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PubMed1983

Effect of thymectomy on peripheral lymphocyte subsets in myasthenia gravis: selective effect on T-cells in patients with thymic atrophy.

Myasthenia gravis (MG) is an autoimmune disease affecting nicotinic acetylcholine receptors. The clinical improvement that follows thymectomy in some myasthenic patients implicates thymic factors as well in the pathogenesis of MG. We have studied circulating immunoregulatory T cell subsets before and after thymectomy in 11 adult patients with MG. Six patients had thymic hyperplasia and five patients had atrophic thymus at the time of thymectomy. Before thymectomy, patients who subsequently were shown to have an atrophic thymus, had lower lymphocyte counts than either patients later shown to have a hyperplastic thymus (1315 +/- 143 lymphocytes/mm3 vs. 2434 +/- 350 lymphocytes/mm3, p less than 0.01), or age-matched controls (1315 +/- 143 lymphocytes/mm3 vs. 2636 +/- 589 lymphocytes/mm3, p less than 0.02). Moreover, after thymectomy, in MG patients with an atrophic thymus, there was a significant rise in lymphocyte count (from 1315 +/- 143 lymphocytes/mm3 to 2279 +/- 292 lymphocytes/mm3, p less than 0.02) beginning 3 days postthymectomy and persisting for at least 6 weeks thereafter. In comparison, patients with a hyperplastic thymus showed no change in circulating lymphocyte counts (p greater than 0.1). Enumeration of lymphocyte subsets in MG patients with an atrophic thymus demonstrated normal B cell numbers before and after thymectomy (p greater than 0.1), whereas, T cells were significantly decreased before thymectomy compared with age-matched normal subjects (859 +/- 82 T cells/mm3 vs. 2215 +/- 545 T cells/mm3, p less than 0.05), and rose to near normal levels after thymectomy (1796 +/- 294 T cells/mm3, p less than 0.02 compared with prethymectomy levels). Using monoclonal anti-T cell antibodies 3A1, OKT4, and OKT8, we found that, before thymectomy in the atrophic thymus group, 3A 1+ T cells were significantly depressed compared with postthymectomy levels (620 +/- 173 cells/mm3 vs. 1627 +/- 331 cells/mm3, p less than 0.02) as were OKT4+ cells 436 +/- 88 cells/mm3 vs. 1112 +/- 63 cells/mm3, p less than 0.001), In contrast, no significant change was seen after thymectomy in the OKT8+ cell subset (p greater than 0.1). MG patients with an atrophic thymus had decreased plasma cortisol levels postthymectomy compared with prethymectomy levels, whereas thymectomy in MG patients with a hyperplastic thymus effected no change in plasma cortisol levels. These data demonstrate in MG patients with an atrophic thymus that thymectomy has an effect on the number of circulating T cells, and in particular, on those T cells expressing antigens 3A1 and OKT4. This effect may in part be mediated by changes in plasma adrenal corticosteroid levels after thymectomy or may be due to a factor produced by atrophic thymuses in MG.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1995

Deletion of high-avidity T cells by thymic epithelium.

Tolerance induction by thymic epithelium induces a state of so-called "split tolerance," characterized in vivo by tolerance and in vitro by reactivity to a given thymically expressed antigen. Using a model major histocompatibility complex class I antigen, H-2Kb (Kb), three mechanisms of thymic epithelium-induced tolerance were tested: induction of tolerance of tissue-specific antigens exclusively, selective inactivation of T helper cell-independent cytotoxic T lymphocytes, and deletion of high-avidity T cells. To this end, thymic anlagen from Kb-transgenic embryonic day 10 mouse embryos, taken before colonization by cells of hemopoietic origin, were grafted to nude mice. Tolerance by thymic epithelium was not tissue-specific, since Kb-bearing skin and spleen grafts were maintained indefinitely. Only strong priming in vivo could partially overcome the tolerant state and induce rejection of some skin grafts overexpressing transgenic Kb. Furthermore, the hypothesis that thymic epithelium selectively inactivates those T cells that reject skin grafts in a T helper-independent fashion could not be supported. Thus, when T-cell help was provided by a second skin graft bearing an additional major histocompatibility complex class II disparity, tolerance to the Kb skin graft was not broken. Finally, direct evidence could be obtained for the avidity model of thymic epithelium-induced negative selection, using Kb-specific T-cell receptor (TCR) transgenic mice. Thymic epithelium-grafted TCR transgenic mice showed a selective deletion of those CD8+ T cells with the highest density of the clonotypic TCR. These cells presumably represent the T cells with the highest avidity for Kb. We conclude that split tolerance induced by thymic epithelium was mediated by the deletion of those CD8+ T lymphocytes that have the highest avidity for antigen.

