Abstract
BackgroundInfant dietary exposures have been linked to type 1 diabetes (T1D) development. IgG4 antibody responses to food antigens are associated with food intolerances but have not been explored prospectively in the period preceding T1D.MethodsUsing a case-cohort design, IgG4 antibodies to ß-lactoglobulin, gluten, and ovalbumin were measured in plasma collected annually from 260 DAISY participants. Of those, 77 developed islet autoimmunity (IA), defined as positive for either insulin, GAD65 or IA-2 autoantibodies on two consecutive visits, and 22 developed T1D.ResultsIn mixed model analysis adjusting for HLA-DR status, T1D family history, age and ethnicity, higher ß-lactoglobulin IgG4 concentrations were associated with shorter breastfeeding duration (beta = −0.03, 95% Confidence Interval: −0.05, −0.006) and earlier first cow’s milk exposure (beta = −0.04, 95% Confidence Interval: −0.08, 0.00). Higher gluten IgG4 was associated with older age at gluten introduction (beta = 0.06, 95% Confidence Interval: 0.00, 0.13). In proportional hazards analysis adjusting for HLA-DR status, T1D family history and ethnicity, IgG4 against individual or multiple dietary antigens throughout childhood were not associated with IA. In addition, mean antigen-specific IgG4 concentrations in infancy (age <2 years) were not associated with risk of IA nor progression to T1D. Higher ovalbumin IgG4 at first IA positive visit was marginally associated with progression to T1D (Hazard Ratio: 1.39, 95% Confidence Interval: 1.00, 1.92).ConclusionWe found no association between the IgG4 response to β-lactoglobulin, gluten, and the development of either IA or T1D. The association between higher ovalbumin and progression to T1D in children with IA should be explored in other populations.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease preceded by a period of sub-clinical islet autoimmunity (IA) [1]
In order to test the hypothesis that a generalized antigenic response may be associated with IA and progression to type 1 diabetes (T1D), we designed a composite measure of antigenic response (‘quartile rank of dietary antibodies’), in which concentrations of each IgG4 were divided into quartiles, ranked 1 (‘low’) through 4 (‘high’), and summed for each clinic visit We examined whether mean IgG4 concentrations prior to age 2 years were associated with risk of developing IA and T1D
Correlations between Dietary Antibodies In the representative sub-cohort, concentrations of IgG4 antibodies to ß-lactoglobulin, gluten, and ovalbumin were correlated with each other (ß-lactoglobulin and gluten: Spearman’s rho 0.50, p,0.0001; ß-lactoglobulin and ovalbumin: Spearman’s rho = 0.44, p,0.0001; Gluten and ovalbumin: Spearman’s rho = 0.63, p,0.0001)
Summary
Type 1 diabetes (T1D) is an autoimmune disease preceded by a period of sub-clinical islet autoimmunity (IA) [1]. Increased IA risk has been associated with shorter breastfeeding duration and earlier introduction to cow’s milk formula in some studies [2,3,4] but not others [5,6,7,8,9,10]. When infants are exposed to foods other than breast milk, dietary antigens may cross the intestinal barrier and trigger a mucosal immune response [13]. Increased intestinal permeability has been found in patients both prior to [14] and following the development of T1D [14,15,16,17,18]. Infant dietary exposures have been linked to type 1 diabetes (T1D) development. IgG4 antibody responses to food antigens are associated with food intolerances but have not been explored prospectively in the period preceding T1D
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