Persistent Infection of Human Thymic Epithelial Cells by Coxsackievirus B4

Brilot, Fabienne; Chehadeh, Wassim; Charlet-Renard, Chantal; Martens, Henri; Geenen, Vincent; Hober, Didier

doi:10.1128/jvi.76.10.5260-5265.2002

Cited by 54 publications

(60 citation statements)

References 33 publications

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“…In the current investigation, CV-B4 E2 infection did not damage the architecture of foetal thymic tissue and did not induce any obvious cell lysis, which is reminiscent of previously described in vitro studies of CV-B infections without cytopathic effect in human thymic epithelial cells [Brilot et al, 2002], pancreatic b-cells [Yoon et al, 1978;Chehadeh et al, 2000a], lymphoid cell lines [Matteucci et al, 1985], glomerular and tubular cells, or vascular endothelial cells [Conaldi et al, 1997a,b]. Altogether these data show that CV-B can infect various tissues without dramatic cell lysis in contrast with the effect of those viruses in continuous epithelial cell lines such as Hep-2, Vero and KB.…”

Section: Discussionsupporting

confidence: 85%

“…Through thymus infection, CV-B4 may severely impair the physiologic function of that organ. In this perspective, it has been demonstrated previously that CV-B4 can persistently infect primary cultures of human thymic epithelial cells and modulate the profile of LIF, IL-6 and GM-CSF secretion by these cells [Brilot et al, 2002]. It has also been observed that CV-B4 infection of cultures of human foetal thymus dissected into small pieces resulted in a dramatic depletion of immature CD4 þ CD8 þ thymocytes with an increased expression of MHC I that is one of the three-molecular complex TCR/MHC/self-antigen actors responsible for negative selection of self-reactive T cells in the thymus [Brilot et al, 2004].…”

Section: Introductionmentioning

confidence: 94%

“…Yoon, Julia McFurlane Diabetes Research Center, Calgary, Alberta, Canada) was generated as described previously [Brilot et al, 2002]. Briefly, CV-B4 E2 was grown in Vero cells (American Type Culture Collection, Manassas, VA) in Eagle's Minimum Essential Medium (Cambex, Verviers, Belgium) supplemented with 10% foetal calf serum (FCS) (a generous gift from Dr. M. De Smedt, University of Gent, Belgium).…”

Section: Virusmentioning

confidence: 99%

“…1). The detection of cellular cytokeratins has previously been shown to identify the network of thymic epithelial cells within the thymus [Brilot et al, 2002], and thus can be used as a marker of tissue integrity. No difference in the cytokeratin staining could be observed between mock-and CV-B4 E2-infected thymic lobes (Fig.…”

Section: Cv-b4 E2 Infects Murine Foetal Thymus Organ Culturesmentioning

confidence: 99%

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Coxsackievirus B4 infection of murine foetal thymus organ cultures

Brilot

Jaïdane

Geenen

et al. 2008

Journal of Medical Virology

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The infection of foetal thymus with coxsackievirus B4 (CV-B4) E2 has been studied ex vivo by using CD-1 mice on foetal day 14, as a ready source of organs for experimentation to investigate the hypothesis of the role of thymic viral infections in the pathogenesis of type 1 diabetes. The replication of CV-B4 E2 in murine foetal thymus organ cultures has been demonstrated by evaluating the levels of positive-and negativestranded viral RNA in cells by using a real-time quantitative RT-PCR method and by determining titres of infectious viral particles in culture supernatants for 7 days post-infection (p.i.). Staining of tissue sections with an anti-cytokeratin antibody and haematoxylin-eosin showed that CV-B4 infection had no visible effect on cell survival and organ integrity. Cell counts in mock-and virus-infected foetal thymus organ cultures increased from day 1 through day 7, and live cell numbers were comparable in both conditions as shown by Trypan blue exclusion test and 7-amino-actinomycin D staining of thymocytes. Compared with controls on day 7 p.i., cytofluorometric analyses on cells from CV-B4 E2-infected foetal thymus organ cultures displayed a marked increase in the percentage of the most immature CD3 À CD4 À CD8 À thymocytes, and a decrease in the percentage of immature CD3 À CD4 þ CD8 þ cells, together with an increase in the percentage of mature CD3 þ CD4 þ and CD3 þ CD8 þ cells. These data show that CV-B4 E2 disturbs T-cell maturation and differentiation processes in infected murine foetal thymus organ cultures and provide evidence of a suitable system to investigate the effect of viruses in T-cell differentiation.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 94%

Section: Virusmentioning

confidence: 99%

Section: Cv-b4 E2 Infects Murine Foetal Thymus Organ Culturesmentioning

confidence: 99%

See 2 more Smart Citations

Coxsackievirus B4 infection of murine foetal thymus organ cultures

Brilot

Jaïdane

Geenen

et al. 2008

Journal of Medical Virology

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“…In collaboration with Didier Hober (Laboratory of Virology EA3610, CHRU Lille, France), we have shown that CVB4 is capable to directly infect the epithelial and lymphoid compartments of the human and murine thymus, and to induce a severe thymus dysfunction with massive pre-T-cell depletion and marked upregulation of MHC class I expression by TECs and by CD4+ CD8+ immature thymic T cells [89,90]. Interestingly, outbred mice can be infected with CVB4 following an oral inoculation, which results in systemic spreading of viral RNA and a prolonged detection of CVB4 RNA in thymus, spleen, and blood up to 70 days postinoculation [91].…”

