Development Of Beta-cell Autoimmunity Research Articles

Infections in the first year of life and development of beta cell autoimmunity and clinical type 1 diabetes in high-risk individuals: the TRIGR cohort

Aims/hypothesisAccumulated data suggest that infections in early life contribute to the development of type 1 diabetes. Using data from the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), we set out to assess whether children who later developed diabetes-related autoantibodies and/or clinical type 1 diabetes had different exposure to infections early in life compared with those who did not.MethodsA cohort of 2159 children with an affected first-degree relative and HLA-conferred susceptibility to type 1 diabetes were recruited between 2002 and 2007 and followed until 2017. Infections were registered prospectively. The relationship between infections in the first year of life and the development of autoantibodies or clinical type 1 diabetes was analysed using univariable and multivariable Cox regression models. As this study was exploratory, no adjustment was made for multiple comparisons.ResultsAdjusting for HLA, sex, breastfeeding duration and birth order, those who had seven or more infections during their first year of life were more likely to develop at least one positive type 1 diabetes-related autoantibody (p=0.028, HR 9.166 [95% CI 1.277, 65.81]) compared with those who had no infections. Those who had their first viral infection aged between 6 and 12 months were less likely to develop at least one positive type 1 diabetes-related antibody (p=0.043, HR 0.828 [95% CI 0.690, 0.994]) or multiple antibodies (p=0.0351, HR 0.664 [95% CI 0.453, 0.972]). Those who had ever had an unspecified bacterial infection were more likely to develop at least one positive type 1 diabetes-related autoantibody (p=0.013, HR 1.412 [95% CI 1.075, 1.854]), to develop multiple antibodies (p=0.037, HR 1.652 [95% CI 1.030, 2.649]) and to develop clinical type 1 diabetes (p=0.011, HR 2.066 [95% CI 1.182, 3.613]).Conclusions/interpretationWe found weak support for the assumption that viral infections early in life may initiate the autoimmune process or later development of type 1 diabetes. In contrast, certain bacterial infections appeared to increase the risk of both multiple autoantibodies and clinical type 1 diabetes.Graphical abstract

Prediction and Prevention of Type 1 Diabetes.

Type 1 Diabetes (T1D) is one of the most common chronic autoimmune diseases in children. The disease is characterized by the destruction of beta cells, leading to hyperglycemia, and to a lifelong insulin-dependent state. Although several studies in the last decades have added relevant insights, the complex pathogenesis of the disease is not yet completely understood. Recent studies have been focused on several factors, including family history and genetic predisposition (HLA and non-HLA genes) as well as environmental and metabolic biomarkers, with the aim of predicting the development and progression of T1D. Once a child becomes symptomatic, beta cell mass has already reached a critical threshold (usually a residual of 20–30% of normal amounts), thus representing only the very late phase of the disease. In particular, this final stage follows two preceding asymptomatic stages, which have been precisely identified. In view of the long natural history and complex pathogenesis of the disease, many strategies may be proposed for primary, secondary, and tertiary prevention. Strategies of primary prevention aim to prevent the onset of autoimmunity against beta cells in asymptomatic individuals at high risk for T1D. In addition, the availability of novel humoral and metabolic biomarkers that are able to characterize subjects at high risk of progression, have stimulated several studies on secondary and tertiary prevention, aimed to preserve residual beta cell destruction and/or to prolong the remission phase after the onset of T1D. This review focuses on the major current knowledge on prediction and prevention of T1D in children.

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility.

In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility. We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2years (range 0.9-21.1years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes. Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51years in rapid progressors (n=42, 17%) and 5.4years in slower progressors. Rapid progression was observed both among young (<5years) and early pubertal children (>7years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (≥2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion. At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.

Human Intestinal Microbiota and Type 1 Diabetes

The role of intestinal microbiota in immune-mediated diseases, such as type 1 diabetes, has deservedly received a lot of attention. Evidently, changes in the intestinal microbiota are associated with type 1 diabetes as demonstrated by recent studies. Children with beta-cell autoimmunity have shown low abundance of butyrate-producing bacteria and increase in the abundance of members of the Bacteroidetes phylum in fecal microbiota. These alterations could explain increased gut permeability, subclinical small intestinal inflammation, and dysregulation of oral tolerance in type 1 diabetes. However, these studies do not provide evidence of the causative role of the gut microbiota in the development of beta-cell autoimmunity, yet. In animal models, the composition of gut microbiota modulates the function of both innate and adaptive immunity, and intestinal bacteria are regulators of autoimmune diabetes. Thus, prevention of type 1 diabetes could, in the future, be based on the interventions targeted to the gut microbiota.

