bromochloroacetic-acid and Myasthenia-Gravis

The human thymus is a lymphoepithelial organ in which T cells develop during fetal life. After maturation and selection in the fetal thymic microenvironment, T cells emigrate to peripheral lymphoid tissues such as the spleen, gut, and lymph nodes, and establish the peripheral T cell repertoire. Although the thymus has enormous regenerative capacity during fetal development, the regenerative capacity of the human postnatal thymus decreases over time. With the advent of intensive chemotherapy regimens for a variety of cancer syndromes, and the discovery that infection with the Human Immunodeficiency Virus (HIV) leads to severe loss of CD4+ T cells, has come the need to understand the role of the human thymus in reconstitution of the immune system in adults. During a recent study of the thymus in HIV infection, we observed many CD8+ T cells in AIDS thymuses that had markers consistent with those of mature effector cytotoxic T cells usually found in peripheral immune tissues, and noted these CD8+ effector T cells were predominately located in a thymic zone termed the thymic perivascular space. This article reviews our own work on the thymus in HIV-1 infection, and discusses the work of others that, taken together, suggest that the thymus contains peripheral immune cell components not only in the setting of HIV infection, but also in myasthenia gravis, as well as throughout normal life during the process of thymus involution. Thus, the human thymus can be thought of as a chimeric organ comprised of both central and peripheral lymphoid tissues. These observations have led us to postulate that the thymic epithelial atrophy and decrease in thymopoiesis that occurs in myasthenia gravis, HIV-1 infection, and thymic involution may in part derive from cytokines or other factors produced by peripheral immune cells within the thymic perivascular space.

Topics: Adult; Aging; CD4-Positive T-Lymphocytes; Embryonic and Fetal Development; Forecasting; HIV Infections; Humans; Immunohistochemistry; Keratins; Myasthenia Gravis; T-Lymphocytes; Thymus Gland

To study the clinicopathologic characteristics of thymic epithelial tumors and to evaluate the diagnostic reproducibility and clinical relevance of the 2004 WHO histologic classification system.. The morphology and immunophenotype of 52 cases of thymic epithelial tumor were reviewed. The tumors were classified according to the new WHO classification system and the clinical data were analyzed.. Of the 52 cases studied, 45 were thymomas and 7 were thymic carcinomas. Amongst the 45 cases of thymoma, 6 (13.4%) were type A, 15 (33.3%) were type AB, 4 (8.9%) were type B1, 9 (20.0%) were type B2, 9 (20.0%) were type B3 and 2 (4.4%) were metaplastic thymoma. Amongst the 7 cases of thymic carcinoma, 6 were squamous cell carcinomas and 1 was neuroendocrine carcinoma. The commonest presentations were cough and chest pain. Some cases were incidentally discovered by routine physical examination. Thirteen cases (25.0%) of thymoma were associated with myasthenia gravis. CT scan showed that 49 cases (94.2%) were located in the anterior mediastinum. All cases of type A, AB and B1 thymoma and most cases of B2 thymoma appeared as well-defined homogeneous mass, whereas a few cases of type B2 thymoma and most cases of type B3 thymoma and thymic carcinoma were poorly demarcated and heterogeneous. According to Masaoka staging system, 20 cases (41.7%) belonged to stage I, 15 cases (31.3%) stage II, 11 cases (22.9%) stage III and 2 cases (4.1%) stage IV. The histologic subtypes of thymic epithelial tumors significantly correlated with the clinical stages (chi(2) = 32.5, P < 0.01).. The 2004 revision of WHO histologic classification system for thymic epithelial tumors shows a high degree of reproducibility. Correlation with the radiologic, clinical and prognostic parameters is helpful in determining the management strategy for individual patients.

