Early-pregnancy cytokines in mothers to children developing multiple, persistent islet autoantibodies, type 1 diabetes, or both before 7 years of age.

PROBLEM: Increased levels of serum cytokines in early pregnancy may increase the risk of type 1 diabetes in the offspring. METHOD OF STUDY: Early-pregnancy (between 10 and 16 gestational weeks) serum samples from non-diabetic index mothers (n = 48) of children who developed islet autoimmunity, type 1 diabetes, or both before 7 years of age were analyzed for IFN-γ, IL-10, IL-12, IL-13, IL-1ß, IL-2, IL-4, IL-5, CXCL8, and TNF. Control mothers (n = 93) were matched for age, sampling date, and HLA-DQ genotypes. RESULTS: IFN-γ (P = 0.02) and IL-1ß (P = 0.04) were elevated in the index mothers. All cytokines except IL-4 were highly correlated (P < 0.0001). IFN-γ [OR 1.39 (1.04, 1.85), P = 0.026] and possibly IL-2 [OR 1.21 (0.99, 1.48), P = 0.057] in early pregnancy were associated with an increased risk of multiple, persistent islet autoantibodies, type 1 diabetes, or both before 7 years of age in the offspring. However, the statistical significance for IL-2 was lost in the logistic regression when adjusted for gestational length at delivery and parity. CONCLUSION: Increased Th1 cytokine levels during early pregnancy might contribute to an increased risk of islet autoimmunity, type 1 diabetes, or both in the offspring.

Early human pregnancy serum cytokine levels predict autoimmunity in offspring.

It is generally believed that pregnancy is mediated by a Th2 response, which includes cytokines that promote placental growth and are involved in inducing tolerance to the foetus. If the balance between Th1/and Th2-mediated cytokines is disrupted, systemic and local changes could predispose the foetus to future disease. Therefore, a shift in the Th1/Th2 balance during pregnancy, possibly caused by underlying environmental factors, could be associated with post-partum autoimmune disease in the offspring. Based on this presumption, we used celiac disease as a model to investigate whether autoimmunity is triggered in the foetus during early pregnancy, observed as changes in the mother's cytokine profile. Ten cytokines were measured by electro-chemi-luminescent multiplex ELISA in serum samples obtained from mothers during early pregnancy. Cases included women with children who had developed verified celiac disease before the age of 5, who were compared with other women as matched controls. We observed that 7 out of 10 cytokine levels were significantly increased in our case mothers when compared to controls. Five of these belonged to what is generally known as a Th1-mediated response (TNFα, IFNγ, IL-2, IL-1ß and IL-12) and two were Th2 cytokines (IL-13 and IL-10). However, the IL-10 cytokine is known to have features from both arms of the immune system. These results were confirmed in a logistic regression model where five out of the initial seven cytokines remained. This study suggests that increase in Th1 serum cytokines may be associated with celiac disease in offspring.

Seroconversion to islet autoantibodies between early pregnancy and delivery in non-diabetic mothers.

Islet autoantibodies are currently used to classify type 1 diabetes at diagnosis as they reflect the autoimmune pathogenesis of the disease. The presence of maternal autoantibodies reactive with pancreatic islet antigens is thought to increase the risk for type 1 diabetes in the offspring. The objective of this study was to determine seroconversion to islet autoantibodies in non-diabetic mothers during pregnancy. Screening of 33,682 mothers between September 2000 and August 2004 in the Diabetes Prediction in Skåne (DiPiS) study showed that at delivery, 242 non-diabetic mothers had increased titers of islet autoantibodies reactive with glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A) or insulin (IAA), alone or in combination. Control mothers (n=1419), who were islet autoantibody negative at delivery, were randomly selected and matched by age, parity and pregnancy sampling date. Mothers positive for GADA (92%), IA-2A (84%) or IAA (65%) at delivery had increased titers already evident in early pregnancy. Titers declined for GADA (p<0.0001), IA-2A (p<0.0001) and IAA (p<0.0001). Seroconversion during pregnancy was observed for GADA in 10 (8%), IA-2A in 3 (16%) and IAA in 37 (35%) mothers. It is concluded that non-diabetic mothers with islet autoantibodies at delivery had significantly higher titers during early pregnancy than at delivery. As the statistical power in the seroconverting mothers was insufficient, further studies are needed to determine if the risk for type 1 diabetes in the offspring differs between mothers who already had increased titers of islet autoantibodies during early pregnancy or acquired them during pregnancy.