Functional Difference between Cortical and Medullar Thymic Epithelial Cells in Patients with Myasthenia Gravis

The coincidence of autoantibodies against the acetylcholine receptor (AChR) and muscle striational antigens (SA) is a characteristic finding in thymoma-associated myasthenia gravis (MG), but their origins are still unresolved. Some common muscle antigens that were shown to be targets of anti-SA autoantibodies in thymoma-associated MG have also been detected in normal or neoplastic thymic epithelial cells, suggesting that the release of (eventually altered) antigens from the thymic tumors could elicit SA autoimmunity. In contrast to this model, we report here that titin, which is a recently reported target of SA autoimmunity, is not expressed in thymomas. In addition, we show that skeletal muscle type-II fibers exhibit a striational immunoreactivity with monoclonal antibody mAb155, which was previously identified to label a very immunogenic cytoplasmic epitope of the AChR and neoplastic epithelial cells of MGassociated thymomas. We conclude from these findings that titin autoimmunity in thymoma-associated MG is either due to a molecular mimicry mechanism involving tumor antigens (other than titin) or is a secondary phenomenon following release of titin from muscle. Based on the common immunoreactivity of the AChR, a striational antigen and thymoma, we suggest as the pathogenetic mechanism of thymoma-associated MGa "circulus vitiosus" in which SA autoimmunity could help maintain the AChR autoimmunity that is primarily elicited by the thymomas.

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IDENTIFICATION OF HUMAN THYMIC EPITHELIAL CELLS WITH ANTIBODIES TO THYMOSIN ?1, IN MYASTHENIA GRAVIS

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1981.tb33754.x ◽

1981 ◽

Vol 377 (1 Myasthenia Gr) ◽

pp. 477-485 ◽

Cited By ~ 20

Author(s):

Marinos C. Dalakas ◽

W. King Engel ◽

John E. McClure ◽

Allan L. Goldstein ◽

Valerie Askanas

Keyword(s):

Epithelial Cells ◽

Myasthenia Gravis ◽

Thymic Epithelial Cells

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Thymic B lymphocyte clones from patients with myasthenia gravis secrete monoclonal striational autoantibodies reacting with myosin, alpha actinin, or actin.

Journal of Experimental Medicine ◽

10.1084/jem.164.4.1043 ◽

1986 ◽

Vol 164 (4) ◽

pp. 1043-1059 ◽

Cited By ~ 80

Author(s):

C L Williams ◽

V A Lennon

Keyword(s):

Skeletal Muscle ◽

Epithelial Cells ◽

Myasthenia Gravis ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

B Lymphocyte ◽

High Yield ◽

Thymic Epithelial Cells ◽

Anchoring Proteins ◽

Mucosal Cells

Striational autoantibodies (StrAb), which react with elements of skeletal muscle cross-striations, occur frequently in patients with thymoma associated with myasthenia gravis (MG). Dissociated thymic lymphocytes from 22 of 72 MG patients secreted StrAb when cultured with PWM. A high yield of EBV-transformed B cell lines was established from thymus, thymoma, and peripheral blood of seven patients with MG, but clones secreting StrAb arose only from the three patients who had StrAb in their sera. The monoclonal StrAb bound to A bands or I bands in skeletal muscle of human, rat, and frog. One bound to mitochondria in addition to myofibrillar I bands. None bound to nuclei, smooth muscle, or gastric mucosal cells. In immunoblot analyses and ELISAs the monoclonal StrAb bound to muscle and nonmuscle isotypes of myosin, alpha actinin, and/or actin. All bound to contractile proteins common to thymus and muscle, and one selectively immunostained epithelial cells of the thymic medulla. From these antigenic specificities we suggest that StrAb might arise as an immune response directed against the cytoskeletal anchoring proteins associated with nicotinic acetylcholine receptors in thymic epithelial cells undergoing neoplastic transformation to thymoma.

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Medullary but not cortical thymic epithelial cells present soluble antigens to helper T cells.

Journal of Experimental Medicine ◽

10.1084/jem.175.6.1601 ◽

1992 ◽

Vol 175 (6) ◽

pp. 1601-1605 ◽

Cited By ~ 62

Author(s):

T Mizuochi ◽

M Kasai ◽

T Kokuho ◽

T Kakiuchi ◽

K Hirokawa

Keyword(s):

Monoclonal Antibody ◽

Epithelial Cells ◽

Cell Lines ◽

Helper T Cells ◽

Thymic Epithelial Cells ◽

Thymic Epithelial Cell ◽

Functional Difference ◽

Epithelial Cell Lines ◽

T Cell Lines ◽

Antigen Presenting

Thymic epithelial cell lines (TECs) were established from newborn C57BL/6 mice. They were classified into two types (medullary and cortical TECs) by using the monoclonal antibody (Th-3) that recognizes the meshwork structure of thymic cortical epithelial cells. Antigen-presenting activity of each TEC was determined by using ovalbumin-specific, I-Ab-restricted helper T cell lines. It was demonstrated that the medullary but not the cortical TECs functioned as antigen-presenting cells. This is the first evidence for the functional difference between the cortical and the medullary TEC.

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