Topics: Adult; Aged; Antibodies, Monoclonal; Antigens, CD20; Carcinoma, Neuroendocrine; Carcinoma, Squamous Cell; CD5 Antigens; Female; Follow-Up Studies; Humans; Keratins; Male; Middle Aged; Myasthenia Gravis; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Radiotherapy, Adjuvant; Retrospective Studies; Thymoma; Thymus Neoplasms; Tomography, X-Ray Computed

The concurrent development of Guillain-Barré syndrome (GBS) and myasthenia gravis (MG) is rare. It has been associated with molecular mimicry between infectious agents and self-antigens. Such antibodies may show cross-reactions against both myelin proteins of peripheral nerves and acetylcholine receptors of neuromuscular junctions. Thymoma-associated multi-organ autoimmunity may also play a role in initiating autoimmune process. We present such a case with the concurrent development of GBS and MG.

Topics: Action Potentials; Adult; Antibodies; Electric Stimulation; Female; Guillain-Barre Syndrome; Humans; Keratins; Myasthenia Gravis; Neural Conduction; Reaction Time; Receptors, Cholinergic; Taiwan; Tomography, X-Ray Computed

Here we show that in myasthenic thymus several cell types, including thymic epithelial cells (TEC) and immune cells, were the source and the target of the neurotrophic factor brain-derived growth factor (BDNF). Interestingly, many actively proliferating medullary thymocytes expressed the receptor TrkB in vivo in involuted thymus, while this population was lost in hyperplastic or neoplastic thymuses. Furthermore, in hyperplastic thymuses the robust coordinated expression of BDNF in the germinal centers together with the receptor p75NTR on all proliferating B cells strongly suggests that this factor regulates germinal center reaction. Finally, all TEC dying of apoptosis expressed BDNF receptors, indicating that this neurotrophin is involved in TEC turnover. In thymomas both BDNF production and receptor expression in TEC were strongly hindered. This may represent an attempt of tumour escape from cell death.

Topics: Adult; Aged; Antigens, CD; Brain; Brain-Derived Neurotrophic Factor; Caspase 3; Cell Death; Cell Differentiation; Cells, Cultured; Female; Flow Cytometry; Humans; Keratins; Ki-67 Antigen; Leukocytes, Mononuclear; Male; Middle Aged; Myasthenia Gravis; Receptors, Nerve Growth Factor; Thymus Extracts; Thymus Gland

A mediastinal tumor in a 49-year-old woman with myasthenia gravis is reported. The tumor was well-demarcated and located in the supero-anterior mediastinum. Microscopically, the tumor consisted of thymic and neuroblastic tumor components, the latter of which consisted of immature and maturing neuronal cells, abundant neuropils, and Schwannian stroma. The two components intermingled with each other inside the tumor capsule. The tumor was diagnosed as thymoma with a ganglioneuroblastomatous component. The coexistence of epithelial and neuronal tissues in the thymic neoplasm is extremely rare.

Topics: 12E7 Antigen; Antigens, CD; CD3 Complex; CD5 Antigens; Cell Adhesion Molecules; Female; Ganglioneuroblastoma; Humans; Immunohistochemistry; Keratins; Mediastinal Neoplasms; Middle Aged; Myasthenia Gravis; Thymectomy; Thymoma; Thymus Neoplasms

There were investigated 22 cases from which the thymic tissue was removed either during surgery for cardiovascular malformations (n = 14), or for myasthenia gravis (n = 8). Histological sections were stained with routine morphologic methods, and immunohistochemistry was performed for cytokeratin, CD20, CD3, and S100 protein. Aspects characteristic for thymus involution were found in 11 cases without myasthenia gravis and in all cases with myasthenia gravis. Morphological changes of the thymus of involution are age-dependent. There were characterized stages of involution, with special reference to cortical - medulla inversion, lymphocyte depletion and sequestration. In advanced-stage of involution, epithelial cells are arranged in cords or compact islands, and could mimic a thymoma or a metastatic carcinoma. The immunohistochemical profile is similar but not identical to the active thymus. We noticed a decreased expression of cytokeratin, and a reduced number of CD3, CD20, and S100 positive cells. Morphologic and immunohistochemical peculiarities of the thymus of involution are discussed in relation with the specific pathology of the organ.

