Epstein-barr virus and inflammatory bowel disease

Zusammenfassung Die Häufigkeit und der Antikörpertiter gegen Epstein-Barr-Virus (EBV) wurde in Patienten mit Ulkus-Colitis und Crohn's Krankheit, eine granulomatische Abnormalität ähnlich zur Sarkoidose untersucht und normale Häufigkeit und Antikörpertiter gegen EBV bei ihnen gefunden.

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Supported by Research Contract No. NIH-69-2078 within the Special Virus Cancer Program of the National Cancer Institute, National Institutes of Health, USPHS, National Institutes of Health Grant No. AM 05126 and the National Foundation for Ileitis and Colitis, Inc., New York, New York.

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Dr.Grotsky is a recipient of a National Institutes of Health Graduate Training Grant in Gastroenterology, No. Am 05126.

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Dr.Hirshaut is a recipient of a National Cancer Institute Grant No. CA 08748 an a grant from the New York Cancer Research Institute.

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Dr.Glade is a recipient of a Research Career Development Award No. A1-46371 of the USPHS.     

Type I IFN-mediated regulation of IL-1 production in inflammatory disorders

Although contributing to inflammatory responses and to the development of certain autoimmune pathologies, type I interferons (IFNs) are used for the treatment of viral, malignant, and even inflammatory diseases. Interleukin-1 (IL-1) is a strongly pyrogenic cytokine and its importance in the development of several inflammatory diseases is clearly established. While the therapeutic use of IL-1 blocking agents is particularly successful in the treatment of innate-driven inflammatory disorders, IFN treatment has mostly been appreciated in the management of multiple sclerosis. Interestingly, type I IFNs exert multifaceted immunomodulatory effects, including the reduction of IL-1 production, an outcome that could contribute to its efficacy in the treatment of inflammatory diseases. In this review, we summarize the current knowledge on IL-1 and IFN effects in different inflammatory disorders, the influence of IFNs on IL-1 production, and discuss possible therapeutic avenues based on these observations.     

Heparanase enzyme in chronic inflammatory bowel disease and colon cancer

Heparanase is the sole mammalian endoglycosidase that cleaves heparan sulfate, the key polysaccharide of the extracellular matrix and basement membranes. Enzymatic cleavage of heparan sulfate profoundly affects a variety of physiological and pathological processes, including morphogenesis, neovascularization, inflammation, and tumorigenesis. Critical involvement of heparanase in colorectal tumor progression and metastatic spread is widely documented; however, until recently a role for heparanase in the initiation of colon carcinoma remained underappreciated. Interestingly, the emerging data that link heparanase to chronic inflammatory bowel conditions, also suggest contribution of the enzyme to colonic tumor initiation, at least in the setting of colitis-associated cancer. Highly coordinated interplay between intestinal heparanase and immune cells (i.e., macrophages) preserves chronic inflammatory conditions and creates a tumor-promoting microenvironment. Here we review the action of heparanase in colon tumorigenesis and discuss recent findings, pointing to a role for heparanase in sustaining immune cell-epithelial crosstalk that underlies intestinal inflammation and the associated cancer.     

Aberrant O-glycosylation and anti-glycan antibodies in an autoimmune disease IgA nephropathy and breast adenocarcinoma

Glycosylation abnormalities have been observed in autoimmune diseases and cancer. Here, we compare mechanisms of aberrant O-glycosylation, i.e., formation of Tn and sialyl-Tn structures, on MUC1 in breast cancer, and on IgA1 in an autoimmune disease, IgA nephropathy. The pathways of aberrant O-glycosylation, although different for MUC1 and IgA1, include dysregulation in glycosyltransferase expression, stability, and/or intracellular localization. Moreover, these aberrant glycoproteins are recognized by antibodies, although with different consequences. In breast cancer, elevated levels of antibodies recognizing aberrant MUC1 are associated with better outcome, whereas in IgA nephropathy, the antibodies recognizing aberrant IgA1 are part of the pathogenetic process.     

Lymphocyte-fibroblast interaction in the pathogenesis of inflammatory gingival disease

Zusammenfassung Eine morphometrische Analyse menschlicher, entzündeter Gingiva ergab im Vergleich zu normalem Bindegewebe 70% weniger Kollagenfasern, dreifach vergrösserte und pathologisch veränderte Fibroblasten und eine kleine Population charakteristischer Immunoblasten mit einer Zellansammlung, die zu 76% aus Zellen der Lymphozytenserie bestand. Die Grösse der Fibroblasten war positiv mit der steigenden Zahl der Lymphozyten korreliert. Diese Befunde weisen auf eine Immunreaktion mit zytotoxischen Auswirkungen auf Fibroblasten des gingivalen Bindegewebes hin.     