Animals↗
PubMed2005

Thymectomy in myasthenia gravis: comparison of outcome in Santiago, Cuba and Nottingham, UK.

OBJECTIVES: We compared the outcome of thymectomy for myasthenia gravis (MG) in two healthcare systems. In Nottingham, UK, thymectomy is performed for thymic enlargement and considered in acetylcholine receptor (AchR) antibody positive patients. In Santiago, Cuba, thymectomy is considered in all generalised MG patients irrespective of their radiological findings or AchR antibodies. METHOD: 22 MG patients in Nottingham and 75 in Santiago who had a thymectomy were identified and their notes reviewed. We compared the median age, stage of disease, thymic histology and clinical outcome at two years post-thymectomy. RESULTS: The median ages for the Cuban and Nottingham patients were 25 and 35 years respectively. The median stage of disease was IIa by Osserman's classification in both. In Nottingham, 59% (13/22) showed an improvement compared with 88 % (66/75) in Santiago (p < 0.01). There were significantly more cases of thymoma in Nottingham whereas thymic hyperplasia and atrophy were a more frequent finding in Cuban patients. The majority of cases who improved post-thymectomy had thymic hyperplasia on histology in both Nottingham (46%) and Cuban (61%) patients. CONCLUSION: Selecting MG patients based on thymic enlargement alone or AchR antibody positivity may be inadequate and thymectomy should perhaps be considered in all patients with generalised myasthenia.

Adult↗
PubMed1999

Aberrations in the primary T-cell receptor repertoire as a predisposition for synovial inflammation in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an HLA-DR associated disease with a pivotal role of T cells in the pathogenesis. The mechanisms underlying the HLA association and the generation of a synovial T-cell response are unclear. We have hypothesized that the selection of the primary T-cell repertoire is a predisposing factor for rheumatoid synovitis. METHODS: The repertoire of T-cell receptors (TCR) expressed by circulating naive CD4+ CD45RO- T cells was compared in 10 patients with RA, 11 HLA-DR matched normal donors and 10 mismatched normal donors by determining the frequencies of TCR BV-BJ combinations in 3 different BV gene segment families. Clonally expanded synovium-specific CD4 T cells were identified in 8 patients by TCR BV-BJ-specific PCR of purified T-cell subsets followed by size fractionation and sequencing of the PCR product. The TCR BV-BJ repertoires of naive peripheral T cells and of synovial clones were compared. RESULTS: The repertoires of naive circulating CD4+ CD45RO- T cells were different in RA patients and in HLA-DR matched and unmatched controls, suggesting HLA-DR as well as disease-specific features of T-cell selection. To test the disease relevance of the shifts in the naive repertoire, CD4 T cells undergoing joint-specific clonal expansion were identified. The usage of BV-BJ gene combinations in these synovium-specific clones was biased and significantly different from the expected distribution with a preference for combinations favored in the naive TCR repertoire of RA patients. CONCLUSIONS: These data suggest that primary T-cell selection in RA patients is of functional importance for the generation of synovium-specific T-cell responses. The synovial repertoire is influenced by aberrations in the naive T-cell repertoire that might indicate a defect in thymic education with the selection of high-affinity self-reactive T cells in RA.

Alleles↗
PubMed1992

Positive selection of T-lymphocytes induced by intrathymic injection of a thymic epithelial cell line.

T lymphocytes recognize antigens as peptide fragments associated with molecules encoded by the major histocompatibility complex (MHC) and expressed on the surface of antigen-presenting cells. In the thymus, T cells bearing alpha beta receptors that react with the MHC molecules expressed by radioresistant stromal elements are positively selected for maturation. In (A x B-->A) bone marrow chimaeras, T cells restricted to the MHC-A haplotype are positively selected, whereas MHC-B-reactive thymocytes are not. We investigated whether the introduction of particular thymic stromal elements bearing MHC-B molecules could alter the fate of B-reactive T cells in these (A x B-->A) chimaeras. Thymic epithelial cell (TEC) lines expressing H-2b were introduced by intrathymic injection into (H-2b/s-->H2s) bone marrow chimaeras and we measured their ability to generate H-2b-restricted cytotoxic T-lymphocytes (CTLs). We report here that one TEC line, 427.1, was able positively to select CTLs specific for influenza and vesicular stomatitis virus antigens in association with class I H-2b molecules. In addition, line 427.1 can process cytoplasmic proteins for presentation to H-2Kb- and H-2Db-restricted CTLs. Thus, a TEC line capable of normal class I MHC antigen processing and presentation in vitro can induce positive selection after intrathymic injection.