Topics: Adolescent; Adult; Antigens, CD20; Atrophy; Carcinoma; Cardiovascular Abnormalities; CD3 Complex; Child; Child, Preschool; Diagnosis, Differential; Humans; Infant; Infant, Newborn; Keratins; Lymphatic Diseases; Middle Aged; Myasthenia Gravis; Thymus Gland; Thymus Neoplasms

We have studied responses in thymoma patients to interferon-alpha and to the acetylcholine receptor (AChR) in early-onset myasthenia gravis (EOMG), seeking clues to autoimmunizing mechanisms. Our new evidence implicates a two-step process: (step 1) professional antigen-presenting cells and thymic epithelial cells prime AChR-specific T cells; then (step 2) thymic myoid cells subsequently provoke germinal center formation in EOMG. Our unifying hypothesis proposes that AChR epitopes expressed by neoplastic or hyperplastic thymic epithelial cells aberrantly prime helper T cells, whether generated locally or infiltrating from the circulation. These helper T cells then induce antibody responses against linear epitopes that cross-react with whole AChR and attack myoid cells in the EOMG thymus. The resulting antigen-antibody complexes and the recruitment of professional antigen-presenting cells increase the exposure of thymic cells to the infiltrates and provoke local germinal center formation and determinant spreading. Both these and the consequently enhanced heterogeneity and pathogenicity of the autoantibodies should be minimized by early thymectomy.

Topics: Age of Onset; Animals; Autoantibodies; Autoimmunity; B-Lymphocytes; Bungarotoxins; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epitopes; Fluorescent Antibody Technique; Germinal Center; Histocompatibility Antigens Class II; Humans; Insulin; Interferon-alpha; Interleukin-2; Keratins; Models, Immunological; Mutation; Myasthenia Gravis; Receptors, Cholinergic; Stromal Cells; T-Lymphocytes; Thymoma; Thymus Gland; Thymus Neoplasms; Troponin I

Topics: Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Cell Adhesion Molecules; Child; DNA-Binding Proteins; Humans; Hyperplasia; Immunohistochemistry; Keratins; Lectins; Myasthenia Gravis; Nerve Tissue Proteins; Nuclear Proteins; Receptors, Steroid; Receptors, Thyroid Hormone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sialic Acid Binding Ig-like Lectin 2; Thymoma; Thymus Gland; Transforming Growth Factor beta; Transforming Growth Factor beta1

In this study coexpression of cytokeratin and desmin, and occasionally also Ki-1 antigen, was displayed in extrafollicular reticulum cells of reactive lymph nodes. The absence or expression of trace amounts of these proteins in normal lymphoid tissue suggests that activation of T cell regions is correlated with the increased frequency of cytokeratin, desmin and Ki-1 expressing cells, and therefore may be a transient phenomenon. S-100-positive interdigitating reticular cells were found occasionally in extrafollicular T cell region of normal lymph nodes. They were, however, more numerous in reactive lymphatic tissue. In the myasthenic thymuses cells forming Hassall's corpuscles displayed coexpression of cytokeratin, desmin and Ki-1 antigen. Medullary epithelial cells were also cytokeratin-positive and, additionally, Ki-1 antigen was expressed on some cells dispersed in whole thymic tissue. S-100-positive interdigitating reticular cells were especially numerous in the thymic medulla and some of them found inside the Hassall's corpuscles. In Hodgkin's disease deficiency of cytokeratin and desmin in extrafollicular reticulum cells is a constant phenomenon in spite of a classic inflammatory background. However, Ki-1 antigen displayed Reed-Sternberg cells which, similar as some thymic cell elements, appear to originate from stromal perivascular mesenchyme. This fact suggests that Reed-Sternberg cells in Hodgkin's disease are pathologic counterparts of extrafollicular reticulum cells which represent a cellular differentiation defect to produce desmin and cytokeratin but with a possibility of Ki-1 antigen expression. The consequence of this may be the disregulation of immune system and the observed immunologic abnormalities. Further studies are needed to elucidate the role of Epstein-Barr viruses in this process. S-100-positive interdigitating reticular cells were in close contact with Reed-Sternberg cells and they were especially large and with numerous cells processes in the mixed cellularity (MC) subtype. The occurrence of interdigitating reticulum cells with S-100 protein expression, especially numerous in the T cell region activated of peripheral lymphatic tissue, as well as their close contact with Reed-Sternberg cells and with cells forming Hassall's corpuscles suggest their eventual possible role in the function of the immune system.

