T cells and cytokines in the pathogenesis of acquired myasthenia gravis.
Although the symptoms of myasthenia gravis (MG) and experimental MG (EAMG) are caused by autoantibodies, CD4(+) T cells specific for the target antigen, the nicotinic acetylcholine receptor, and the cytokines they secrete, have an important role in these diseases. CD4(+) T cells have a pathogenic role, by permitting and facilitating the synthesis of high-affinity anti-AChR antibodies. Th1 CD4(+) cells are especially important because they drive the synthesis of anti-AChR complement-fixing IgG subclasses. Binding of those antibodies to the muscle AChR at the neuromuscular junction will trigger the complement-mediated destruction of the postsynaptic membrane. Thus, IL-12, a crucial cytokine for differentiation of Th1 cells, is necessary for development of EAMG. Th2 cells secrete different cytokines, with different effects on the pathogenesis of EAMG. Among them, IL-10, which is a potent growth and differentiation factor for B cells, facilitates the development of EAMG. In contrast, IL-4 appears to be involved in the differentiation of AChR-specific regulatory CD4(+) T cells, which can prevent the development of EAMG and its progression to a self-maintaining, chronic autoimmune disease. Studies on the AChR-specific CD4(+) cells commonly present in the blood of MG patients support a crucial role of CD4(+) T cells in the development of MG. Circumstantial evidence supports a pathogenic role of IL-10 also in human MG. On the other hand, there is no direct or circumstantial evidence yet indicating a role of IL-4 in the modulatory or immunosuppressive circuits in MG.
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA. mmilani@cbs.umn.edu
Monica
M
Milani
Norma
N
Ostlie
Wei
W
Wang
Bianca M
BM
Conti-Fine
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000145:classification / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007114:Immunization; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009132:Muscles / Q000378:metabolism / Q000503:physiopathology / Q000637:transplantation; D009157:Myasthenia Gravis / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits; D011950:Receptors, Cholinergic / Q000276:immunology; D013601:T-Lymphocytes / Q000145:classification / Q000276:immunology / Q000473:pathology*; D013997:Time Factors
D000906:Antibodies; D016207:Cytokines; D021122:Protein Subunits; D011950:Receptors, Cholinergic