Animals↗
PubMed1997

Evolution of neuroendocrine thymus: studies on POMC-derived peptides, cytokines and apoptosis in lower and higher vertebrates.

In previous papers, we showed that neuroendocrine cells reactive to anti-POMC-derived peptides and cytokines are present in the thymus of a fish and an anuran amphibian. Here we report that this phenomenon is general, as neuroendocrine cells positive to anti-POMC-derived peptides (ACTH, beta-endorphin, alpha-MSH) and cytokines (IL-1 alpha, IL-2, IL-6, TNF-alpha) are also present in the thymus of chicken and rat. However, the number and the intrathymic localization and distribution of these cells varies in the different species examined. An analysis of apoptotic cells or cells involved in apoptosis, such as interdigitating cells and macrophages, in fish, frog, chicken and rat thymus, using an immunocytochemical method and anti-DNA mAb conjugated with peroxidase (anti-DNA-POD), showed that cells positive to anti-DNA-POD mAb are present in the same thymic areas in which POMC-derived peptides and cytokines were found. In conclusion, these data on apoptotic cells in the thymus of lower and higher vertebrates are compatible with the hypothesis that neuroendocrine cells might play a role in the selection and apoptosis of thymic lymphocytes, a phenomenon which could vary slightly in different species and taxa.

Animals↗
PubMed1981

Expression and function of major histocompatibiliby complex antigens in the developing thymus: studies on normal and nude mice.

Direct access of lymphoid precursors to the thymic environment appears to be an essential step in the differentiation of normal T cell populations and it is possible that intimate cellular interactions between T cells and the thymic stroma are involved in selective processes leading to self-tolerance and major histocompatibility complex (MHC) restriction. As an approach to investigating the intrathymic environment, MHC antigen expression during normal thymic development and lymphopoiesis, and in the embryonic thymus of T cell-deficient nude mice, has been examined. Evidence has been obtained to show that MHC antigens controlled by both the K and I regions are expressed from an early stage on epithelial cells in normal thymus development but that the thymic rudiment in nude mice shows a selective absence of I regions antigens. The implications of these findings for T cell development and the derivation and constitution of the intrathymic environment are considered.

Animals↗
PubMed2000

Tec family kinases modulate thresholds for thymocyte development and selection.

Tec family kinases are implicated in T cell receptor (TCR) signaling, and combined mutation of inducible T cell kinase (Itk) and resting lymphocyte kinase (Rlk)/Txk in mice dramatically impairs mature T cell function. Nonetheless, mutation of these kinases still permits T cell development. While itk(-)(/)- mice exhibit mild reductions in T cells with decreased CD4/CD8 cell ratios, rlk(-)(/)-itk(-)(/)- mice have improved total T cell numbers yet maintain decreased CD4/CD8 ratios. Using TCR transgenics and an in vitro thymocyte deletion model, we demonstrate that mutation of Tec kinases causes graded defects in thymocyte selection, leading to a switch from negative to positive selection in rlk(-)(/)-itk(-)(/)- animals. The reduction in both positive and negative selection and decreased CD4/CD8 ratios correlates with decreased biochemical parameters of TCR signaling, specifically defects in capacitive Ca(2+) influx and activation of the mitogen-activated kinases extracellular signal-regulated kinase 1 and 2. Thus, Tec kinases influence cell fate determination by modulating TCR signaling, leading to altered thresholds for thymocyte selection. These results provide support for a quantitative model for thymic development and provide evidence that defects in negative selection can substantially alter thymic cellularity.

Animals↗
PubMed1997

Influence of the affinity of selecting ligands on T cell positive and negative selection and the functional maturity of the positively selected T cells.

Interaction of the TCR on immature thymocytes with ligands on antigen presenting cells can lead to different fates including positive and negative selection. The affinity of the selecting ligands plays an important role in determining these outcomes. We used the 2C TCR transgenic model to evaluate the efficacy of ligands with widely differing affinity (3 x 10(3) - 2 x 10(6) M-1) for the 2C TCR in mediating thymic negative and positive selection. Our results support the conclusions that the deletion of immature thymocytes is not only mediated by high-affinity ligands but also by low-affinity/avidity ligands. However, high- and low-affinity ligands differ in their requirements for negative selection. We also present evidence that positive selection is not an all or none process but depending on the strength of interaction between the ligand and the TCR during the positive selection process can result in single positive thymocytes that are at different stages of functional maturity.