Human parechovirus and the risk of type 1 diabetes

Human parechoviruses (HPeVs) are RNA viruses associated mainly with mild gastrointestinal and respiratory infections in children and also cause neonatal sepsis and CNS infections. Human enteroviruses, close relatives of HPeVs, associate with the development of type 1 diabetes. In this study, the potential role of HPeV infections in promoting beta cell autoimmunity was investigated by analyzing stool samples of 54 prediabetic case and 134 healthy control children for the presence of HPeV RNA and comparing the derived infection frequencies. All 188 children were participants of the Finnish prospective Diabetes Prediction and Prevention study. Viral RNA was screened for using an HPeV-specific RT-PCR method coupled to liquid hybridization of the PCR product. The overall HPeV infection frequency did not differ between prediabetic case and control children. However, case boys had more HPeV positive samples in the 6-month period before becoming autoantibody positive, when compared to the matching time-period in controls (P < 0.01). HPeV infection at a young age does not appear to play a major role in the development of beta-cell autoimmunity. In boys, however, HPeVs showed time-dependent association with the first detection of diabetes-associated autoantibodies. Thus, in boys, HPeV infections cannot be excluded as a gender-specific risk factor which promotes the development of type 1 diabetes.

Diet in Infancy and Later Signs of Beta-Cell Autoimmunity

To the Editor: The analysis by Knip et al (Nov. 11 issue), 1 which suggests that dietary intervention through infant weaning to hydrolyzed formula has a long-lasting effect on markers of betacell autoimmunity, is flawed in that it has overestimated the evidence of benefit because of failure to adequately use the intention-to-treat principle. 2 First, children from whom follow-up samples were not obtained were excluded from the primary analysis of seroconversion to autoantibody positivity. Of the children who were excluded, diabetes (and presumably autoantibody positivity before clinical disease) developed in three in the treatment group versus none in the control group. Correct inclusion of these 3 children in an intention-to-treat protocol would minimize evidence of treatment effect, with the development of beta-cell autoimmunity in 11 of 113 infants randomly assigned to hydrolyzed formula (9.7%) and in 17 of 109 infants assigned to standard formula (15.6%). A second breach of the principle occurred by adjusting for the duration of exposure to the study formula. In so doing, the authors were able to invalidly “improve” the P value regarding the hazard of development of two or more markers of beta-cell autoimmunity between treatment groups from 0.12 to 0.07.

Infant feeding and the risk of type 1 diabetes

Type 1 diabetes is generally considered to be a chronic, immune-mediated disease with a subclinical prodrome during which beta cell autoimmunity becomes overt disease at a variable rate in genetically susceptible individuals. Accumulated evidence supports a critical role of environmental factors in its development. Prospective birth cohort studies show that the first signs of beta cell autoimmunity may be initiated during the first year of life. This implies that risk factors for beta cell autoimmunity and type 1 diabetes must be operative in infancy. Early nutrition provides essential exogenous exposures in that period. This article discusses the role of factors related to infant nutrition in the development of beta cell autoimmunity and type 1 diabetes and the potential mechanistic pathways involved. So far, no specific dietary factor has been shown to be an unequivocal risk factor for beta cell autoimmunity or type 1 diabetes, and there are a number of contradictory observations with regard to the effect of various foods. This may reflect geographic and cultural differences in infant-feeding practices. Most studies suggest that the early introduction of complex foreign proteins may be a risk factor for beta cell autoimmunity, and a pilot intervention trial has implied that weaning to a highly hydrolyzed formula may decrease the risk of beta cell autoimmunity. Lack of vitamin D supplementation and accelerated growth might increase the risk of type 1 diabetes. Additional work, which includes the application of modern approaches such as metabolomics and epigenomics, is needed to discern the contribution of dietary factors in infancy to the diabetic disease process.

Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes

Evidence for the role of infant feeding in the development of beta cell autoimmunity is inconsistent. We set out to study the effects of breastfeeding and of age at introduction of supplementary foods on the development of beta cell autoimmunity. A prospective birth cohort of 3,565 infants with HLA-DQB1-conferred susceptibility to type 1 diabetes was recruited between 1996 and 2001 from two university hospital areas in Finland. Blood samples were collected at 3- to 12-month intervals to measure antibodies against islet cells, insulin, glutamate dehydroxylase and islet antigen 2. The families kept a record on the age at introduction of new foods, and for each visit completed a structured dietary questionnaire. The endpoint was repeated positivity for islet cell antibodies together with at least one of the other three antibodies. The overall or exclusive duration of breastfeeding was not associated with the risk of developing the endpoint. An early age at introduction of fruits and berries (< or =4 months) was related to increased risk of developing positivity for the endpoint (hazard ratio [95% CI] for earliest tertile 2.02 [1.03-3.95] and for midtertile 1.97 [1.06-3.64] compared with latest tertile >4 months). Also, introducing roots between 3 and 3.9 months (midtertile) was related to increased risk of the endpoint (hazard ratio [95% CI] for the earliest tertile 1.04 [0.57-1.90] and for midtertile 1.82 [1.19-2.79] compared with latest tertile). These associations were independent of several putative socio-demographic and perinatal confounding factors. Our findings suggest that an early age at introduction of fruits and berries and roots associates independently with beta cell autoimmunity, contradicting earlier findings from smaller birth cohort studies.

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

The aim of this study was to explore the contribution of genetic factors to the emergence of beta-cell-specific humoral autoimmunity. We analysed the effect of HLA class II, insulin (INS; -23 HphI variant) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4 [+49 and CT60]) genes on the appearance of beta-cell-specific autoantibodies in a large population-based birth cohort recruited in Finland. Infants carrying increased risk HLA DQB1 genotypes were monitored for the appearance of autoantibodies (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies [IA-2A]). Those who developed beta-cell-specific autoantibodies were studied (n=574, mean follow-up time: 4.9 years; range 0.5-9.3). IAA emerged at a higher rate in children with the -23 HphI AA INS genotype than in those carrying AT or TT variants (hazard ratio 2.1, 95% CI 1.4-2.9, p<0.001). This effect of the INS locus was present in both HLA DQB1 risk groups. The appearance of IAA showed a strong association also with the HLA DRB1*0401 allele (hazard ratio 13.1, 95% CI 1.8-93.4, p<0.001). The development of IA-2A was also somewhat accelerated by the DRB1*0401 variant (p=0.03). Isolated ICA positivity was independent of the HLA and INS genotypes. None of the humoral immune markers showed association with the CTLA4 gene. The INS and the DRB1 loci appear to contribute to the pathogenesis of type 1 diabetes by initiating/modifying insulin-specific autoimmunity. The emergence of IAA represents a crucial step in the development of beta cell autoimmunity in young children, in whom the appearance of GADA and IA-2A is linked to IAA.

Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study.

Previous studies suggest that enterovirus infections may initiate and accelerate beta-cell damage years before the clinical manifestation of type 1 diabetes. We have now analyzed the role of enterovirus infections in the initiation of autoimmunity in children who have tested positive for diabetes-associated autoantibodies in a prospective study starting at birth (the Finnish Diabetes Prediction and Prevention Study). The frequency of enterovirus infections was studied using both serology and testing for the presence of enterovirus RNA in the sera of 21 children who developed and retained autoantibodies and in 104 control subjects chosen from the same study cohort and matched for the time of birth, sex, and HLA alleles determining genetic diabetes susceptibility. Sample intervals were taken as basic units of follow-up, to which the observed number of infections was adjusted. Enterovirus infections were detected in 26% of sample intervals in the case subjects and in 18% of the sample intervals in the control children (P = 0.03). A temporal relationship between enterovirus infections and the induction of autoimmunity was found; enterovirus infections were detected in 57% of the case subjects during a 6-month follow-up period preceding the first appearance of autoantibodies compared with 31% of the matched control children in the same age-group (odds ratio 3.7, 95% CI 1.2-11.4). The frequency of adenovirus infections did not differ between the patient and control groups. Our data imply that enterovirus infections are associated with the development of beta-cell autoimmunity and provide evidence for the role of enteroviruses in the initiation of beta-cell destruction.

Gut and the induction of immune tolerance in type 1 diabetes.

The origin of beta-cell specific autoimmunity is not known in Type 1 diabetes. Several studies of this disease in animal models indicate that the manifestation of autoimmune diabetes can be modified by factors which influence the gut immune system. Some indirect evidence from studies in patients with Type 1 diabetes also suggests that aberrant function of the gut immune system may be involved in the development of this disease. These studies have encouraged the search for treatments interfering with mucosal immunity for the prevention of Type 1 diabetes. Our understanding of the function of the gut immune system in humans is, however, limited and the use of drugs (e.g. oral antigens or immune adjuvants) which modify the function of the gut immune system may involve serious problems. In this review, the possible role of the gut immune system in the development of beta-cell autoimmunity and Type 1 diabetes is discussed with special reference to the putative therapeutic implications.