Topics: Adolescent; Adult; Child; Desmin; Female; Herpesvirus 4, Human; Hodgkin Disease; Humans; Immunohistochemistry; Keratins; Ki-1 Antigen; Lymph Nodes; Lymphocyte Activation; Male; Middle Aged; Myasthenia Gravis; S100 Proteins; Thymus Gland

This study demonstrates that the stromal thymus elements of postcapillary venules are the source of desmin-positive mesenchyme from which both myoid and epithelial cells arise. The double staining revealed various degrees of desmin and keratin positivity in the same kind of cells in the medulla as well as in Hassall's corpuscles. Hassall's corpuscles seem to arise from several kinds of cells of which one appears to be monocytogenic and expressed S100 protein.

Topics: Adolescent; Adult; Biomarkers; Cell Differentiation; Cell Fusion; Child; Desmin; Epithelium; Female; Humans; Hyperplasia; Keratins; Male; Monocytes; Myasthenia Gravis; Myoglobin; S100 Proteins; Thymus Gland; Venules

Forty-seven thymomas were histologically classified to 28 cases of cortical type, 13 cases of medullary type, and 6 cases of mixed type. They were analyzed morphometrically and immuno-histochemically, and the results were examined with their invasiveness and association with myasthenia gravis (MG). Thirty-seven resected thymic tissues were used as controls. Cortical thymomas were more often invasive ones and associated with MG than the medullary type, with significant difference. Epithelial cell nuclei of the cortical thymomas were significantly larger than those of the medullary ones. Epithelial cell nuclei of cortical and medullary thymomas were significantly larger than those of thymic cortex and medulla, respectively. Morphometrical results showed that the cortical thymomas were more malignant than the medullary ones. Immunohistochemically, all cases of thymomas were positive for Leu7 and keratin, but stainability of them were variable among each subtype. In thymic tissues epithelial cells in outer cortex were positive for Leu7 and keratin, whereas those in inner cortex and medulla were negative for Leu7 and positive for keratin.

Topics: Adult; Aged; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Myasthenia Gravis; Neoplasm Invasiveness; Thymoma; Thymus Neoplasms

The so-called lymphofollicular hyperplasia, which is caused by the occurrence of hyperplastic lymph follicles within the organ, is constantly associated with autoimmune diseases (e.g., myasthenia gravis) and in rare instances with malignant tumors. The architecture of lymphofollicular hyperplasia was studied immunohistochemically using antibodies against epithelial, vascular, lymphocytic, and histiocytic antigens. There is evidence, that the configuration, microtopography, cellular composition, and immunohistological findings of the lymph follicles with germinal centers in the myasthenic thymus are essentially the same as in those occurring in lymph nodes and in other lymphatic tissue. Furthermore it could be shown that the follicles originate in the interlobular septal space and displace the thymic parenchyma by extension.