Heat shock proteins in autoimmune disease. From causative antigen to specific therapy?

Heat shock proteins (hsp) are highly conserved from bacteria to man. Bacterial hsp, with approximate molecular weights of 60 kDa (hsp60), are immunodominant antigens that are immunologically cross-reactive with their mammalian counterparts. Hsp molecules are therefore useful in studies of fundamental questions concerning immune responses to foreign as opposed to self antigens. The finding that immune responses to hsp are associated with both experimentally-induced and spontaneous autoimmune diseases in animals has prompted intensive research to assess the role of bacterial hsp as the etiological agents involved in the development of autoimmune diseases. Recent evidence from animal models of autoimmune disease has clearly demonstrated the involvement of hsp in both the pathogenesis and the immunoregulation of autoimmune diseases. Studies with arthritogenic and diabetogenic T cell clones have identified immunogenic epitopes of hsp. These have been shown to ameliorate adjuvant arthritis in Lewis rats, and insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. Such studies may have important therapeutic implications for the future treatment of human autoimmune disease.Dedicated to Professor Hermann A. Moser on the occasion of his 71st birthday.     

Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis

Molecular mimicry of viral antigens with self determinants has been proposed as one of the pathogenic mechanisms in autoimmune disease. Evidence of viral mimicry in animal models of autoimmunity is accumulating. Murine adenovirus, Semliki forest virus, lactate dehydrogenase-elevating virus, herpes simplex virus type-1, hepatitis B virus, encephalomyocarditis virus, Theiler's murine encephalomyelitis virus, Coxsackievirus and cytomegalovirus have been found to mimic physiologically important host proteins. However, epitope homology of a viral and self determinant is not in itself strong evidence for mimicry as a pathogenic mechanism. The mimicking determinant must also be capable of inducing disease in the absence of replicative virus. Animal models provide evaluation of the viral trigger, and development and therapy for autoimmune diseases. Identification of host proteins that can induce disease together with the knowledge of immune system dysregulation, genetic association and environmental factors may lead to improved immunotherapeutic strategies for human autoimmune diseases.     

Heat shock proteins in autoimmune disease. From causative antigen to specific therapy?

Heat shock proteins (hsp) are highly conserved from bacteria to man. Bacterial hsp, with approximate molecular weights of 60 kDa (hsp60), are immunodominant antigens that are immunologically cross-reactive with their mammalian counterparts. Hsp molecules are therefore useful in studies of fundamental questions concerning immune responses to foreign as opposed to self antigens. The finding that immune responses to hsp are associated with both experimentally-induced and spontaneous autoimmune diseases in animals has prompted intensive research to assess the role of bacterial hsp as the etiological agents involved in the development of autoimmune diseases. Recent evidence from animal models of autoimmune disease has clearly demonstrated the involvement of hsp in both the pathogenesis and the immunoregulation of autoimmune diseases. Studies with arthritogenic and diabetogenic T cell clones have identified immunogenic epitopes of hsp. These have been shown to ameliorate adjuvant arthritis in Lewis rats, and insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. Such studies may have important therapeutic implications for the future treatment of human autoimmune disease.     

Tryptophan degradation in autoimmune diseases

Recent evidence points to tryptophan (Trp) degradation as a potent immunosuppressive mechanism involved in the maintenance of immunological tolerance. Both Trp depletion and downstream Trp catabolites (TCs) appear to synergistically confer protection against excessive inflammation. In this review, we give an overview of the immunosuppressive properties of Trp degradation with special focus on TCs. Constitutive and inducible Trp degradation in different cell types and tissues of human and murine origin is summarized. We address the influence of Trp degradation on different aspects of autoimmune disorders such as multiple sclerosis. Possible therapeutic approaches for autoimmune disorders targeting Trp degradation are presented, and key issues relevant for the development of such therapeutic strategies are discussed.     

