Enhanced levels of cow's milk antibodies in infancy in children who develop type 1 diabetes later in childhood

Abstract

Background: Early exposure to cow's milk (CM) proteins have been implicated in the pathogenesis of type 1 diabetes (T1D).

Objective: We analyzed the development of the humoral immune response to dietary CM proteins in early childhood and its relation to later T1D.

Subjects and methods: We studied a subgroup of 94 children randomized to be weaned to a CM-based infant formula in the trial to reduce insulin-dependent diabetes mellitus in the genetically at risk (TRIGR) pilot study. All subjects carried human leukocyte antigen-conferred T1D susceptibility and had an affected first-degree relative. After 7 years of follow-up, 8 subjects had progressed to T1D, 15 had at least one disease-associated autoantibody, and 71 remained autoantibody negative (controls). Immunoglobulin (Ig) G and IgA class antibodies to whole CM formula, beta-lactoglobulin (BLG), bovine serum albumin, and alpha-casein and IgG antibodies to bovine insulin (BI) were measured with enzyme-linked immunosorbent assays from sequential samples.

Results: The children with later T1D showed increased IgG levels to BLG from 3 to 18 months of age (p = 0.028) and enhanced IgA levels to CM formula at the age of 9 months (p = 0.022) compared with controls. In the children with an affected father or sibling, IgG antibodies to BI were higher in autoantibody-positive subjects than in autoantibody-negative subjects at 18 months of age (p = 0.022).

Conclusion: An enhanced humoral immune response to various CM proteins in infancy is seen in a subgroup of those children who later progress to T1D. Accordingly, a dysregulated immune response to oral antigens is an early event in the pathogenesis of T1D.

Fig. 1

Immunoglobulin A antibody levels to cow’s milk formula at the age of 9 months in children who later progressed to type 1 diabetes (T1D), children who developed at least one disease-associated autoantibody (AAB+) during 7 years follow-up, and autoantibody-negative subjects, that is, the control group. The horizontal lines represent median values and p values derived from the Mann–Whitney U test are shown in the figure. CM, cow’s milk; NS, not significant.

Fig. 2

Median levels of immunoglobulin G antibodies to beta-lactoglobulin (BLG) at the age of 0, 3, 6, 9, 12, 18, 24, and 36 months in children diagnosed with type 1 diabetes (■), children who developed at least one disease-associated antibody (□), and antibody-negative subjects, that is, the control group (▲). The IgG antibody levels to BLG were increased during the time period from 3 to 18 months of age among the children who later developed to T1D compared with the controls (comparison of the area under the curve; p = 0.028).

Fig. 3

Immunoglobulin A antibody levels to bovine serum albumin (BSA) at the age of 9 months in children who later progressed to type 1 diabetes (T1D), children who developed at least one disease-associated autoantibody (AAB+) during 7 years follow-up, and autoantibody-negative subjects, that is, the control group. The horizontal lines represent median values and p values derived from the Mann–Whitney U test are shown in the figure. NS, not significant.

Fig. 4

Immunoglobulin G antibody levels to bovine insulin (BI) at the age of 18 months in subjects with a diabetic father or sibling among children who developed at least one disease-associated autoantibody [type 1 diabetes (T1D) or AAB+] during 7 years follow-up and among autoantibody-negative children, that is, the control group. The horizontal lines represent median values and p values derived from the Mann–Whitney U test are shown in the figure. The children who later progressed to T1D are marked with an arrow.