Topics: Adolescent; Adult; Autoimmune Diseases; Child; Child, Preschool; Epithelium; Humans; Immunoenzyme Techniques; Infant; Keratins; Myasthenia Gravis; Thymectomy; Thymus Gland; Thymus Hyperplasia

The authors report an immunohistologic study of primary thymomas from 23 cases with myasthenia gravis (MG) and 7 without. Typical T6+ cortical thymocytes were usually abundant. Most epithelial cells initially appeared to be of cortical type, too, though many bore subcapsular markers in most samples. However, two-color immunofluorescence revealed unexpected heterogeneity, numerous epithelial cells simultaneously expressing some or all of the markers of both these subsets (even in two pleural metastases). It is inferred that there is a common tumor stem cell whose normal counterpart may be related to the rare patches of similar phenotype in the cortex in control samples. The authors could detect no major differences in 5 of 7 samples from nonmyasthenics; thus, most thymoma cases may risk the development of MG. Finally, thymomas from 6 of 7 further MG cases pretreated with corticosteroids showed very few cortical thymocytes, and the (phenotypically similar) epithelium was more obvious.

Topics: Adult; Aged; Antibodies, Monoclonal; Antigens, Surface; Epithelium; Fluorescent Antibody Technique; Humans; Immunosuppression Therapy; Keratins; Middle Aged; Myasthenia Gravis; Neoplasm Metastasis; T-Lymphocytes; Thymoma; Thymus Neoplasms

Six thymomas were classified histologically and studied immunohistochemically with a panel of mouse and rat monoclonal antibodies directed against thymic epithelial and lymphoid components. The antibodies included monoclonal antibodies directed against cytokeratin, medullary epithelial cells (ER-TR5), and HLA-DR and HLA-ABC antigens, as well as antibodies with specificity for thymocytes. Histologically, one thymoma was characterized by epithelial predominance (EP type), two showed lymphoid predominance (LP type), and two showed mixed lymphoid/epithelial composition (MLE type); one thymoma was a malignant pure epithelial thymoma (PE type). In the thymomas of the MLE and EP types the major populations of cells consisted of HLA-DR-negative, cytokeratin-positive epithelial cells with large ER-TR5-positive subpopulations (i.e., the phenotype of medullary epithelium). In the thymomas of the LP type, the neoplastic population was composed of cytokeratin-positive, ER-TR5-negative cells that expressed the HLA-DR antigen (i.e., the phenotype of cortical epithelium). The thymoma of the PE type consisted of cytokeratin-positive cells, some of which were ER-TR5- and HLA-DR-positive. Double immunofluorescence studies revealed the presence of varying numbers of additional nonepithelial (nonlymphoid) HLA-DR-positive cells in thymomas of the LP, MLE, and EP types. The intervening lymphoid population in the thymomas of the LP, MLE, and EP types consisted largely of cortical thymocytes, as defined by immunologic characterization. These results suggest that thymomas can be classified as medullary or cortical epithelial neoplasms on the basis of their immunologic phenotypes.

Topics: Adult; Aged; Anemia, Aplastic; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Antigens, Surface; Child, Preschool; DNA Nucleotidylexotransferase; Epithelium; Female; Histocompatibility Antigens Class II; HLA Antigens; HLA-DR Antigens; Humans; Infant; Keratins; Male; Middle Aged; Myasthenia Gravis; Thymoma; Thymus Neoplasms

17 thymomas were studied by indirect immunofluorescence for the presence of thymic hormones and antigens of the major histocompatibility complex (MHC). The thymoma epithelial cells (specifically identified by their keratin content) contained thymic hormones (thymulin and thymosin alpha 1), a finding corroborated by the observation of elevated thymulin serum levels. In contrast with normal or hyperplastic thymuses, thymoma epithelial cells did not express HLA-DR and HLA-DC antigens as assessed by immunofluorescence as well as immunoblot analyses. Conversely, MHC class I antigens (HLA-ABC) were normally expressed. Thus, we conclude that thymoma epithelial cells are endocrinologically active but are defective for the expression of some MHC products (class II molecules) known to play an essential role in intrathymic T cell differentiation.