Animals↗
PubMed2000

Glucocorticoid production in the murine thymus.

Glucocorticoid hormones are known to act as important modulatory factors in the development of autoimmune diseases, and to play an important role in thymic T-cell selection. There seems to be a finely balanced equilibrium between the apoptosis-inducing effects of glucocorticoid and T cell receptor ligand binding. Here we are investigating whether glucocorticoid-induced T cell apoptosis is mainly dependent on circulating glucocorticoid levels or if the thymus itself is able to produce glucocorticoids. To this end, we attempted to demonstrate enzyme activities of the whole set of steroidogenic enzymes for the synthesis of glucocorticoids in murine thymic tissue. We isolated steroidogenic organelles from thymic tissue, incubated these with radioactive (precursor) steroids in vitro, and visualized the resulting products by thin-layer chromatography. Our results show that the thymus possesses all enzymes and cofactors required for glucocorticoid production. However, an intact thymic architecture is necessary for glucocorticoid production, since 11beta-hydroxylase was not detected in irradiated thymi or in a thymic epithelial cell line. The results of these experiments show that the whole glucocorticoid metabolism takes place within the thymus. This finding provides the biochemical basis for the in situ effects of glucocorticoid hormones on thymocyte development and selection.

Animals↗
PubMed1992

In vitro growth of bone marrow-resident T cell precursors supported by mast cell growth factor and IL-3.

The growth requirements of bone marrow-resident cells that are able to differentiate along the T cell lineage (pre-T cells) have not been well established. We recently have shown that the T cell-derived lymphokine IL-3 is able to maintain pre-T cells in vitro for at least 2 weeks. However, in our initial studies, we were not able to ascertain whether IL-3 induced pre-T cell growth during culture, or whether IL-3 simply maintained the viability of these progenitors. To address this issue, we used a multiple dose assay system to assess the level of pre-T cell activity (thymic repopulation) in a selected population of bone marrow cells (CD3-, Thy-1.2+) both before and after culture in IL-3. In addition, we tested the potential role of mast cell growth factor (MGF) in the growth and maintenance of pre-T cells in vitro. The results of these studies showed that IL-3 produced a modest, but consistent increase in the pre-T cell activity during culture. Culture of CD3-, Thy-1.2+ bone marrow cells in MGF also resulted in an increase in the total amount of detectable pre-T cell activity among the cultured cells. The most dramatic increases in pre-T cell activity, however, were induced by the culture of the selected marrow cells in both MGF and IL-3. Cultures supplemented with both cytokines produced net increases in pre-T cell activity of 40- to 75-fold after 10 days of culture. Because the increases in pre-T cell activity were not accompanied by observable increases in the size of thymic colonies produced by the pre-T cells, the increased levels of pre-T cell activity appeared to result from increases in pre-T cell numbers during culture. Thus, in addition to the other activities ascribed to MGF, this cytokine displays pre-T cell growth factor activity and can synergize with IL-3 in that capacity. The use of MGF in conjunction with IL-3 provides the best system described to date for the propagation of pre-T cells in primary bone marrow cell cultures.

Animals↗
PubMed1994

Thymic epithelial defects and predisposition to autoimmune disease in BB rats.

We report an association between thymic epithelial defects and predisposition to autoimmunity. Diabetes-prone (DP) BB rats develop spontaneous hyperglycemia and are deficient in T cell subsets expressing the RT6 alloantigen. Diabetes resistant (DR) BB rats become diabetic if depleted of RT6+ T cells. The inciting immune system defects are unknown. We made the following observations: 1) Regions of thymic cortex and medulla devoid of thymic epithelium exist in DP-BB, DR-BB, and Lewis rats, all of which are susceptible to autoimmune disorders. Such defects were absent in eight normal rat strains. 2) Thymic epithelial defects are absent at birth, but present in BB rats at 4 weeks of age. 3) The genetic predisposition to thymic epithelial defects is an autosomal dominant trait. 4) The observation of thymic defects in (DP x WF)F1 rats led to the prediction that such animals, which never develop spontaneous autoimmunity, might be susceptible to its induction. Following depletion of RT6+ T cells we observed diabetes in 91%, and thyroiditis in 43%, of treated F1 animals (n = 23). Pancreatic insulitis was uniformly present. Because thymic epithelium participates in the positive and negative selection of developing thymocytes, we propose that thymic epithelial defects may play an important role in the predisposition of BB rats to autoimmunity.

