An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood

Abstract

Islet autoimmunity develops before clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for presymptomatic type 1 diabetes. RESEARCH DESIGN AND METHODSThe Environmental Determinants of Diabetes in the Young study prospectively monitored 8,556 genetically at-risk children at 3-to 6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. RESULTSThe 5-year risk of developing multiple islet autoantibodies was 4.3% (95% CI 3.8-4.7) at 7.5 months of age and declined to 1.1% (95% CI 0.8-1.3) at a landmark age of 6.25 years (P < 0.0001). Risk decline was slight or absent in single insulin and GAD autoantibody phenotypes. The influence of sex, HLA, and other susceptibility genes on risk subsided with increasing age and was abrogated by age 6 years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5-7 years of age. CONCLUSIONSThe risk of developing islet autoimmunity declines exponentially with age, and the influence of major genetic factors on this risk is limited to the first few years of life.Age is a modulator of autoimmune diseases (1). Most autoimmune diseases show periods of high and low incidence, and these differences are likely to have an etiological basis. Type 1 diabetes is an autoimmune disease in which the presymptomatic stage is defined by the presence of autoantibodies against multiple islet autoantigens (2). Most children with multiple islet autoantibodies progress to clinical type 1 diabetes (3). The peak incidence of the development of islet autoantibodies occurs in the first years of life (4-6). This early peak also indicates that the risk of developing islet autoantibodies attenuates with age and that age influences the child's risk for developing islet autoantibodies, as demonstrated in relatives of patients with type 1 diabetes (7).

Probiotic normalization of systemic inflammation in siblings of type 1 diabetes patients: an open-label pilot study

“…Figure 5 models how a modern low-fiber diet and associated proinflammatory microbiota may impair temporal induction of counter regulation in individuals with an inherited hyper-responsiveness to innate stimuli. Under either illustrated scenario, genetically at-risk younger children have a higher level of baseline inflammation and are more susceptible to tolerance breaking inflammatory excursions, consistent with (1) the age-related decline in the risk of multiple antibody seroconversion during childhood 68 , and (2) the commonly observed pediatric onset of T1D. In the absence of a high fiber diet and protective microbiota, evidence suggests that the intestinal mucus barrier can be compromised 69 , promoting bacterial translocation and systemic inflammation, while impairing Treg differentiation and proliferation.…”

Preventing type 1 diabetes in childhood

“…However, it is important to note that this will miss cases presenting before screening, cases that seroconvert after screening, and will identify some children who are "at risk" by being single autoantibody positive but probably will not progress. Recent data from the The Environmental Determinants of Diabetes in the Young (TEDDY) study suggest a single screen for multiple islet autoantibodies between the ages of 3 and 4 years has a near 40% sensitivity (with >90% specificity) for T1D presenting before the age of 12, with a risk of T1D within the next 5 years of 50-60% [22]. A solution to increase the sensitivity of screening is to include a second autoantibody screen at a later stage.…”

Supplementation withBifidobacterium longumsubspeciesinfantisEVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol

“…(3) Children who have the T1D susceptible INS AA genotype versus the remainder; (4) Sex; (5) Caesarean section versus vaginal birth; (6) body mass index at age 1 year as tertiles and ( 7) Genetic risk score tertiles.…”