Thymopoiesis, Regulatory T Cells, and TCRVβ Expression in Thymoma With and Without Myasthenia Gravis, and Modulatory Effects of Steroid Therapy

Abstract

We analyzed thymocyte and thymic regulatory T cell (CD4SPCD25+Foxp3+cells, Treg) development in thymoma with and without myasthenia gravis (MG, MG-thymoma, non-MG-thymoma) and in MG-associated non-neoplastic thymus (MG-NNT). An increased number of immature CD4+CD8(-)CD3(-) thymocytes through the CD4+CD8+ to CD4+CD8(-) transition and an abnormal T cell receptor Vbeta (TCRVbeta) development through the CD4+CD8+ to CD4(-)CD8+ transition were seen both in MG-and non-MG-thymomas. Terminal thymopoiesis, i.e., CD45RA+ cells within the CD4+CD8(-)CD3+ and CD8+CD4(-)CD3+ subsets, was skewed towards the CD4+ compartment in MG-thymoma and CD8+ compartment in non-MG-thymoma, but thymic export was increased only in the latter in keeping with the hypothesis that CD8+ lymphocytes may play a role in the initial stages of autosensitization and in disagreement with the relevance of an increased output of CD4+ T lymphocytes in paraneoplastic MG. Treg level in normal thymus and MG-NNT and both MG- and non-MG-thymoma was similar, and TCRVbeta development in Treg cells was slightly altered in thymoma but irrespective of MG presence. Thus, the relevance of a defective Treg development in MG context remains to be established. Most alterations in thymopoiesis were corrected by therapeutic corticosteroid administration, and the effects of steroid administration may be mediated by thymic microenvironment.

Different molecular expression in thymoma with ocular or generalized myasthenia gravis

“…A research with French MG patients has found a normal Treg number but a severe dysfunction in thymus tissues [10], whereas other studies have shown that the Treg was decreased in both peripheral blood and the thymus of MG patients [9,25], and the Foxp3 expression was dramatically down-regulated [26]. Herein, we stratified all the MG patients based upon the histological type of thymoma, and observed similar expressions of CD4 and CD25 in all types of thymoma with OMG, GMG, and Non-MG.…”

The role of FoxP3+CD4+CD25hi Tregs in the pathogenesis of myasthenia gravis

“…11 patients have been thymectomized because of thymic hyperplasia or thymoma, while other 10 patients have no abnormality of thymus. Until the study, all of the patients have not received the treatment of corticosteroid and other immune depressant at least one year to prevent from their effects [4]. 20 healthy controls (HCs), 10 males and 10 females Thymic histology Disease duration 1 M 26 IV Thymic hyperplasia 3 years 2 F 53 IIB Thymoma 2 months 3 F 63 IIA -7 years 4 F 30 IIA -6 months 5 F 84 IIB -8 years 6 M 58 I -2 years 7 F 56 IV Thymoma 12 years 8 M 63 IIA -5 years 9 F 37 IIA Thymic hyperplasia 1 year 10 M 77 I -2 years 11 F 48 IIA Thymoma 8 years 12 M 66 I -5 …”

A novel thymoma-associated autoimmune disease: Anti-PIT-1 antibody syndrome

“…On the other hand, PIT-1-reactive CTLs plays an essential role in the development of the disease 13 . In MG, it has been speculated that the first alteration in intratumorous T cell thymopoiesis may involve the generation of muscle-specific CTLs, and the resulting muscle damage could lead to various autoimmune responses including a production of autoantibodies against AChR and intracellular antigens 32 . It is speculated that anti-PIT-1 antibody may be produced after the injury of PIT-1 expressing cells by CTL and the resulting exposure of the nuclear protein PIT-1.…”