Project: Research project

Project Details


Our goal is to investigate the intrathymic genesis of
autoimmunity. Specific investigations are based on a new
concept of the role of the thymus in at least one form of
autoimmunity, the neuromuscular disease myasthenia gravis
(MG). Most thymic epithelial cells express Ia constitutively,
and medullary epithelial cells express nicotinic acetylcholine
receptors (AChR), the antigen of MG. Much is known about the
role of anti-AChR autoantibodies in causing failure of
neuromuscular transmission in MG, but nothing is known about
why these antibodies arise. In MG the thymus is a major site
of anti-AChR antibody production. Its removal frequently is
followed by remission of the disease. The thymus undergoes
neoplastic transformation in 15% of MG patients. Studies
outlined in this proposal concern the role of thymic epithelial
cells in initiating autoimmunity to AChR.

Hypotheses to be tested are that: i) AChR associated with
thymic epithelial cells is the primary immunogen of
spontaneously acquired MG; ii) this immunogenicity is promoted
by activation of vertically transmitted proviral genes; iii)
production of anti-AChR autoantibodies reflects an
anti-tumor/virus immune response that is progressing in situ in
the thymus; iv) some epitopes of the AChR expressed on thymic
epithelial cells are neuroectoderm-specific and are expressed
selectively on cranial (oculobulbar) muscles. The long-term
goal is to find a basis for new and more effective methods of
treating MG. Materials to be tested include normal thymus
tissues from mice, rats and humans, and cryopreserved thymus
tissue and thymomas from MG patients. The AKR/J strain of
mouse, which has a 90% incidence of thymic tumors and a
paradoxical susceptibility to experimental autoimmune MG
(EAMG), will be investigated as a novel model of the
relationship between thymoma and MG. Methods include culture
of thymic epithelial cells and thymomas, probing
immunologically and with 32P-cDNA for coexpression of AChR and
viral or onc gene products, generation of T cell clones,
testing ability of thymic epithelial cells to present AChR,
testing EAMG susceptibility in AKR/J mice with thymoma
suppressed by neonatal treatment with anti-gp70 antibodies,
serologic comparisons of the antigenicity of AChR in thymus and
cranial and limb muscles.
StatusNot started


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