Thymus in myasthenia gravis. Isolation of T-lymphocyte lines specific for the nicotinic acetylcholine receptor from thymuses of myasthenic patients.

Abstract

The thymus is believed to play a central role in the pathogenesis of Myasthenia gravis (MG). According to a previous hypothesis, MG is initiated within the thymus by immunogenic presentation of locally produced nicotinic acetylcholine receptor (AChR) to potentially autoimmune T cells. Data of 10 consecutive MG patients demonstrate two critical features of MG thymuses that support the concept of intrathymic activation of autoreactive, AChR-specific lymphocytes. Morphologically, the thymuses showed lympho-follicular hyperplasia in nine cases and benign thymoma in one case. The paramount feature revealed by immunohistological double marker analyses was the intimate association of myoid cells (antigen producing) with interdigitating reticulum cells (potentially antigen presenting cells), both of which were surrounded by T3+ lymphocytes in thymus medulla. All 10 thymuses contained T lymphocytes reactive with AChR. This was in contrast to the peripheral immune compartment (blood) where in only 3 of 10 patients, significant T cell responses to AChR were observed. AChR-specific T cell lines could be established from 8 of 10 thymuses, all members of the helper/inducer subset as indicated by the expression of markers T3 and T4.

Prednisolone Treatment Induces Tolerogenic Dendritic Cells and a Regulatory Milieu in Myasthenia Gravis Patients

“…The disease is controlled by AChR-specific T cells found in the thymus and peripheral blood of MG patients. The presence of the pathogenic T cells within the myasthenic thymus suggests that the disease is initiated in the pathologically transformed thymus (20,21). Corticosteroids, especially prednisolone (pred), are the treatment of choice for many MG patients (22), because they seem to be effective in inducing remission in a large cohort of patients.…”

Microarrays Reveal Distinct Gene Signatures in the Thymus of Seropositive and Seronegative Myasthenia Gravis Patients and the Role of CC Chemokine Ligand 21 in Thymic Hyperplasia

“…These thymic abnormalities are correlated with the antiAChR Ab titer which decreases after thymectomy (7). The hyperplastic thymus includes all the components of the anti-AChR response: the AChR (8), B cells producing anti-AChR Abs (9), and anti-AChR autoreactive T cells (10). Thus, the thymus plays a pivotal role in the pathogenesis of SP MG and an understanding of the mechanisms leading to ectopic GC formation is expected to shed light on the pathogenesis of this disease.…”

Alternatively spliced transcripts of the thymus-specific protease PRSS16 are differentially expressed in human thymus

“…24 The presence of germinal centers and maturation of B cells in the thymus support the idea of presentation of autoantigens and development of autoreactive cells that escape the mechanisms of negative selection, although it is currently unknown whether the pathology originates in the thymus or if the thymus is filled with autoreactive T cells that have re-entered the thymus after being activated in the periphery. 10 As a paraneoplastic syndrome in thymomas, about 40% of patients have MG and are positive for anti-AChR autoantibodies, and, vice versa, thymic tumors are found in about 10% of the MG patients, usually between 40 and 60 years of age. Thymic tumors associated with MG are predominantly thymomas of the cortical, mixed or medullary subtype, or welldifferentiated thymic carcinoma, and it is suspected that the etiology of the MG-associated thymoma is different from that of MG-associated TFH.…”

“…4,5 This thymitis or thymic lymphofollicular hyperplasia (TFH) is characterized by the presence of germinal centers within the thymic medulla, 6,7 which support expansion and affinity maturation of B-cell clones and facilitate the production and export of AChR-specific antibodies. 8 AChR-specific T cells are found in the myasthenic thymus, 9 and T-cell lines could be established from thymi from myasthenia patients, 10 suggesting that autoantigen-specific T cells mature in the pathologically transformed thymus and influence the humoral immune response in the periphery. 11 To test whether PRSS16 is altered in the thymus of MG patients, we investigated the expression of this protease in thymi from healthy controls and in thymic samples from patients with MG. We found that PRSS16 is alternatively spliced in the human thymus.…”