A pathogenetic role for the thymoma in myasthenia gravis. Autosensitization of IL-4- producing T cell clones recognizing extracellular acetylcholine receptor epitopes presented by minority class II isotypes.
Myasthenia gravis (MG) is caused by helper T cell-dependent autoantibodies against the muscle acetylcholine receptor (AChR). Thymic epithelial tumors (thymomas) occur in 10% of MG patients, but their autoimmunizing potential is unclear. They express mRNAs encoding AChR alpha and epsilon subunits, and might aberrantly select or sensitize developing thymocytes or recirculating peripheral T cells against AChR epitopes. Alternatively, there could be defective self-tolerance induction in the abundant maturing thymocytes that they usually generate. For the first time, we have isolated and characterized AChR-specific T cell clones from two MG thymomas. They recognize extracellular epitopes (alpha75-90 and alpha149-158) which are processed very efficiently from muscle AChR. Both clones express CD4 and CD8alpha, and have a Th-0 cytokine profile, producing IL-4 as well as IFN-gamma. They are restricted to HLA-DP14 and DR52a; expression of these minority isotypes was strong on professional antigen-presenting cells in the donors' tumors, although it is generally weak in the periphery. The two clones' T cell receptor beta chains are different, but their alpha chain sequences are very similar. These resemblances, and the striking contrasts with T cells previously cloned from non-thymoma patients, show that thymomas generate and actively induce specific T cells rather than merely failing to tolerize them against self antigens.
Nagvekar
N
N
Neuroscience Group, Institute for Molecular Medicine, University of Oxford, OX3 9DS, United Kingdom.
Moody
A M
AM
Moss
P
P
Roxanis
I
I
Curnow
J
J
Beeson
D
D
Pantic
N
N
Newsom-Davis
J
J
Vincent
A
A
Willcox
N
N
D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D002999:Clone Cells / Q000276:immunology; D018604:Epitope Mapping; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism*; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000276:immunology*; D017422:Sequence Analysis, DNA; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D013945:Thymoma / Q000276:immunology / Q000503:physiopathology*
D015703:Antigens, CD; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D011950:Receptors, Cholinergic; D015847:Interleukin-4; D007371:Interferon-gamma