Central IL-1 differentially regulates peripheral IL-6 and TNF synthesis

Centrally given interleukin (IL)-1 is known to induce a rapid rises in blood IL-6. To extend this and to examine the mechanism by which this occurs, the effects of intracerebroventricular (icv) injection of human recombinant IL-1β on mRNA expression of IL-6 and tumour necrosis factor (TNF) in the spleen and liver were examined in rats. Icv injection of IL-1 produced a rapid rise of the tissue mRNA levels of IL-6 and TNF in both organs, prior to and/or in parallel with an increase in their serum levels. Pretreatment with chlorisondamine, a ganglionic blocking agent, inhibited the IL-6 responses, while it had little influence on the TNF responses. The results suggest that brain IL-1 induces peripheral production of IL-6, but not of TNF, through autonomic nervous system activation. Received 27 October 1997; received after revision 15 December 1997; accepted 12 January 1998     

热性惊厥儿童血液IL-6、IL-10和MMP-9表达的研究

目的 热性惊厥是儿童痫性发作最常见的形式.炎性细胞因子可能导致热性惊厥的发展.本研究探讨白介素-6(IL-6)、白介素-10(IL-100和金属蛋白酶-9(MMP-9)等炎性细胞因子在小儿热性惊厥中是否被激活以及其表达与原发性癫痫中的不同.方法 回顾性研究自2010年12月到2012年11月入院的相关病人资料.分热性惊厥组(N=43)、高热对照组(N=40)、原发性癫痫组(N=32)及正常儿童组(N=15).在惊厥发生的24h内收集病人血液.酶联免疫吸附试验(ELISA)进行IL-6、IL-10和MMP-9等细胞因子水平测定.结果 IL-6、IL-10和MMP-9在热性惊厥组的表达均高于原发性癫痫组(p＜0.05)和正常组(p＜0.05).IL-6与MMP-9在热性惊厥组的表达高于高热对照组,IL-10的表达在热性惊厥组与高热对照组之间无明显差异(P＞0.05).结论 IL-6、IL-10和MMP-9在热性惊厥儿童表达明显升高;炎性因子可能参与热性惊厥的病理过程,且其参与机制可能不同于其在原发性癫痫病理过程中的作用.     

Valproic acid attenuates inflammation in experimental autoimmune neuritis

Valproic acid (VPA) is a short-chain branched fatty with anti-inflammatory, neuro-protective and axon-remodeling effects. We investigated the effects of VPA in rats in which experimental autoimmune neuritis (EAN) had been induced (EAN rats). VPA (300 mg/kg, intraperitoneally) administration to EAN rats once daily immediately following immunization significantly suppressed mRNA levels of interferon-γ, tumor necrosis factor-α, interleukin (IL)-1β, IL-4, IL-6 and IL-17 in the lymph nodes of EAN rats. In peripheral blood and sciatic nerves of EAN rats, Foxp3⁺ cells were increased but IL-17⁺ cells were decreased during VPA treatment. Furthermore, suppressive and therapeutic treatment with VPA greatly attenuated both accumulation of macrophages, T cells and B cells, and demyelination in sciatic nerves, and greatly reduced the severity and duration of EAN. In summary, our data demonstrated that VPA could effectively suppress inflammation in EAN, suggesting that VPA could be a potent candidate for treatment of autoimmune neuropathies.     

Current cases in which epitope mimicry is considered as a component cause of autoimmune disease: immune-mediated (type 1) diabetes

Autoimmune diseases result from a combination of genetic, immunologic, hormonal, and environmental factors. Infectious agents may induce the breakdown of immunological tolerance and the appearance of autoreactivity. However, the specific relationship between infection and autoimmunity is still unclear. One of the mechanisms responsible could be molecular mimicry between the infectious agent and self. The concept of molecular mimicry is a viable hypothesis in the investigation of the etiology, pathogenesis, treatment, and prevention of autoimmune disorders. Immune-mediated (type 1) diabetes in humans and in non-obese diabetic (NOD) mice is polygenic and characterized by autoimmune destruction of insulin-producing pancreatic beta cells in islets of Langerhans. In NOD mice, a T-helper 1 (Th1)-based autoimmune response arises spontaneously against glutamate decarboxylase (GAD) concurrently with the onset of insulitis. Subsequently. this Th1-type autoreactivity spreads intra- and intermolecularly to other beta cell autoantigens, suggesting that a Th1-type response is responsible for the progression of the disease, whereas Th2 responses when experimentally induced are protective. In humans, a homology between GAD and the P2-C protein of Coxsackie B make a cause-and-effect molecular mimicry an attractive hypothesis. Evidence to support the concept of molecular mimicry in diabetes is reviewed.