receptor (AChR), MHC class II-restricted, AChR-specific CD4 cell activation is critical for the development of experimental autoimmune myasthenia gravis (EAMG) in C57BL/6 mice. To study the contributions of B7-1 and B7-2 costimulatory molecules in EAMG, B7-1, B7-2, and B7-1/B7-2 gene knockout (KO) mice were immunized with Torpedo AChR in CFA. Compared with wild-type C57BL6 mice, B7-1 and B7-1/2 KO mice were resistant to EAMG development. B7-1 KO mice had reduced anti-AChR Ab compared with C57BL/6 mice. However, neither B7-1 nor B7-2 gene disruption impaired AChR-induced or dominant alpha(146-162) peptide-induced in vitro lymphoproliferative responses. Blocking of the B7-1 or B7-2 molecule by specific mAbs in vivo led to a reduction in the AChR-specific lymphocyte response, and the reduction was more pronounced in mice treated with anti-B7-2 Ab. The findings implicate B7-1 molecules as having a critical role in the induction of EAMG, and the resistance of B7-1 KO mice is associated with suppressed humoral, rather than suppressed AChR-specific, T cell responses. The data also point to B7-2 molecules as being the dominant costimulatory molecules required for AChR-induced lymphocyte proliferation.
Subject(s)
B7-1 Antigen/physiology , Myasthenia Gravis, Autoimmune, Experimental/genetics , Myasthenia Gravis, Autoimmune, Experimental/immunology , Animals , Antibodies, Blocking/administration & dosage , Antigens, CD/genetics , Antigens, CD/immunology , Autoantibodies/biosynthesis , B-Lymphocyte Subsets/cytology , B-Lymphocyte Subsets/immunology , B7-1 Antigen/genetics , B7-1 Antigen/immunology , B7-2 Antigen , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Cells, Cultured , Cytokines/biosynthesis , Growth Inhibitors/administration & dosage , H-2 Antigens/immunology , Histocompatibility Antigen H-2D , Injections, Intraperitoneal , Injections, Subcutaneous , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/genetics , Membrane Glycoproteins/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Mitosis/genetics , Mitosis/immunology , Mutagenesis, Site-Directed , Myasthenia Gravis, Autoimmune, Experimental/prevention & control , Peptide Fragments/immunology , Receptors, Nicotinic/administration & dosage , Receptors, Nicotinic/immunology , Receptors, Nicotinic/physiologyABSTRACT
To analyze the role of the Th2 cytokine interleukin-5 (IL-5) in experimental autoimmune myasthenia gravis (EAMG) pathogenesis, we induced clinical EAMG in C57BL/6 and IL-5 gene-knockout (KO) mice in the C57BL/6 background. IL-5 KO mice had a significantly reduced incidence and severity of EAMG. Despite their increased resistance to EAMG, IL-5 KO mice displayed intact secondary antibody and lymphoproliferative responses to acetylcholine receptor (AChR) after immunization with this molecule. However, the relative resistance of IL-5 KO mice was associated with a reduced primary lymphocyte response to AChR, and reduced C3 levels in muscle extracts compared to those in C57BL/6 mice.