Aging↗
PubMed1991

An unusual lineage of alpha/beta T cells that contains autoreactive cells.

In male mice that express a transgenic alpha/beta T cell receptor (TCR) specific for a male-specific peptide presented by class I Db major histocompatibility complex (MHC) molecules, we describe an unusual lineage of alpha/beta T cells that are thymus dependent but do not require selection by Db MHC molecules on thymic epithelium in the absence of the specific peptide (positive selection). These cells express the transgenic alpha/beta TCR and have the CD4-8- or CD4-8low phenotype. Cells with the latter phenotype are only detected when hemopoietic cells express both the male-specific peptide as well as Db MHC molecules. In fact, these cells are autoreactive, as they expand relatively slowly after transfer into male nude mice. Also in male but not female alpha/beta TCR transgenic mice, the CD8+ cells with the transgenic TCR bear the Pgp1 marker characteristic of mature T cells activated by antigen. CD4-8- as well as CD4-8low cells do not respond significantly when cultured with male stimulator cells but proliferate vigorously when stimulated by TCR antibodies. By this latter criterion, cells in the periphery of male alpha/beta TCR transgenic mice differ from mature male-specific T cells from female alpha/beta TCR transgenic, which become intrinsically anergic when transferred into male nude mice and cannot be stimulated significantly by TCR antibodies. Thus, intrathymic deletion does not eliminate all autoreactive T cells and it is possible that cells with an apparently "benign" autoreactivity may be involved in certain forms of autoimmunity.

Animals↗
PubMed2004

The pathophysiology of chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) still remains the most significant complication after allogeneic hematopoietic stem cell transplantation. The disease usually appears after day 100 and is characterized by signs and symptoms similar to autoimmune diseases. The pathophysiology of chronic GVHD is poorly understood because of the lack of highly satisfactory animal models and basic studies in patients. It has not been clearly determined whether the disease is a distinct entity or a continuation of acute GVHD. In experimental and clinical studies of chronic GVHD, thymic atrophy, lymphocyte depletion, and autoantibody formation have been described. Conditioning regimens and acute GVHD may disrupt thymic function and dysregulate the negative selection process of potentially autoreactive T-lymphocytes. Disruption of thymic apoptosis and failure to eliminate the majority of self-reactive lymphocytes may lead to impairment of lymphocyte homeostasis and self tolerance. Expansion and effector functions of autoreactive T-cells will then promote autoreactive B-cell activation and production of autoantibodies with target-organ damage. Chronic GVHD requires continuous CD4+ T-cell help for B-cells and is known as T-helper 2 (Th2) disease. Murine models have demonstrated the roles of interleukin (IL)-12 and IL-18 in chronic GVHD. IL-12 may cause an increase in donor CD8+ cytotoxic T-cells leading to conversion of chronic GVHD to an acute form. In contrast, IL-18 prevents chronic GVHD by decreasing numbers of CD4+ (Th2) cells and host-reactive B-cell activation and reducing alloantigen-specific immune response. Mouse and human cellular genomics coupled with advances in cell biology in donor-recipient tolerance will improve our understanding of transplantation immunology and may offer new approaches to the challenge of ameliorating chronic GVHD.

Animals↗
PubMed2000

Evidence for migration of donor bone marrow stromal cells into recipient thymus after bone marrow transplantation plus bone grafts: A role of stromal cells in positive selection.

Intrathymic T-cell differentiation is characterized by two selection events: positive and negative selection. It has been shown that thymic epithelial cells in the cortex are involved in the positive selection, while macrophages and dendritic cells, derived from hemopoietic stem cells, are involved in the negative selection. Here we investigate whether donor-derived bone marrow stromal cells can migrate into the thymus and participate there in positive selection after bone marrow transplantation plus bone grafts (to recruit bone marrow stromal cells). Allogeneic bone marrow transplantation with or without bone grafts was carried out in the [C57BL/6-->C3H] combination. Fluorescence-activated cell sorter analyses of recipient thymic adherent cells showed that donor-type bone marrow stromal cells exist in the thymus of mice that received bone marrow plus bone grafts but not in the mice that received bone marrow cells alone. Histological examination using confocal microscopy also confirmed the existence of donor-type stromal cells in the thymus of mice that received bone marrow cells plus bones. Both T-cell proliferation and plaque-forming cell assays indicated that the T cells of such mice show donor-type major histocompatibility complex-restriction. These findings strongly suggest that stromal cells can migrate from the bone marrow to the thymus, where they participate in the positive selection of thymocytes.

