Evidence of enhanced recombinant interleukin-2 sensitivity in thymic lymphocytes from patients with myasthenia gravis: possible role in autoimmune pathogenesis

Cohen‐Kaminsky, Sylvia; Levasseur, P; Binet, J P; Berrih‐Aknin, Sonia

doi:10.1016/0165-5728(89)90101-x

Cited by 30 publications

(18 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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). Several signs of activation among T cells have been demonstrated, including an increase in Fas expression in the thymic CD4 ϩ population showing autoreactivity (17).…”

Section: Yasthenia Gravis (Mg)mentioning

confidence: 99%

“…Thymic B cells from MG thymic hyperplasia are activated as demonstrated by expression of activation markers and by the ability of B cells to spontaneously produce Ab to AChR (16). Thymic T cells proliferate spontaneously to rIL-2 (14) and express high levels of Fas (17). In the present study, we also showed that the thymic environment of MG hyperplasia is activated as evidenced by increased expression of IFNregulated genes, including both MHC and non-MHC genes.…”

Section: Intrathymic Pathogenesis Mechanims In Mgmentioning

confidence: 99%

See 1 more Smart Citation

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

Poëa-Guyon

Christadoss

Panse

et al. 2005

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Yasthenia Gravis (Mg)mentioning

confidence: 99%

Section: Intrathymic Pathogenesis Mechanims In Mgmentioning

confidence: 99%

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

Poëa-Guyon

Christadoss

Panse

et al. 2005

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…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. 29 AChR expression has been demonstrated in both normal and MG thymi, enabling efficient autoantigen presentation.…”

Section: Introductionmentioning

confidence: 99%

“…The thymus of patients with MG with follicular hyperplasia is a site of cellular activation containing activated anti-AChR autoreactive T cells together with activated B cells. 25,28,29 The localization of myasthenic CD25 ϩ thymocytes in the areas of antibody production together with the lack of suppressive activity indicates that this population includes activated effector T cells.Second, myasthenic CD4 ϩ CD25 ϩ thymocytes expressed higher levels of major histocompatibility complex (MHC) class II molecules (HLA-DR) and were enriched in cells with strong Fas expression compared to newborn and young adult healthy subjects. Up-regulation of expression of the apoptosis-related Fas protein is associated with peripheral CD4 ϩ lymphocyte activation in vivo in patients with systemic lupus erythematosus and multiple sclerosis.…”

mentioning

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

Self Cite

379

281

View full text Add to dashboard Cite

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...

show abstract

“…A bias of intrathymic selection in favour of Vβ5.1 cells was observed [17]. Several activation features of B and T cells were demonstrated in the thymus from MG patients [18][19][20][21]. In addition, the AChR is present in the thymus in both epithelial and myoid cells [22,23], and its expression is regulated by pro-inflammatory cytokines [24,25].…”

Section: Introductionmentioning

confidence: 99%

Vaccines against myasthenia gravis

Berrih‐Aknin¹,

Fuchs²,

Souroujon³

2005

Expert Opinion on Biological Therapy

Self Cite

View full text Add to dashboard Cite

Myasthenia gravis (MG) is an autoimmune disease mediated by antibodies to nicotinic acetylcholine receptor (AChR) interfering with the neuromuscular transmission. Experimental autoimmune MG serves as an excellent animal model to study possible therapeutic modalities for MG. This review will focus on the different ways to turn off the autoimmune response to AChR, which results in suppression of myasthenia. This paper will describe the use of fragments or peptides derived from the AChR, antigen-presenting cells and anti-T cell receptor antibodies, and will discuss the underlying mechanisms of action. Finally, the authors propose new promising therapeutic prospects, including treatment based on the modulation of regulatory T cells, which have recently been found to be functionally defective in MG patients.

show abstract

Evidence of enhanced recombinant interleukin-2 sensitivity in thymic lymphocytes from patients with myasthenia gravis: possible role in autoimmune pathogenesis

Cited by 30 publications

References 33 publications

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

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

Vaccines against myasthenia gravis

Contact Info

Product

Resources

About