Nicotinic acetylcholine receptors (AChRs) are a family of acetylcholine-gated cation channels that form the predominant excitatory neurotransmitter receptors on muscles and nerves in the peripheral nervous system. AChRs are also expressed on neurons in lower amounts throughout the central nervous system. AChRs are even being reported on unexpected cell types such as keratinocytes. Structures of these AChRs are being determined with increasing precision, but functions of some orphan subunits are just beginning to be established. Functional roles for postsynaptic AChRs in muscle are well known, but in neurons the post-, peri-, extra-, and presynaptic roles of AChRs are just being revealed. Pathogenic roles of AChRs are being discovered in many diseases involving mechanisms ranging from mutations, to autoimmune responses, to the unknown; involving cell types ranging from muscles, to neurons, to keratinocytes; and involving signs and symptoms ranging from muscle weakness to epilepsy, to neurodegenerative disease, to psychiatric disease, to nicotine addiction. Awareness of AChR involvement in some of these diseases has provoked new interests in development of therapeutic agonists for specific AChR subtypes and the use of expressed cloned AChR subunits as possible immunotherapeutic agents. Highlights of recent developments in these areas will be briefly reviewed.

Nicotinic acetylcholine receptors in health and disease.

Summary The Second Conference on Biological and Clinical Aspects of Thymic Epithelial Tumors in Leiden, The Netherlands, 1998, set the stage for an interdisciplinary meeting of immunologists, pathologists and membersof various clinical disciplines to exchange their recent findings in the field of thymus-related biology, pathology, and medicine. The contributions covered such diverse subjects as the role of transcription factors and cytokines in the development of the thymic microenvironment, thymic T, B and NK cell development, the pathogenesis of myasthenia gravis and other thymomaassociated autoimmunities, the pathology of thymic epithelial tumors and germ cell neoplasms, and new approaches to their diagnosis and treatment. This editorial will briefly sum up the data presented at the Conference and will comment on related novel findings that have been reported since then. Because it was also at the Leiden Conference, that the proposal of the WHO committee for the classification of thymic tumors was discussed for the first time, a description of the upcoming WHO Classification of Tumors of the Thymus is given with emphasis on the diagnostic criteria of thymic epithelial tumors, that should now be termed as type A, AB, B1-3 and type C thymomas, to make pathological and clinical studies comparable in the future.

From basic immunobiology to the upcoming WHO-classification of tumors of the thymus. The Second Conference on Biological and Clinical Aspects of Thymic Epithelial Tumors and related recent developments.

Recent advances in tissue culture technology and molecular biology have extended our understanding of the functional morphology of the thymus. The importance of a crosstalk between lymphoid cells and stroma has been appreciated as a prerequisite for the normal development of both. The network of direct cellular interactions and soluble factors comprising part of the microenvironment is far from being elucidated but the highly ordered thymic architecture clearly plays a pivotal role in normal thymic function. Insight into the genetic control of stroma development is only emerging while knowledge on the genetic control of the various steps in T cell development is already advanced and rapidly expanding. The present paper gives an overview on the cellular components and matrix molecules of the human thymic microenvironment and their development during ontogeny. The intrathymic cytokine network is shortly reviewed. Special emphasis is put on molecules mediating lymphoepithelial interactions that are necessary for the expansion and early selection of immature thymocytes from precursor cells and for the generation of an MHC restricted and self tolerant T cell repertoire by positive and negative selection. Considering these physiological mechanisms we summarize the molecular pathology of the microenvironment and lymphocyte/stroma interactions in thymic epithelial tumors (thymomas). Finally, a pathogenetic model for paraneoplastic myasthenia gravis is given. We suggest abnormal auto-antigen-specific positive selection of naive T cells as the essential molecular mechanism by which thymomas contribute to the autoimmunization against the acetylcholine receptor and other muscle proteins.

https://www.jstage.jst.go.jp/article/aohc1988/60/1/60_1_9/_pdf

Characterization of the human thymic microenvironment: lymphoepithelial interaction in normal thymus and thymoma.

