Immunological function of thymoma and pathogenesis of paraneoplastic myasthenia gravis

Abstract

Thymoma and thymic carcinoma are the representative tumors arising from the thymic epithelium. Thymoma is well known for association with autoimmune diseases including myasthenia gravis, suggesting its biological activity. Herein, recent progress in research of thymoma is reviewed with reference to its immunological function. Myasthenia gravis is frequently associated with WHO type B1 and B2 thymomas. These types of thymomas hold a significant number of CD4(+)CD8(+) double-positive T cells, and at the same time, the neoplastic epithelial cells express HLA-DR molecules at a slightly reduced level compared with the normal thymus. The impaired expression of HLA-DR molecules in neoplastic epithelial cells of thymomas possibly affects positive selection of CD4(+)CD8(-) single-positive T cells and may result in alteration of its repertoire. The function of thymoma neoplastic cells as the cortical epithelium of the thymus and the morphological resemblance of thymomas to the cortex suggest that thymoma is of cortical epithelial origin; this might imply that thymoma lacks the functional medulla where professional antigen-presenting cells are engaged in negative selection. These findings suggest that thymoma generates autoreactive T cells causing autoimmunity. Further investigation on immunological function of thymoma is supposed to elucidate the pathogenesis of thymoma-related autoimmunity and the high affinity of thymoma with myasthenia gravis. In addition, studying the biology of thymoma is also expected to contribute to further understanding of T-cell development and immunological tolerance in the human, because thymoma can be considered an acquired thymus.

Thymoma and autoimmunity

“…6 Additionally, in the study by Okumura et al, 9 a strong connection was documented between MG and thymoma in 467 MG patients who underwent thymectomy between 1962 and 2001. The majority of patients were female, and no sex differences were documented between patients with thymoma-associated MG and those with non-thymoma MG. 9 Furthermore, a link was found between MG and certain types of thymomas (B1 and B2) that matched the WHO classifications (Table 1). These thymomas contain a significant number of CD4 1 /CD8 1 double-positive T cells, indicating that a malfunction of the thymus medullary selection process observed in these types of thymomas could be the cause of autoreactive T-cell release.…”

“…In patients with thymoma-associated MG, a reduction of anti-AChR antibody titer was observed, suggesting a role for the intrathymic germinal centers (characteristic of thymoma) in the pathogenesis of MG. In another study, Okumura et al 9 reported that prethymectomy anti-AChR antibody levels can be viewed as a risk factor for post-thymectomy MG.…”

“…These data suggest that at least a portion of the thymic pathology that is linked to autoimmunity involves genetic aberrations. 9 The combined cellular and humeral deregulation theory This theory suggests a link between the adaptive arms of the immune system that allows them to act in concert to promote autoimmune disease. The export of thymoma-derived autoreactive T cells to the periphery is presumed to be a critical step in the development of thymoma-associated autoimmunity; however, an additional step has been suggested as being required to link these auto reactive T cells to autoantibody-producing B cells.…”

Anti-cytokine autoantibodies are associated with opportunistic infection in patients with thymic neoplasia

“…Conversely, 40% of thymoma patients will develop an autoimmune condition, approximately half of which will be myasthenia gravis. 10,11 Many other autoimmune diseases have been described in association with thymoma, ranging from pure red cell aplasia to systemic lupus erythematosis. 12,13 In patients with thymoma, myasthenia gravis or both, autoantibodies to IFN-␣, IFN-, IFN-, and interleukin-12 (IL-12) occur and may neutralize cytokine signaling in vitro.…”

Diminished regulatory T cells in cutaneous lesions of thymoma-associated multi-organ autoimmunity: a newly described paraneoplastic autoimmune disorder with fatal clinical course

“…Recently, the complete lack of Aire and minimal expression of FoxP3 in intratumoural T cells were reported in patients with enterocolonopathy caused by thymoma-associated multi-organ autoimmunity [9], suggesting that self-reactive T cells, but not Tregs, might be preferentially differentiated in thymomas. In addition, self-reactive T cells might escape negative selection because professional antigen-presenting cells that 'educate' naive T cells in the normal thymic medulla are absent in thymoma [29]. This failure of central tolerance might cause autoimmune diseases in thymoma patients.…”