Section: Environmental Factorsmentioning

confidence: 99%

Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes

Geenen

Mottet

Dardenne

et al. 2010

Current Opinion in Pharmacology

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Before being able to react against infectious nonself-antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins and this critical process takes place only in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programing central self-tolerance to pancreatic insulin-secreting islet b cells, leading to the breakdown of immune homeostasis with an enrichment of islet b-cell reactive effector T cells and a deficiency of b-cell specific natural regulatory T cells (nTregs) in the peripheral Tlymphocyte repertoire. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/protein. The very low degree of insulin gene transcription in normal murine and human thymus explains why the insulin protein is poorly tolerogenic as demonstrated in many studies, including the failure of all clinical trials that have attempted immune tolerance to islet b cells via various methods of insulin administration. On the basis of the close homology and crosstolerance between insulin, the primary T1D autoantigen, and IGF-2, the dominant self-antigen of the insulin family, a novel type of vaccination, so-called 'negative/tolerogenic selfvaccination', is currently being developed for the prevention and cure of T1D. If this approach were found to be effective for reprograming immunological tolerance in T1D, it could pave the way for the design of other self-vaccines against autoimmune endocrine diseases, as well as other organspecific autoimmune diseases. ''Autoimmune disease can be a depressing subject. In Shakespearian terms, 'it is a tale told by an idiot. . .signifying nothing'. In more modern metaphor, it is an error made at random in an enormous, delicately programmed computer. Nature has no other way of handling genetic error than by eliminating the faulty, and the physician handling autoimmune diseases can expect no help from her.'' Sir F. MacFarlane Burnet, 1972 IntroductionIn 1965, our late Belgian colleague Willy Gepts observed inflammatory infiltrates of mononuclear cells invading Langerhans' islets in the pancreas of deceased young diabetic patients [1]. In a prophetical analysis, he discussed his innovative results with the following words: 'It seems probable that, in the pancreas of acute diabetics, we had the opportunity to catch the final stages of a process which has been going on for an indefinite time, perhaps from birth on'. Since this pioneering work, research conducted worldwide has firmly established that type 1 diabetes (T1D) -previously called juvenile diabetes, and insulin-dependent diabetes -is the final result of a highly selective autoimmune response that generates an inflammation (insulitis), followed by the death of insulin-secreting islet b cells in the pancreas. Incidence of T1D peaks around 10-14 years and this disease affects AE20 million people worldwide (approximately 10%...

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Evidence for coxsackievirus infection in primary Sjögren's syndrome

Triantafyllopoulou¹,

Tapinos²,

Moutsopoulos³

2004

Arthritis & Rheumatism

137

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Objective. Primary Sjögren's syndrome (SS) is an autoimmune disease characterized by activation of minor salivary gland (MSG) epithelial cells and B and T lymphocytic infiltrates. These findings have long encouraged the hypothesis that a persistent viral infection of the MSG epithelial cells may drive the autoimmune response; however, the identity of that virus has remained elusive. The aim of this study was to test this hypothesis.Methods. We applied the differential display protocol to MSG RNA samples from patients with primary SS and healthy controls. We then used seminested reverse transcriptase-polymerase chain reaction to amplify the 5 -noncoding region (5 -NCR) of the enteroviral genome in 8 patients with primary SS, 9 patients with secondary SS, and 8 control subjects. Immunohistochemistry was performed to study the expression of the VP1 enteroviral capsid protein in MSG biopsy samples from 12 patients with primary SS, 8 patients with secondary SS, and 16 controls.Results. Differential display analysis yielded a 94-bp fragment of coxsackievirus B4 (CVB4) P2A gene in the primary SS samples. The 5 -NCR was amplified in 7 samples from patients with primary SS and in no samples from patients with secondary SS or controls. The 7 amplified products were sequenced; 4 of the sequences were found to be 98-99% identical to the 5 -NCR of CVB4, and 3 were found to be 97-98% identical to the 5 -NCR of CVA13. Immunohistochemistry for the enteroviral capsid protein VP1 revealed positive staining in epithelial cells and lymphocytic infiltrates in 11 primary SS samples, 1 secondary SS sample, and no control samples.Conclusion. We provide evidence that primary SS may be associated with coxsackievirus infection of the MSG epithelial cells and focal lymphocytic infiltrates. Our findings are formulated in a hypothesis concerning the possible role of coxsackieviruses in the induction and maintenance of autoimmunity in primary SS.

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Persistent Infection of Human Thymic Epithelial Cells by Coxsackievirus B4

Cited by 54 publications

References 33 publications

Coxsackievirus B4 infection of murine foetal thymus organ cultures

Coxsackievirus B4 infection of murine foetal thymus organ cultures

Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes

Evidence for coxsackievirus infection in primary Sjögren's syndrome

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