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: 4.59). 08/2005; 167(1):129-39. DOI: 10.1016/S0002-9440(10)62960-4
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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.

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Available from: Renato Mantegazza, Oct 06, 2015
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    • "TLR 4 expression is increased in epithelioid cells in inflamed thymus from MG patients[66] and a recent study found that TLR9 levels in peripheral PBMCs from MG patients correlate with clinical severity[67]. TLR3 is a nucleotide-sensing receptor that recognizes double-stranded RNA (dsRNA) and is therefore important for viral detection. "
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    ABSTRACT: THIS IS NOT THE FINAL POST-PRINT VERSION. To get full post-print version, please, go to Myasthenic disorders are a well characterized group of diseases of the neuromuscular junction. Their pathogenesis is diverse, including genetic and autoimmune mechanisms. We review recent findings on risk factors, pathogenesis and treatment of autoimmune myasthenia gravis. Better knowledge of congenital myasthenia has led to the development of efficient diagnostic algorithms that have therapeutic implications. New epidemiological and genetic risk factors have been identified and are considered to play a role in the development of myasthenia gravis. The study of the role of innate immunity in myasthenia gravis has identified relevant pathways to explain myasthenia gravis causes. The description of the pathogenic role of IgG4 anti-MuSK antibodies has revealed heterogeneous immune mechanisms that should lead to more specific therapies. Rituximab seems to be particularly effective in MuSK myasthenia gravis, and eculizumab arises as an option in refractory AChR myasthenia gravis. Therapeutic algorithms need to be tailored to each myasthenia subtype. Increasing knowledge about the environmental and genetic risk factors and basic immunopathogenesis of myasthenia gravis, including the role of innate immunity, regulatory T cell impairment and autoantibody heterogeneity, is providing a rationale for treatment with new biological agents. Current immunotherapies in myasthenia gravis undoubtedly provide benefits, but also cause side-effects. Controlled trials are, therefore, needed to confirm initial results from pilot studies.
    Current opinion in neurology 08/2013; DOI:10.1097/WCO.0b013e328364c079 · 5.31 Impact Factor
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    • "Some of them are potent inflammatory molecules mainly involved in acute inflammation (i.e., IL-6, IL-1β, TNF-α, and CSF); others are mainly involved in establishing chronic inflammation and promoting humoral and cellular immune response (i.e., IL-7, IL-10, IL-12, and IFN-γ) [25]. Upregulation of IL-6 and the chemokine RANTES in MG compared to normal thymus was in line with previous studies showing that these genes were abnormally overexpressed in MG TECs either at basal condition [37] or (IL-6) when stimulated by lipopolysaccharide (LPS) [38], a major activator of Toll-like receptor (TLR) 4 known to be upregulated in MG thymus [39]. IL-6 is a well-known proinflammatory agent with pathological regulatory function on growth and differentiation of T- and B-cells [40]; RANTES has been observed to regulate the transepithelial migration of T cells [41]. "
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    ABSTRACT: The thymus plays a major role in myasthenia gravis (MG). Our recent finding of a persistent Epstein-Barr (EBV) virus infection in some MG thymuses, combined with data showing that the thymus is in a proinflammatory state in most patients, supports a viral contribution to the pathogenesis of MG. Aim of this study was to gain further evidence for intrathymic chronic inflammation and EBV infection in MG patients. Transcriptional profiling by low density array and real-time PCR showed overexpression of genes involved in inflammatory and immune response in MG thymuses. Real-time PCR for EBV genome, latent (EBER1, EBNA1, LMP1) and lytic (BZLF1) transcripts, and immunohistochemistry for LMP1 and BZLF1 proteins confirmed an active intrathymic EBV infection, further supporting the hypothesis that EBV might contribute to onset or perpetuation of the autoimmune response in MG. Altogether, our results support a role of inflammation and EBV infection as pathogenic features of MG thymus.
    09/2011; 2011(1):213092. DOI:10.4061/2011/213092
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    • "Viral involvement has been suspected for a long time but without a definite conclusion. In this regard, we have already shown that Toll-like receptor 4 (an activator of the innate immune response) is overexpressed in the thymus of some MG patients.10 More recently, we demonstrated Epstein-Barr virus persistence and reactivation in MG thymus, suggesting again that a dysregulated infection may contribute to the initiation or perpetuation of the autoimmune response underlying the disease.11 "
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    ABSTRACT: Myasthenia gravis (MG) is an autoimmmune disease in which autoantibodies to different antigens of the neuromuscular junction cause the typical weakness and fatigability. Treatment includes anticholinesterase drugs, immunosuppression, immunomodulation, and thymectomy. The autoimmune response is maintained under control by corticosteroids frequently associated with immunosuppressive drugs, with improvement in the majority of patients. In case of acute exacerbations with bulbar symptoms or repeated relapses, modulation of autoantibody activity by plasmapheresis or intravenous immunoglobulins provides rapid improvement. Recently, techniques removing only circulating immunoglobulins have been developed for the chronic management of treatment-resistant patients. The rationale for thymectomy relies on the central role of the thymus. Despite the lack of controlled studies, thymectomy is recommended as an option to improve the clinical outcome or promote complete remission. New videothoracoscopic techniques have been developed to offer the maximal surgical approach with the minimal invasiveness and hence patient tolerability. The use of biological drugs such as anti-CD20 antibodies is still limited but promising. Studies performed in the animal model of MG demonstrated that several more selective or antigen-specific approaches, ranging from mucosal tolerization to inhibition of complement activity or cellular therapy, might be feasible. Investigation of the transfer of these therapeutic approaches to the human disease will be the challenge for the future.
    Neuropsychiatric Disease and Treatment 03/2011; 7(1):151-60. DOI:10.2147/NDT.S8915 · 1.74 Impact Factor
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