The Role of the Thymus in Myasthenia Gravis: Immunohistological and Immunological Studies in 115 Cases<sup>a</sup>

Berrih‐Aknin, Sonia; Morel, E.; Raimond, F.; Safar, D.; Gaud, C; Binet, J P; Levasseur, P; Bach, Jean‐François

doi:10.1111/j.1749-6632.1987.tb51282.x

Cited by 109 publications

(47 citation statements)

References 56 publications

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“…Medullary TECs, by expressing a broad panoply of tissue-specific Ags, play a crucial role in central tolerance (negative selection) and any defect in thymocyte selection could lead to autoimmune diseases (5). In MG, functional and morphological abnormalities of the thymus occur frequently and 50 -60% of the SP patients exhibit thymic hyperplasia of lymphoproliferative origin with ectopic germinal center (GC) development (6). These thymic abnormalities are correlated with the antiAChR Ab titer which decreases after thymectomy (7).…”

Section: A Cquired Myasthenia Gravis (Mg)mentioning

confidence: 99%

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

Panse

Cizeron-Clairac

Bismuth

et al. 2006

The Journal of Immunology

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Myasthenia gravis (MG) is an autoimmune disease mainly caused by antiacetylcholine receptor autoantibodies (seropositive (SP) disease) or by Abs against unknown autoantigenic target(s) (seronegative (SN) disease). Thymectomy is usually beneficial although thymic hyperplasia with ectopic germinal centers is mainly observed in SP MG. To understand the role of thymus in the disease process, we compared the thymic transcriptome of non-MG adults to those of SP patients with a low or high degree of hyperplasia or SN patients. Surprisingly, an overexpression of MHC class II, Ig, and B cell marker genes is observed in SP but also SN MG patients. Moreover, we demonstrate an overexpression of CXCL13 in all MG thymuses leading probably to the generalized B cell infiltration. However, we find different chemotactic properties for MG subgroups and, especially, a specific overexpression of CCL21 in hyperplastic thymuses triggering most likely ectopic germinal center development. Besides, SN patients present a peculiar signature with an abnormal expression of genes involved in muscle development and synaptic transmission, but also genes implicated in host response, suggesting that viral infection might be related to SN MG. Altogether, these results underline differential pathogenic mechanisms in the thymus of SP and SN MG and propose new research areas.

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Section: A Cquired Myasthenia Gravis (Mg)mentioning

confidence: 99%

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

Panse

Cizeron-Clairac

Bismuth

et al. 2006

The Journal of Immunology

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“…It frequently shows abnormalities (50 -60% hyperplasia, 10 -15% thymoma) (10) and thymectomy is clinically beneficial (11)(12)(13). The hyperplastic thymus is one of the sites of T and B cell hyperactivation and autoreactivity to AChR (14,15), and B cells isolated from thymic hyperplasia spontaneously produce Abs to AChR (16).…”

Section: Yasthenia Gravis (Mg)mentioning

confidence: 99%

“…This increase could be due to a higher number of cells expressing HLA class II Ags in the pathological tissues. Indeed, the microarray analysis was performed on whole thymic extracts, and it is clear that thymuses from MG patients contain more B cells and follicular dendritic cells than normal thymuses (10), and because B and follicular dendritic cells express high levels of MHC class II, they may count in the increased expression of the thymic class II Ags in the whole thymic extracts. However, we cannot exclude that the significant increase of MHC class II Ags in the MG thymuses could also be due to the overexpression of the transcription factor CIITA that plays a central role in the control of MHC class II transcription (47).…”

Section: Significance Of Ifn-inducible Genes In Thymic Hyperplasiamentioning

confidence: 99%

Effects of Cytokines on Acetylcholine Receptor Expression: Implications for Myasthenia Gravis

Poëa-Guyon

Christadoss

Panse

et al. 2005

The Journal of Immunology

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Myasthenia gravis is an autoimmune disease associated with thymic pathologies, including hyperplasia. In this study, we investigated the processes that may lead to thymic overexpression of the triggering Ag, the acetylcholine receptor (AChR). Using microarray technology, we found that IFN-regulated genes are more highly expressed in these pathological thymic tissues compared with age- and sex-matched normal thymus controls. Therefore, we investigated whether proinflammatory cytokines could locally modify AChR expression in myoid and thymic epithelial cells. We found that AChR transcripts are up-regulated by IFN-γ, and even more so by IFN-γ and TNF-α, as assessed by real-time RT-PCR, with the α-AChR subunit being the most sensitive to this regulation. The expression of AChR protein was increased at the cytoplasmic level in thymic epithelial cells and at the membrane in myoid cells. To examine whether IFN-γ could influence AChR expression in vivo, we analyzed AChR transcripts in IFN-γ gene knock-out mice, and found a significant decrease in AChR transcript levels in the thymus but not in the muscle, compared with wild-type mice. However, up-regulation of AChR protein expression was found in the muscles of animals with myasthenic symptoms treated with TNF-α. Altogether, these results indicate that proinflammatory cytokines influence the expression of AChR in vitro and in vivo. Because proinflammatory cytokine activity is evidenced in the thymus of myasthenia gravis patients, it could influence AChR expression and thereby contribute to the initiation of the autoimmune anti-AChR response.

