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Paraneoplastic Autoimmunity in Thymus Tumors

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Paraneoplastic Autoimmunity in Thymus Tumors Developmental Immunology, 1998, Vol. 6, pp. 129-140 (C) 1998 OPA (Overseas Publishers Association) Reprints available directly from the publisher N.V. Published by license under the Photocopying permitted by license only Harwood Academic Publishers imprint, part of the Gordon and Breach Publishing Group Printed in Malaysia Paraneoplastic Autoimmunity in Thymus Tumors ALEXANDER MARX*, ANJA SCHULTZ, ANNETTE WILISCH, MARKUS HELMREICH, REGINA NENNINGER and HANS KONRAD MLLER-HERMELINK Department of Pathology, University of Wiirzburg, Josef-Schneider-Strasse 2, D-97080 Wiirzburg, Germany (Revised 22 May 1997; In final form 30 May 1997) Autoimmune phenomena are more frequent in thymic epithelial tumors (TET) than in any other human tumor. Mysthenia gravis (MG) is by far the most common autoimmune disease in thymoma patients. MG is characterized by muscle weakness due to autoantibodies against the acetylcholine receptor (AChR), and CD4 AChR-specific T cells play a pivotal role for the production of these autoantibodies. About 10% of MG patients have a thymoma and, interestingly, only such thymomas exhibit an MG association that maintains thymuslike morphological and functional features with respect to the homing and differentiation of immature T cells. Since AChR protein is not expressed in thymomas, the specificity of the autoimmunity in thymoma-associated MG is thought to be determined by nonreceptor proteins with AChR epitopes. Such proteins are overexpressed in cortical-type MG-associated thymomas, and medullary thymomas express these proteins at barely detectable levels. Aside from this quantitative difference, the pathogenesis of anti-AChR autoimmunity might be qualitatively different in these thymoma subtypes. Our findings suggest that an antigen-specific abnormal T- cell selection,by cortical-type TET may contribute to the pathogenesis of paraneoplastic MG. In contrast, an abnormal (intratumorous) activation of autoreactive T cells may be operative in medullary thymomas. Keywords: Thymoma, acetylcholine receptor, titin, neurofilaments, T cells Classification Categories Abbreviations AChR--Acetylcholine receptor, MG---myasthenia gravis, TET--thymic epithelial tumor(s) INTRODUCTION munity is a feature only of TET (Miiller-Hermelink, 1997). Among TET, organotypic and nonorganotypic Thymus tumors can be histologically divided into TET can be distinguished (Kirchner et al., 1992). thymic epithelial tumors (TET, including thymomas Organotypic TET are benign or malignant epithelial and thymic carcinoms), lymphomas, thymic germ-cell neoplasms that retain functional properties of the tumors, and mesenchymal neoplasms (Mtiller-Herme- normal thymus with respect to the homing and link et al., 1996). Strikingly, paraneoplastic autoim- maturation of immature thymocytes (Kirchner et al, *Corresponding author. 129 130 A. MARX et al. TABLE Frequency of MG and Expression of the AChR Epitope Alpha 373-380 in Thymic Epithelial Tumors (TET) Investigated Between 1970 and 1994 in the Department of Pathology, University of Wtirzburg Tumor Cases investigated Frequency of MG(%) Tumors with a 373-380b Tumors without a 373-380b Organotypic TET Medullary thymoma 10 30 0 3 Mixed thymoma 33 40 14 Predominantly 15 40 6 5 coritical thymoma Cortical thymoma 81 69 14 Well-differentiated 33 79 11 0 thymic carcinoma Nonorganotypic TET 24 0 2 Tumors with MG 30 8 Tumors without MG 4 16 aAll cases available (frozen and paraffin). bCases with available frozen material (allowing reactivity with mAb 155 against the AChR alpha 373-380 epitope). TABLE II Presumed Autoimmune Diseases and Immunological Systemic Disorders Observed in Association with Thymoma and MG Pure red-cell aplasia; Hypogammaglobulinemia; white blood cells aplasia; autoimmune hemolytic anaemia Grave's disease (Morbus Basedow), Hashimoto thyroiditis Lupus erythematodes, rheumatoid arthritis, polymyositis, Sj6gren's disease Subacute motor neuropathy Vitiligo, alopecia areata, bullous dermatoses Wegener's granulomatosis, Crohn's disease, Sarcoidosis Sources: aRosai, 1996; Marx et al., 1996ab; and Andonopoulos et al., 1991. bOut own observations. 