Animals↗
PubMed1998

HLA-DR binding analysis of peptides from islet antigens in IDDM.

HLA molecules are essential for thymic education and HLA restriction of T-cell responses. We therefore analyzed the HLA-DR binding affinities of synthetic peptides covering the entire sequences of GAD65, islet cell antigen 69 (ICA69), and (pro)insulin, which are candidate antigens in the autoimmune process of T-cell-mediated destruction of the pancreatic beta-cells. Subsequently, peptide HLA-DR binding was correlated to peptide antigenicity by comparing known T-cell epitopes with their HLA-binding affinities defined in this study. The results demonstrate the following. 1) (Pro)insulin peptides display a strong binding affinity for HLA-DR2, which is associated with negative genetic predisposition to IDDM, whereas poor binding was observed for HLA-DR molecules neutrally or positively associated with IDDM. This suggests that the absence of insulin-reactive T-cells in DR2+ individuals may be explained by negative selection on high-affinity DR2 binding insulin peptides. 2) Most autoantigenic peptides display promiscuous HLA-DR binding patterns. This promiscuity in itself is not sufficient to explain the genetic association of HLA-DR with development of IDDM. 3) HLA-DR3 binding of autoantigenic GAD65 peptides is relatively weak compared with that of other known T-cell epitopes. 4) All peptide epitopes recognized by HLA-DR-restricted T-cells from either IDDM patients or GAD65-immunized HLA-DR transgenic mice bind with high affinity to their HLA-DR restriction molecule (P < 0.0006). In contrast, T-cell epitopes recognized by nondiabetic controls bind DR molecules with weak or undetectable affinity. These results thus indicate a strong correlation between antigenicity and HLA-DR binding affinity of GAD65 peptides in IDDM. Furthermore, negative thymic selection of insulin peptides in low-risk (HLA-DR2 expressing) subjects may explain the lack of autoreactivity to insulin in such individuals.

Amino Acid Sequence↗
PubMed1995

The positively selected T cell repertoire: is it exclusively restricted to the selecting MHC?

Transgenic lines of mice showing compartmentalized expression of MHC I-E in different thymic microenvironments and nearly normal expression in the periphery were used to ask whether the mature T cell repertoire is restricted exclusively to the selecting MHC molecules expressed on thymic cortical epithelial cells. We show that upon in vivo priming, mice with a T cell repertoire selected in the thymic cortex on MHC I-A, in the absence of MHC I-E, display a clearly significant T cell response to two I-E-restricted peptides. Our results suggest that expression of one isotype or allele of class II MHC molecules in the appropriate thymic environment enables the selection of a polyclonal repertoire restricted in part to non-selecting class II MHC molecules. Thus, although the requirement for interaction with the MHC by the TCR on developing thymocytes exists, the available adult repertoire need not be solely faithful to the specific MHC expressed on the thymic cortical epithelium: it can also be restricted to other isotypes and alleles of this same class of MHC molecule.

Animals↗
PubMed1981

Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes.

We investigated the role of the thymus in 16 patients with myasthenia gravis without thymoma by studying the production of anti-acetylcholine-receptor antibody by thymic and blood lymphocytes cultured alone or together. In 19 responders (with the highest receptor-antibody titers in their plasma), cultured thymic cells spontaneously produced measurable receptor antibody. Receptor-antibody production by autologous blood lymphocytes was enhanced by the addition of responders' thymic cells, irradiated to abrogate antibody production and suppression (P less than 0.01). This enhancement was greater and more consistent than that by pokeweed mitogen; it depended on viable thymic cells, appeared to be selective for receptor antibody, and correlated with the ratio of thymic helper (OKT4-positive or OKT4+) to suppressor (OKT8+) T cells (P less than 0.01). These results suggest that myasthenic thymus contains cell-bound acetylcholine-receptor-like material or specific T cells (or both) that can aid receptor-antibody production. This may be relevant to the benefits of thymectomy in myasthenia and to the breakdown in self-tolerance in this and other autoimmune diseases.

Adolescent↗