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“…MG is also characterized by a high incidence of morphologic thymic abnormalities. 22 More than half of patients, especially young women with high titers of anti-AChR antibodies, present with thymic hyperplasia, characterized by numerous lymphoid follicles with germinal centers similar to those found in lymph nodes. 23 The hyperplastic MG thymus contains activated anti-AChR autoreactive T cells [24][25][26][27][28] and anti-AChR antibody-producing B cells.…”

Section: Introductionmentioning

confidence: 99%

Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis

Баландина

Lécart

Dartevelle

et al. 2005

Blood

379

281

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Thymus-derived CD4 IntroductionThe development of autoimmune diseases involves a breakdown in the mechanisms that control self-reactive lymphocytes. The primary mechanism that generally maintains self-tolerance is thymic deletion of autoreactive T cells with high affinity for self-antigens. However, this mechanism is not perfect and autoreactive T cells do escape to the periphery. Recent data suggest that in addition to the mechanisms of clonal deletion and anergy, regulatory T (Treg) cells play a significant role in the generation and maintenance of peripheral tolerance. Indeed, compelling evidence indicates that immune responsiveness is controlled by a subpopulation of Treg cells that are enriched in the naturally activated subset of CD4 T cells and that constitutively express the CD25 (interleukin 2 receptor ␣ [IL-2R␣]) molecule. The thymus is a primary source of this regulatory CD4 ϩ CD25 ϩ T-cell subset, which participates in the active suppression of potentially autoreactive T cells in the periphery. 1,2 CD4 ϩ CD25 ϩ Treg cells have been described in a variety of experimental systems to provide protection from T cell-mediated autoimmune disorders (for a review, see Shevach 3 ). This Treg population has been also isolated from human thymus 4,5 and the peripheral blood of healthy individuals. [6][7][8] Similar to murine CD25 ϩ T cells, 9 they are naturally anergic in vitro and they inhibit the proliferation of cocultured conventional CD4 ϩ CD25 Ϫ T cells in a contact-dependent manner. The possible role of the surface molecules, cytotoxic T lymphocyte associated-antigen 4 (CTLA-4) and transforming growth factor ␤ (TGF-␤), in the regulatory function of CD25 ϩ Treg cells is controversial and their mechanisms of suppression remain to be determined. 3 The forkhead transcription factor, FoxP3, was reported recently to be essential for the development and functional activity of mice and human CD25 ϩ Treg cells. [10][11][12][13] Moreover, FOXP3 transduction converts naïve CD4 ϩ CD25 Ϫ T cells into CD25 ϩ regulatory cells with suppressive activity. Despite a growing interest in CD4 ϩ CD25 ϩ Treg cells and their role in the emergence of autoimmune diseases in animal models, only very limited and controversial information is available on the role of this T-cell population in the pathogenesis of human autoimmune diseases. Indeed, a decrease in the number of circulating CD4 ϩ CD25 ϩ cells in autoimmune diabetes was reported. 14 In multiple sclerosis, either an increase 15 or no alteration 16 was shown, although a very recent paper showed the loss of functional activity for circulating CD4 ϩ CD25 ϩ T cells. 17 In contrast, the CD4 ϩ CD25 ϩ T-cell subset was enriched with functionally active regulatory cells in the inflamed joints of patients with rheumatoid arthritis. 18 The deficiency in numbers of CD4 ϩ CD25 ϩ T cells was reported in the peripheral blood leukocytes (PBLs) of patients with virus-associated autoimmunity hepatitis C-mixed cryoglobulinemia vasculitis, whereas suppressive activity of Treg cells was not chang...

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The Role of the Thymus in Myasthenia Gravis: Immunohistological and Immunological Studies in 115 Cases^a

Cited by 109 publications

References 56 publications

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

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

Effects of Cytokines on Acetylcholine Receptor Expression: Implications for Myasthenia Gravis

Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis

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The Role of the Thymus in Myasthenia Gravis: Immunohistological and Immunological Studies in 115 Casesa

Cited by 109 publications

References 56 publications

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

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

Effects of Cytokines on Acetylcholine Receptor Expression: Implications for Myasthenia Gravis

Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis

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The Role of the Thymus in Myasthenia Gravis: Immunohistological and Immunological Studies in 115 Cases^a