Increased toll-like receptor 4 expression in thymus of myasthenic patients with thymitis and thymic involution.

Department of Neurology IV, Istituto Nazionale Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.
American Journal Of Pathology (Impact Factor: 4.6). 08/2005; 167(1):129-39. DOI: 10.1016/S0002-9440(10)62960-4
Source: PubMed

ABSTRACT Thymic abnormalities are present in approximately 80% of myasthenia gravis (MG) patients, and the thymus seems to be the main site of autosensitization to the acetylcholine receptor. In view of findings that the innate immune system can generate an autoimmune response, we studied the expression of Toll-like receptors (TLRs) 2 to 5, key components of innate immunity signaling pathways, in 37 thymuses from patients with autoimmune MG. TLR4 mRNA levels were significantly greater in thymitis (hyperplasia with diffuse B-cell infiltration) and involuted thymus than in germinal center hyperplasia and thymoma. By immunohistochemistry and confocal microscopy, cells positive for TLR4 protein were rarely detected in thymoma. However, in thymitis TLR4 protein was mostly found on epitheliomorphic (cytokeratin-positive) cells located in close association with clusters of acetylcholine receptor-positive myoid cells in thymic medulla and also at the borders between cortical and medullary areas. B cells were never TLR4-positive. TLR4 protein was also present in remnant tissue of involuted thymus. This is the first finding of a possible link between innate immunity and MG. We speculate that in a subgroup of MG patients, an exogenous or endogenous danger signal may activate the innate immune system and give rise to TLR4-mediated mechanisms contributing to autoimmunity.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Acquired myasthenia gravis (MG) is a rare disease and according to the EU Register of designated Orphan Medicinal Products only two drugs are registered as orphan drugs for MG while no orphan drug for MG has been approved by the US Food and Drug Administration. The aim of this review is to discuss the role and mechanism of action of the recognized orphan drugs for MG and of other therapies potentially useful for MG treatment, which should be considered as orphan drugs. Areas covered: In the context of an updated overview of MG pathogenesis, the authors discuss current MG treatments available in clinical practice, orphan drugs for MG according to the EU Orphan Drugs Registry and emerging therapies, among which are therapies exclusively developed for MG. Expert opinion: New effective drugs for MG are needed to reduce side effects, mainly those related to steroids or to chronic immunosuppression, and to manage patients not responsive to common treatments. Hence, in recent years drugs potentially targeting selective pathogenetic steps of MG have been developed, although the complexity of the immune system makes their application very challenging. To this purpose a great effort at multiple levels, including basic research, clinical practice and health politics, will be necessary.
    04/2013; 1(5). DOI:10.1517/21678707.2013.779920
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy has a large range of physiological functions and its dysregulation contributes to several human disorders, including autoinflammatory/autoimmune diseases such as inflammatory myopathies (IIMs). In order to better understand the pathogenetic mechanisms of these muscular disorders, we sought to define the role of autophagic processes and their relation with the innate immune system in the three main subtypes of IIM, specifically sporadic inclusion body myositis (sIBM), polymyositis (PM), dermatomyositis (DM) and juvenile dermatomyositis (JDM). We found that although the mRNA transcript levels of the autophagy-related genes BECN1, ATG5 and FBXO32 were similar in IIM and controls, autophagy activation in all IIM subgroups was suggested by immunoblotting results and confirmed by immunofluorescence. TLR4 and TLR3, two potent inducers of autophagy, were highly increased in IIM, with TLR4 transcripts significantly more expressed in PM and DM than in JDM, sIBM and controls, and TLR3 transcripts highly up-regulated in all IIM subgroups compared to controls. Co-localization between autophagic marker, LC3, and TLR4 and TLR3 was observed not only in sIBM but also in PM, DM and JDM muscle tissues. Furthermore, a highly association with the autophagic processes was observed in all IIM subgroups also for some TLR4 ligands, endogenous and bacterial HSP60, other than the high-mobility group box 1 (HMGB1). These findings indicate that autophagic processes are active not only in sIBM but also in PM, DM and JDM, probably in response to an exogenous or endogenous 'danger signal'. However, autophagic activation and regulation, and also interaction with the innate immune system, differ in each type of IIM. Better understanding of these differences may lead to new therapies for the different IIM types.
    PLoS ONE 11/2014; 9(11):e111490. DOI:10.1371/journal.pone.0111490 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like receptor 4 (TLR4) has been suggested to play a regulatory role in immune cell development; however, studies regarding the role of TLR4 in the development of the chick thymus are scarce. In this study, we investigated the distribution and expression pattern of TLR4 in normal chick thymi at different stages of development, in order to better understand the role of TLR4 in chick thymus development. We studied the thymi from 15 chicks, collected at days 7, 21 and 35 of age. The relative change in TLR4 mRNA expression in the chick thymus at different ages was determined by quantitative real-time PCR, and changes in protein expression were analyzed by immunohistochemistry and western blotting. Furthermore, the distribution of TLR4 in the chick thymus was analyzed by immunohistochemistry, and compared with the distribution of TLR4 expression in juvenile female pigs (gilts). Our results indicated that TLR4 was constitutively expressed in the chick thymus. TLR4 was primarily expressed in the thymic cortico-medullary junction and the medulla, particularly in the epithelial cells of Hassall's corpuscles. The mRNA and protein expression level of TLR4 increased in the thymus with increasing age (p < 0.05). Taken together, these results indicate that TLR4 is constitutively expressed by epithelial cells in the chick thymus, suggesting it may participate in thymic development by inducing factors affecting its development.
    Veterinary Immunology and Immunopathology 04/2014; 158(3-4). DOI:10.1016/j.vetimm.2014.01.005 · 1.75 Impact Factor

Full-text (2 Sources)

Available from
May 30, 2014