Thymomas occurring in myasthenia gravis (MG) are usually of the cortical subtype and are usually treated by thymectomy. However, the factors that influence MG outcome in thymoma MG patients are not known. In a long-term study, MG severity and treatment was observed in 24 thymoma and 24 non-thymoma MG patients for up to 30 years, and the occurrence of muscle autoantibodies was assayed. The rate of complete stable remission was low and did not differ between the two groups. There was no significant difference in MG severity between thymoma and non-thymoma MG patients at any time during the study. Titin and ryanodine receptor (RyR) antibody occurrence was significantly higher in thymoma MG patients. Four thymoma (all titin and RyR antibody positive) and two non-thymoma (both titin and one RyR antibody positive) MG patients died from MG-related respiratory insufficiency. Seventy percent of thymoma and 75% of non-thymoma MG patients were treated with immunosuppressive drugs. The number of patients who received plasmapheresis did not differ in those who were treated because of acute MG deterioration, irrespective of planned surgery.This study shows equal MG severity and outcome in thymoma and non-thymoma MG, but the presence of RyR antibodies in thymoma MG and titin/RyR in non-thymoma MG indicates a less favorable prognosis.

Disease severity and outcome in thymoma myasthenia gravis: a long-term observation study

https://www.exphem.org/article/S0301-472X(99)00010-7/pdf

Adhesion molecules involved in the interactions between early T cells and mesenchymal bone marrow stromal cells.

Two findings in thymic epithelial tumors are correlated with the occurrence of myasthenia gravis(MG): (1) the expression of an acetylcholine receptor (AChR)-like-epitope in the neoplastic epithelium, and (2) the preservation of thymus-like features in the neoplasms, indicated by the presence of immature thymocytes. On this background it has been proposed that paraneoplastic MG may start with an intratumorous abnormal T cell selection due to aberrantly expressed AChR-epitopes (self-peptides). As appropriate thymocyte-stroma-interactions are prerequisites for thymocyte development in the thymus (and probably in MG-associated thymic tumors, too), we analyzed the expression of CD28/B7(BB1), CD2/:LFA3, LFA-1/ICAM-1 and VLA-4/VCAM-1 in human thymus and thymomas by immunohistochemistry. In normal thymuses and thymitis the stromal molecules were expressed at higher levels in the medulla than in the cortex. This was particularly true for B7(BB1) that was undetectable by immunoperoxidase techniques in the cortex. In contrast, cortical-type thymic epithelial tumors (cortical thymoma and well differentiated thymic carcinoma), known to exhibit the highest association with myasthenia, expressed the stromal molecules at almost medullary levels. The findings may be a clue to a functional difference between neoplastic and normal cortical epithelial cells: while we find the former to have the capacity to present soluble antigen to antigen-specific CD4+ T cells in vitro, normal cortical epithelium failed to do so. This altered microenvironment in thymomas might contribute to the autoimmunization by stimulating mature recirculating AChR-specific T cells.

Distribution of molecules mediating thymocyte-stroma-interactions in human thymus, thymitis and thymic epithelial tumors.

To investigate the role of the acetylcholine receptor (AchR) in the pathogenesis of paraneoplastic Myasthenia gravis (MG), we screened a cDNA library of a MG-associated thymoma with a DNA oligonucleotide coding for aa 371-378, i.e. for part of the very immunogenic cytoplasmatic epitope (VICE-alpha, aa 373-380) of the human AChR alpha-subunit. We isolated two cDNA clones. Analysis of these clones has identified an open reading frame of 1371 bp, coding for the AChR alpha-subunit. No point mutation, insertion or deletion could be detected. Since the thymoma did not contain thymic myoid cells, which normally express AChR, the origin of the AChR transcripts must be the tumor cells itself. These findings confirm former results, where AChR alpha-subunit sequences from MG-thymomas were amplified by PCR.

Cloning of a cDNA coding for the acetylcholine receptor alpha-subunit from a thymoma associated with myasthenia [correction of myastenia] gravis.

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Distribution of molecules mediating thymocyte-stroma-interactions in human thymus, thymitis and thymic epithelial tumors.

Cloning of a cDNA coding for the acetylcholine receptor alpha-subunit from a thymoma associated with myasthenia [correction of myastenia] gravis.