Topics: Adult; Aged; Epithelium; Histocompatibility Antigens Class II; HLA Antigens; HLA-A Antigens; HLA-B Antigens; HLA-C Antigens; HLA-DQ Antigens; HLA-DR Antigens; Humans; Keratins; Middle Aged; Myasthenia Gravis; Thymoma; Thymus Hormones; Thymus Neoplasms

Topics: Adult; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Antigens, Surface; Epithelium; Histocompatibility Antigens Class II; Humans; Keratins; Myasthenia Gravis; T-Lymphocytes; Thymus Gland

We analyzed lymphocyte surface markers in seven thymomas. In six mixed thymomas, the staining patterns were similar for T11, OKT8, OKT6, OKT4, Coulter clone T4, and Leu 3a/3b. Staining patterns for Ia and keratin showed a dendritic pattern. Occasional S 100-positive interdigitating dendritic cells were identified. In three patients with associated myasthenia gravis, no significant differences in staining patterns were identified. A different pattern was seen in a patient with hypogammaglobulinemia, red blood cell aplasia, and a spindle cell thymoma: T11-, T8-, and T6-positive cells each comprised 70% to 80% of the tumor; but, cells of the helper/inducer phenotype differed when measured with OKT4 antibody (0%) vs Coulter clone T4 antibody (60%) and Leu 3a/3b (60%). This unusual phenotype, which was present on both tumor cells and peripheral T cells, appears related to the antigenic polymorphism of the T4 antigen and is believed to have no functional significance. Importantly, this discrepancy among commercial antibodies has significant implications in the general use of these reagents in clinical evaluations.

Topics: Adult; Aged; Antibodies, Monoclonal; Antigens, Surface; Female; Histocompatibility Antigens Class II; Humans; Keratins; Lymphocytes; Male; Middle Aged; Myasthenia Gravis; Thymoma; Thymus Neoplasms

We have investigated cell subpopulations in frozen sections of thymus tissue obtained from myasthenic (MG) and control subjects. With the use of an avidin-biotin immunoperoxidase system with monoclonal antibodies, the following cell surface antigens were studied on frozen sections (12 MG and 3 control thymus); T11, T4, T6, T8, IgM, IgD, and Ia. The pattern of T cell phenotypes in MG thymus is similar to that of normal control thymus when examined by immunohistologic techniques. MG cortical thymocytes are virtually all T11+, T4+, T8+, and T6+. In the medulla, at least 45% of thymocytes are T11+, with T4+ cells predominating over T8+ cells. Approximately 10% of medullary thymocytes are T6+. Scattered medullary cells expressing surface IgM and IgD are identified in both MG and normal thymuses. However, unlike the normal thymus, the MG thymus has numerous secondary follicles containing IgM- and IgD-bearing cells. This finding supports the hypothesis that the MG thymus microenvironment is aberrant. The Ia antigen is found in similar tissue section localization patterns in MG and control thymus. Ultramicroscopic studies show the Ia antigen predominantly on epithelial and interdigitating dendritic cells. By immunoperoxidase techniques, numerous keratin-positive cells are demonstrated in MG and control thymus. This suggests that thymic epithelial cells, like epithelial cells elsewhere, contain keratin. Because these data differ in degree from our previous findings in suspensions of MG thymocytes, this study emphasizes the importance of examining tissue sections as well as cell suspensions when one is studying lymphocyte surface markers.

Topics: Adult; Antibodies, Monoclonal; B-Lymphocytes; Histocompatibility Antigens Class II; Histocytochemistry; Humans; Infant; Keratins; Myasthenia Gravis; Phenotype; T-Lymphocytes; Thymus Gland

Topics: Adolescent; Adult; Antigen-Antibody Reactions; Antigens; Autoantibodies; Autoimmune Diseases; Colitis, Ulcerative; Epithelial Cells; Epithelium; Female; Fluorescent Antibody Technique; Humans; Keratins; Male; Multiple Sclerosis; Myasthenia Gravis; Rheumatic Fever; Skin; Thymus Gland