Enteroviruses (EVs) have been connected to type 1 diabetes in various studies. The current study evaluates the association between specific EV subtypes and type 1 diabetes by measuring typespecific antibodies against the group B coxsackieviruses (CVBs), which have been linked to diabetes in previous surveys. Altogether, 249 children with newly diagnosed type 1 diabetes and 249 control children matched according to sampling time, sex, age, and country were recruited in Finland, Sweden, England, France, and Greece between 2001 and 2005 (mean age 9 years; 55% male). Antibodies against CVB1 were more frequent among diabetic children than among control children (odds ratio 1.7 [95% CI 1.0-2.9]), whereas other CVB types did not differ between the groups. CVB1-associated risk was not related to HLA genotype, age, or sex. Finnish children had a lower frequency of CVB antibodies than children in other countries. The results support previous studies that suggested an association between CVBs and type 1 diabetes, highlighting the possible role of CVB1 as a diabetogenic virus type. A connection between enterovirus (EV) infections and human type 1 diabetes has been documented in a variety of studies (1-3). Meta-analyses of studies on direct detection of EVs in blood or tissues have indicated a clear risk effect (odds ratios [ORs] 5.5-17.4) (4), whereas serological studies have shown inconsistent results (5). Accordingly, invasive infection, as reflected by the presence of EV in blood or tissues, rather than superficial

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Protection in the murine model of Helicobacter pylori infection may be mediated by CD4؉ T cells, but the mechanism remains unclear. To better understand how protection occurs in this model, we generated and characterized H. pylori urease-specific CD4 ؉ T cells from BALB/c mice immunized with Salmonella enterica serovar Typhimurium expressing H. pylori urease (subunits A and B). The CD4 ؉ T cells were found to be specific for subunit A (UreA). Upon antigen-specific stimulation, expression of interleukin 4 (IL-4), IL-10, gamma interferon (IFN-␥), and tumor necrosis factor alpha was induced. Immunocytochemical analysis showed that the majority of cells produced IFN-␥ and IL-10. Adoptive transfer of the UreA-specific CD4 ؉ T cells into naive syngeneic recipients led to a threefold reduction in the number of bacteria in the recipient group when compared to that in the nonrecipient group. Stomach colonization was also reduced significantly after transfer of these cells into patently infected mice. Adoptive transfer of UreA-specific CD4 ؉ T cells into IL-4 receptor ␣ chain-deficient BALB/c mice indicated that IL-4 and IL-13 were not critical in the control of bacterial load. In addition, synthetic peptides were used to identify three functional T-cell epitopes present in subunit A which were recognized by the UreA-specific T cells. Analysis of H. pylori-specific cellular immune responses in recipient challenged and nonrecipient infected mice indicated a strong local restriction of the response in infected animals. The implications of these findings for the mechanism of protection and the development of peptide-based vaccination are discussed.

Coxsackievirus B4 (CVB4)-induced production of alpha interferon (IFN-␣) by peripheral blood mononuclear cells (PBMC) is enhanced in vitro by nonneutralizing anti-CVB4antibodies from healthy subjects and, to a higher extent, from patients with insulin-dependent diabetes mellitus. In this study, we focused on identification of the viral target of these antibodies in CVB systems. High levels of IFN-␣ were obtained in supernatants of PBMC incubated with CVB4E2 or CVB3 and plasma from healthy subjects and, to a higher extent, from patients. The VP4 capsid proteins dissociated by heating at 56°C from CVB4E2 (VP4 CVB4 ) and CVB3 (VP4 CVB3 ) but not H antigen preincubated with plasma from healthy subjects or patients inhibited the plasma-dependent enhancement of CVB4E2-and CVB3-induced IFN-␣ synthesis. There was no cross-reaction between VP4 CVB4 and VP4 CVB3 in the inhibiting effect. IFN-␣ levels in culture supernatants showed dosedependent correlation with anti-VP4 antibodies eluted from plasma specimens using VP4-coated plates. There were higher index values for anti-VP4 antibodies detected by enzyme-linked immunosorbent assay (ELISA) and higher proportions of positive detection in 40 patients than in 40 healthy subjects (80% versus 15% for anti-VP4 CVB4 ). There was no relationship between the levels of anti-CVB neutralizing antibodies and the detection of anti-VP4 antibodies by ELISA. The CVB plasma-induced IFN-␣ levels obtained in PBMC cultures in the anti-VP4 antibody-positive groups were significantly higher than those obtained in the anti-VP4 antibody-negative groups regardless of the titers of anti-CVB neutralizing antibodies. These results show that VP4 is the target of antibodies involved in the plasma-dependent enhancement of CVB4E2-and CVB3-induced IFN-␣ synthesis by PBMC.