The Role of Immune Mechanisms in Pathogenesis

Huber, Sally A.

doi:10.1007/978-1-4757-0247-7_7

Cited by 9 publications

(8 citation statements)

References 34 publications

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“…This observation, which obscures a simple definition of a diabetogenic CVB phenotype, is consistent with CVB diabetogenicity being modulated by the host environment. The impact of the host environment on viral replication is well-established: expression of CVB phenotypes are modulated by a variety of influences, including immune status, age, strain, and gender of the mouse host (14,23,25,49,50).To test the hypothesis whether diabetogenicity is a common phenotype, we used a well-characterized, poorly pathogenic CVB3 strain, CVB3/GA (33,55,56), reasoning that rapid T1D onset should not be observed if the virus lacks a putative …”

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Group B Coxsackievirus Diabetogenic Phenotype Correlates with Replication Efficiency

Kanno

Kim

Kono

et al. 2006

J Virol

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Group B coxsackieviruses can initiate rapid onset type 1 diabetes (T1D) in old nonobese diabetic (NOD) mice. Inoculating high doses of poorly pathogenic CVB3/GA per mouse initiated rapid onset T1D. Viral protein was detectable in islets shortly after inoculation in association with beta cells as well as other primary islet cell types. The virulent strain CVB3/28 replicated to higher titers more rapidly than CVB3/GA in the pancreas and in established beta cell cultures. Exchange of 5-nontranslated regions between the two CVB3 strains demonstrated a variable impact on replication in beta cell cultures and suppression of in vivo replication for both strains. While any CVB strain may be able to induce T1D in prediabetic NOD mice, T1D onset is linked both to the viral replication rate and infectious dose.Insulin-dependent (type 1) diabetes mellitus (T1D) is an autoimmune, largely T-cell-mediated disease typically diagnosed before the end of the teen years (5, 6). A predisposing, multigenic component has been described but accounts for fewer than 50% of cases (7,35,45); environmental factors (e.g., viral infections) have therefore been proposed to explain the remaining cases of T1D (3,6,32,57,58) that cannot be ascribed solely to host-driven pathogenic autoimmunity. Human enterovirus (HEV) infections have long been suspected as environmental triggers of human T1D (12,22,27); infections by common HEVs, such as the group B coxsackieviruses (CVB 1 to 6) and diverse echoviruses, have been implicated as triggers of T1D onset at the time of or shortly after infection (8,9,13,19,28,37,39,40,42,52,60). Nonetheless, it remains unclear whether HEV initiates T1D in humans (18,21,24,26); evidence supporting an etiologic connection between HEV infection and T1D onset is not as well-established as the links between, for example, specific HEV infections and poliomyelitis, aseptic meningitis, or myocarditis (43).The nonobese diabetic (NOD) mouse is widely used as a model for the study of T1D. Previous work demonstrated that CVB inoculation protects young NOD mice significantly better from T1D as they age than no treatment (mock infected) (55). Unlike all other treatments that protect NOD mice from T1D (reviewed in references 4 and 46), the CVB are widely thought to be instigators of T1D onset with no protective effect. The extent of protection from T1D onset correlates directly with replication efficiency of the specific CVB strain that is employed: CVB strains that replicate to higher titers protect more mice than do CVB strains which replicate to lower titers. As NOD mice age, naturally occurring, pathogenic autoimmune insulitis develops rapidly (4) with widespread islet inflammation (insulitis) present by week 12 to 15 of age, when T1D also begins to occur. T1D rapidly ensues following inoculation of old (Ͼ12 weeks of age) NOD mice with virulent CVB (14), a model that recapitulates observations of sudden T1D onset in humans reported to occur during or shortly after an infection (37, 52). Initiation of rapid T1D onset in older mice...

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confidence: 99%

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Group B Coxsackievirus Diabetogenic Phenotype Correlates with Replication Efficiency

Kanno

Kim

Kono

et al. 2006

J Virol

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“…The human protein coxsackievirusadenovirus receptor (CAR) [Carson et al, 1997;Bergelson et al, 1997] is closely related to the murine homologue MCAR [Tomko et al, 1997;Bergelson et al, 1998], largely explaining the facility with which these human viruses replicate in mice. Murine models of CVB-induced acute inflammatory cardiomyopathy or myocarditis [Huber, 1988;Gauntt et al, 1988] and pancreatitis [Vuorinen et al, 1989;Ramsingh, 1997] demonstrate a close similarity to the human disease counterparts. Murine models for the study of CVB-induced murine type 1 diabetes exist as well [Yoon et al, 1979;See and Tilles, 1995;Ramsingh et al, 1997], but these appear to be limited to the use of specific CVB strains [Yoon et al, 1979;Toniolo et al, 1982;Szopa et al, 1986].…”

