Enterovirus RNA sequences in sera of schoolchildren in the general population and their association with type 1-diabetes-associated autoantibodies

Abstract

Type 1 diabetes (T1D) is an autoimmune disease linked with genetic factors as well as with environmental triggers, such as virus infections, but the aetiology is still unclear. The authors analysed serum from autoantibody-positive (n ¼ 50) and autoantibody-negative (n ¼ 50) schoolchildren as well as children newly diagnosed with T1D (n ¼ 47; time from diagnosis, median 5 days, interquartile range 1-12 days) for the presence and frequency of enterovirus (EV) and adenovirus sequences. The autoantibody-positive and -negative groups were part of the Karlsburg Type 1 Diabetes Risk Study of a Normal Schoolchild Population, which represents a general population without T1D first-degree relatives. There was no significant seasonality of sampling in any of the three groups investigated. EV RNA sequences were detected in 10 of 50 (20 %) autoantibody-positive children and in 17 of 47 (36 %) children newly diagnosed with T1D, but only in two of 50 (4 %) of the age-and sex-matched controls (P , 0 . 05, P , 0 . 001). Characterization of the EV amplicons by direct sequencing revealed high homology with coxsackievirus B group. For adenovirus we found no data to support an association with T1D. The data support the hypothesis that different enteroviruses may be aetiologically important as a trigger and/or accelerating factor in the process of T1D development. INTRODUCTIONType 1 diabetes (T1D) results from the progressive destruction of insulin-producing pancreatic beta cells. Both genetic and environmental factors may contribute to the development of the autoimmune process that finally leads to the manifestation of T1D (Szopa et al., 1993; Hyöty & Taylor, 2002;Jun & Yoon, 2004).Viruses are one type of environmental agent suspected of having importance in the expression of the autoantigens of T1D. Associations of many viruses including rubella virus, mumps virus, cytomegalovirus and Epstein-Barr virus have been discussed in terms of the development of T1D, but the strongest evidence suggests a link with enteroviruses.To date, many of the studies suggesting a possible association of enteroviruses with T1D have been based on serological data (Helfand et al., 1995; Hyöty et al., 1995;Hiltunen et al., 1997;Roivainen et al., 1998). Now the introduction of molecular approaches has opened up new possibilities to evaluate the role of viral infections, and some studies have indeed confirmed the preliminary hypothesis that a link exists between enteroviral infection and development of T1D (Clements et al., 1995; Andréoletti et al., 1997; Lönnrot et al., 2000a;Kawashima et al., 2004). Besides, it has been shown in vitro that coxsackievirus B4 can replicate in pancreatic beta cells and can cause an excessive release of insulin (Titchener et al., 1994). The E2 strain of human coxsackievirus B4 can induce a diabetic-like syndrome in a mouse model (Kang et al., 1994). Determinants of virulence have been identified in the 59 untranslated region (59-NTR) and the capsid proteins VP1, VP2 and VP4 (Ramsingh et al., 1992).However, there are also stu...

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

“…vp1 staining in islets was found in~10% of non-diabetic controls of all ages. This is consistent with studies showing that 4-5% of normal children had enteroviral RNA in their serum [4,7,8] and 11.8% had enteroviral RNA present in faecal samples [34,35]. Since a range of enteroviruses can infect human islets in vitro [12,36,37] it is possible that the pancreas is frequently colonised during an enteroviral infection.…”

“…Much of the evidence is circumstantial [1] but includes observations that antibodies against common Coxsackie B enteroviruses (CVB) and enteroviral RNA occur more frequently in the circulation of recent-onset type 1 diabetes patients than in controls [2][3][4][5][6][7][8][9][10].…”

Echovirus Epidemics, Autoimmunity, and Type 1 Diabetes

“…Taken together, these results show the association between echovirus epidemics and the induction of T1D associated autoantibodies. Other studies have shown similar results (Frisk & Tuvemo, 2004;Hiltunen et al, 1997;Lonnrot et al, 2000a;Moya-Suri et al, 2005;Oikarinen et al, 2011;Sadeharju et al, 2001;Salminen et al, 2003;Williams et al, 2006). Diabetogeneicity seems to be associated to HEVs of the B species although it is not restricted to one particular serotype or strain.…”

“…As shown in table 5, subjects at diagnosis and subjects with ICA showed higher frequencies of HEV RNA than their matched controls. These and other results (Andreoletti et al, 1997;Clements et al, 1995;Craig et al, 2003;Moya-Suri et al, 2005;Nairn et al, 1999;Yin et al, 2002) Table 5. Frequency of enterovirus RNA in blood of subjects with T1D at clinical onset, their first degree relatives and controls matched for age, sex, date of collection and location (Sarmiento et al, 2007a).…”

Enterovirus infections in young infants: Are children still protected by maternal antibodies?

“…an epitope common for several enteroviruses, enables to detect antibodies against the majority of existing enterovirus serotypes. 4 Enterovirus infection(s) might be involved in the development of type 1 diabetes, 3,[5][6][7] even though some studies are contradicting. [8][9][10] Our previous epidemiological investigations clearly speak about the existence of inverse association between the prevalence of enterovirus infections and frequency of type 1 diabetes in background population.…”