1992; Mtiller-Hermelink, 1996, 1997). In addition, (MG) (Table I). Only acquired neuromyotonia, which organotypic TET are divided into medullary, mixed, is elicited by autoantibodies against he voltage-gated predominantly cortical (organoid), and cortical thy- potassium channel may be an exception to this rule momas and well-differentiated thymic carcinomas (Vincent et al., 1995) since it was found to be based on the morphological resemblance of neoplastic associated with thymic carcinoids that are considered epithelial cells to the normal thymic epithelial-cell nonorganotypic TET (Mtiller-Hermelink, 1996). subtypes (Mtiller-Hermelink et al., 1996). The occur- The list of autoimmune diseases associated with rence of paraneoplastic autoimmunity is restricted to TET is remarkably long (Table II). While MG, organotypic TET apart from very rare exceptions hypoglobulinemias, pure red-cell aplasia, and other (Rosai, 1996, Mtiller-Hermelink et al., 1996; Marx cytopenias occur frequently enough to suggest a et al., 1996a). In contrast, nonorganotypic TET pathogenetic role of the TET, this is less certain in the (squamous cell carcinomas, lympho-epitheliomalike other autoimmune diseases in which TET are rare carcinomas, clear-cell carcinomas, mucoepidermoid exceptions. Therefore, it has been suggested that carcinomas, carcinoids, small-cell carcinomas, sarco- thymomas may trigger either a specific defect of matoid carcinomas, or papillary adenocarcinomas) immune tolerance (in the case of MG and the resemble their nonthymic counterparts in other organs cytopenias) or a general disturbance of immune and are not associated with paraneoplastic autoim- regulation. This notion is supported by the finding that munity. This is particularly true for myasthenia gravis immune cytopenias and hypogammaglobulinemias PARANEOPLASTIC MYASTHENIA GRAVIS 131 TABLE III MG Subtypes According to Thymus Pathology: Correlation with Clinical and Epidemiological Findings. MG with Neither Thymitis nor TET Exhibits an Age-Related thymus ("atrophy"). Thymus pathology Thymitis "Hyperplasia" Thymoma/WDTC Onset of symptoms age (years) 10-20 15-80 Sex m:f 1:3 1:1 HLA association B8; DR3 (DR2) Autoantibodies against AchR 30-80% >90% striated muscle 10-20% >90% titin <5% >90% neuronal structures < 10% >90% ryanodine receptor <5% >50% Effect of thymectomy Improvement in 80% Deterioration in 80% Sources: See Marx et al., 1996a; Mygland et al., 1994, 1997. aWDTC: well-differentiated thymic carcinoma; Kirchner et al., 1992. almost exclusively occur in medullary thymomas heterogeneous group of diseases. Since clinical and whereas MG is mainly associated with cortical-type epidemiological findings exhibit a high association TET (Rosai, 1996; Mtiller-Hermelink et al., 1996). with characteristic thymic abnormalities, it has Investigations concerning the pathogenetic links become common practice to subdivide MG according between TET and paraneoplastic autoimmunity have to the associated pathological thymic alterations been hampered because of the rarity of almost all (Table III). autoimmune diseases listed in Table II. This is not the It is significant for the pathogenesis of paraneo- case for paraneoplastic MG. Therefore, paraneo- plastic MG that there is no age and gender predilec- plastic MG serves as a model for the analysis of the tion and almost no HLA association in paraneoplastic relationship between functional properties and MG as opposed to the more frequent MG type that morphological features of the tumor, and the develop- occurs in thymitis (Table III). ment of autoimmunity. In this paper, we will Whereas MG in thymitis patients is characterized summarize clinical and pathological features of MG- by autoimmunity almost exclusively against the associated TET and discuss novel findings for both AChR, paraneoplastic MG is distinguished by a range the epithelial and lymphoid compartments of these of additional autoantibodies against striated muscle neoplasms. antigens (actin, myosin, actinin, ryanodine receptor, and titin) and against neuronal structures (Williams et al., 1992; Aarli et al., 1990; Marx et al., 1992; Gautel RESULTS et al., 1993; Mygland et al., 1994). Finally, surgery has strikingly contrary effects on the autoimmune symptoms in MG with thymitis compared with Clinical and Epidemiological Findings in thymoma-associated MG (Table III). These findings Paraneoplastic Myasthenia Gravis clearly separate paraneoplastic MG from nonparaneo- Myasthenia gravis (MG) is an autoimmune disease plastic MG cases. characterized by an autoantibody attack against the AChR at the neuromuscular junction. However, the Most Autoantigens Are not Expressed in MG- disease is not defined by the presence of auto- Associated Thymic Epithelial Tumors but antibodies, but by the abnormal weakness of striated Autoantigen Epitopes Are muscles after contraction and by characteristic elec- trophysiological features (Drachman, 1994). Except To explain the unique pattern of autoimmunity for this common clinical denominator, MG is a against the AChR, titin, and the ryanodine receptor, 132 A. MARX et al. TABLE IV Expression of Autoantigen Epitopes but Not of the Main Antigens Themselves in Myasthenia Gravis-Associated Thymoma Autoantigen Autoantigen expression Expression of autoantigen epitope AChR No Yes Titin No Yes Ryanodine receptors No Yes one has looked for the occurrence of these autoanti- abnormal only due to their incomplete
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