Section: Introductionmentioning

confidence: 99%

Group B coxsackievirus myocarditis and pancreatitis: Connection between viral virulence phenotypes in mice

et al. 2000

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The group B coxsackieviruses (CVB) induce experimental pancreatitis and myocarditis in mice and are established agents of human myocarditis, especially in children. We tested the hypothesis that the development of CVB-induced myocarditis is linked to CVB-induced pancreatitis by studying the replication of different CVB strains in mice. Eight of nine genotypically different type 3 CVB (CVB3) strains induced acute pancreatitis in mice; of these, three viruses also induced acute myocarditis. One CVB3 strain was avirulent for both organs. Myocarditis was not observed in the absence of pancreatitis. The results obtained by inoculation of mice with strains of other CVB serotypes were consistent with these data. Infectious virus titers were measured in serum, pancreas, and heart as a function of time after inoculation of mice with three CVB3 strains. Each strain was representative of one of the three viral virulence phenotypes: avirulent, pancreovirulent only, and cardiovirulent. All strains replicated well and persisted in the pancreas through 8 days post-inoculation, but the cardiovirulent CVB3 strain tended to replicate to higher titer earlier and persist longer in sera, pancreatic, and cardiac tissues than the noncardiovirulent strains. Replication of the CVB3 strains were studied in two human pancreatic tumor lines and in primary human endothelial cell cultures derived from cardiac artery. Cardiovirulent strains, both individually and as a group, tended to replicate to titers as high as, or higher than, noncardiovirulent strains did in cell culture. The data are consistent with the possibility of an etiologic link between CVB-induced pancreatic and heart disease.

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“…Among the many hypotheses to explain the pathogenesis of CVBinduced cardiomyopathy, two concepts have attracted most attention: the direct cytopathic effect of CVB on myocardial tissue and the damage induced by immune mechanisms that may also cause autoimmunity [Carthy et al, 1997]. A hallmark of acute CVB-induced myocarditis is an intense mononuclear leukocyte in®ltration in which macrophages account for 50% or more of invading leukocytes [Huber, 1988]. Macrophages are a particularly rich source of cytokines which have been shown to modulate strongly the immune response, depending on their type and the amounts released.…”

Section: Introductionmentioning

confidence: 99%

Suppression of proinflammatory cytokines and induction of IL‐10 in human monocytes after coxsackievirus B3 infection

Hofmann

Schmidtke

Stelzner

et al. 2001

Journal of Medical Virology

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Coxsackievirus B3 (CVB3) causes acute and chronic myocarditis, which is accompanied by an intense mononuclear leukocyte infiltration. Because myocardial tissue damage may either result from viral infections or from a dysregulated immune response, the susceptibility of human monocytes and macrophages to CVB3 was examined in this study with regard to virus replication, virus persistence, and release of cytokines. Monocytes were infected by CVB3 as shown by the intracellular appearance of plus- and minus-strand viral RNA, which was also capable of persisting for more than 10 days. Fresh monocytes were not permissive for full virus replication whereas monocyte-derived macrophages yielded a low amount of new viruses, which led to cell death. Although CVB3 infection induced the mRNA for the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, and IL-6, only little cytokine production occurred. When infected monocytes were stimulated in addition by lipopolysaccharides (LPS), cytokine production was partially suppressed. In striking contrast, IL-10 expression was strongly and persistently induced by CVB3 on the mRNA and the protein level. These data show a dysregulated cytokine response in CVB3-exposed human monocytes and macrophages, which is characterized by a suppression of proinflammatory cytokines and a dominance of IL-10. This viral strategy may aid CVB3, causing chronic myocardiopathy.

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The Role of Immune Mechanisms in Pathogenesis

Cited by 9 publications

References 34 publications

Group B Coxsackievirus Diabetogenic Phenotype Correlates with Replication Efficiency

Group B Coxsackievirus Diabetogenic Phenotype Correlates with Replication Efficiency

Group B coxsackievirus myocarditis and pancreatitis: Connection between viral virulence phenotypes in mice

Suppression of proinflammatory cytokines and induction of IL‐10 in human monocytes after coxsackievirus B3 infection

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