Anti-CTLA-4 antibody treatment triggers determinant spreading and enhances murine myasthenia gravis.
CTLA-4 appears to be a negative regulator of T cell activation and is implicated in T cell-mediated autoimmune diseases. Experimental autoimmune myasthenia gravis (EAMG), induced by immunization of C57BL/6 mice with acetylcholine receptor (AChR) in adjuvant, is an autoantibody-mediated disease model for human myasthenia gravis (MG). The production of anti-AChR Abs in MG and EAMG is T cell dependent. In the present study, we demonstrate that anti-CTLA-4 Ab treatment enhances T cell responses to AChR, increases anti-AChR Ab production, and provokes a rapid onset and severe EAMG. To address possible mechanisms underlying the enhanced autoreactive T cell responses after anti-CTLA-4 Ab treatment, mice were immunized with the immunodominant peptide alpha(146-162) representing an extracellular sequence of the ACHR: Anti-CTLA-4 Ab, but not control Ab, treatment subsequent to peptide immunization results in clinical EAMG with diversification of the autoantibody repertoire as well as enhanced T cell proliferation against not only the immunizing alpha(146-162) peptide, but also against other subdominant epitopes. Thus, treatment with anti-CTLA-4 Ab appears to induce determinant spreading, diversify the autoantibody repertoire, and enhance B cell-mediated autoimmune disease in this murine model of MG.
Wang
H B
HB
Experimental Neurology Unit, Division of Neurology, and Department of Medicine, Center for Infectious Medicine, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Shi
F D
FD
Li
H
H
Chambers
B J
BJ
Link
H
H
Ljunggren
H G
HG
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D000916:Antibody Diversity; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D060908:CTLA-4 Antigen; D004195:Disease Models, Animal; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D005260:Female; D007114:Immunization; D018796:Immunoconjugates; D016056:Immunodominant Epitopes / Q000378:metabolism*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000209:etiology* / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D011950:Receptors, Cholinergic / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018984:Epitopes, T-Lymphocyte; D018796:Immunoconjugates; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D010446:Peptide Fragments; D011950:Receptors, Cholinergic; D000069594:Abatacept