ABSTRACT
Sera of myasthenia gravis (MG) patients with muscle-specific receptor kinase-antibody (MuSK-Ab) predominantly display the non-complement fixing IgG4 isotype. Similarly, mouse IgG1, which is the analog of human IgG4, is the predominant isotype in mice with experimental autoimmune myasthenia gravis (EAMG) induced by MuSK immunization. The present study was performed to determine whether IgG1 anti-MuSK antibody is required for immunized mice to develop EAMG. Results demonstrated a significant correlation between clinical severity of EAMG and levels of MuSK-binding IgG1+, IgG2+ and IgG3+ peripheral blood B cells in MuSK-immunized wild-type (WT) mice. Moreover, MuSK-immunized IgG1 knockout (KO) and WT mice showed similar EAMG severity, serum MuSK-Ab levels, muscle acetylcholine receptor concentrations, neuromuscular junction immunoglobulin and complement deposit ratios. IgG1 and IgG3 were the predominant anti-MuSK isotypes in WT and IgG1 KO mice, respectively. These observations demonstrate that non-IgG1 isotypes can mediate MuSK-EAMG pathogenesis.
Subject(s)
Immunoglobulin G/immunology , Myasthenia Gravis, Autoimmune, Experimental/chemically induced , Myasthenia Gravis, Autoimmune, Experimental/immunology , Receptor Protein-Tyrosine Kinases/toxicity , Animals , Antigens, CD/immunology , Antigens, CD/metabolism , Autoantibodies/blood , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Freund's Adjuvant/toxicity , Immunization , Immunoglobulin G/genetics , Immunoglobulin G/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myasthenia Gravis, Autoimmune, Experimental/pathology , Neuromuscular Junction/immunology , Neuromuscular Junction/metabolism , Neuromuscular Junction/pathology , Receptors, Cholinergic , Severity of Illness Index , Statistics, NonparametricABSTRACT
INTRODUCTION: Antibodies directed against neuronal surface antigens have recently been identified in patients with focal temporal lobe epilepsy (TLE) of unknown cause and mesial TLE with hippocampal sclerosis (MTLE-HS), thereby emphasizing the role of autoimmunity in TLE. Antibodies to contactin-associated protein-like 2 (CASPR2) are prevalent in MTLE-HS patients. We aimed to find out whether anti-neuronal autoimmunity might be involved in CASPR2 antibody-related MTLE-HS. METHODS: Surgically resected medial temporal lobe specimens of seropositive and seronegative MTLE-HS patients were examined with hematoxylin and eosin and immunohistochemical staining using specific immune cell markers. RESULTS: Two of 5 CASPR2 antibody-positive MTLE-HS patients showed polymorphonuclear and mononuclear cells infiltrating the subarachnoidal region. One of these patients also showed mononuclear cell infiltration in the parenchyma of the temporal lobe cortex. Subarachnoidal and parenchymal infiltrates contained CD3+, CD8+, and CD68+ cells. None of the 13 seronegative MTLE-HS patients displayed cellular infiltrates in their brain samples, and all MTLE-HS patients showed marked neuronal cell loss but no immune cell infiltration in their hippocampi. CONCLUSION: Our results show that CASPR2 antibody-associated MTLE-HS can present with central nervous system inflammation; thus, this subtype of MTLE-HS might have an autoimmune origin.
