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Lynch, K.F.* ; Lee, H.S.* ; Törn, C.* ; Vehik, K.* ; Krischer, J.P.* ; Larsson, H.E.* ; Haller, M.J.* ; Hagopian, W.A.* ; Rewers, M.J.* ; She, J.X.* ; Simell, O.G.* ; Toppari, J.* ; Ziegler, A.-G. ; Akolkar, B.* ; Hyöty, H.* ; Bonifacio, E.* ; Lernmark, A.*

Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident beta-cell autoantibodies.

J. Autoimmun. 86, 93-103 (2018)

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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.

Abstract
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beta-cell autoantibodies against insulin (IAA), GAD65 (GADA) and IA-2 (IA-2A) precede onset of childhood type 1 diabetes (T1D). Incidence of the first appearing beta-cell autoantibodies peaks at a young age and is patterned by T1D-associated genes, suggesting an early environmental influence. Here, we tested if gestational infections and interactions with child's human leukocyte antigen (HLA) and non-HLA genes affected the appearance of the first beta-cell autoantibody. Singletons of mothers without diabetes (n = 7472) with T1D-associated HLA-DR-DQ genotypes were prospectively followed quarterly through the first 4 years of life, then semiannually until age 6 years, using standardized autoantibody analyses. Maternal infections during pregnancy were assessed via questionnaire 3-4.5 months post-delivery. Polymorphisms in twelve non-HLA genes associated with the first appearing beta-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing beta-cell autoantibody in younger children (n = 226, median age at seroconversion 1.8 years) and GADA (n = 212; 3.2 years) in children aged >= 2 years. Gestational infections were not associated with the first appearing beta-cell autoantibodies overall. However, gestational respiratory infections (G-RI) showed a consistent protective influence on IAA (HR 0.64, 95% CI 0.45-0.91) among CTLA4-(AG, GG) children (G-RI*CTLA4 interaction, p = 0.002). The predominant associations of HLA-DR-DQ4-8/8-4 with IAA and HLA-DR-DQ 3-2/3-2 with GADA were not observed if a G-RI was reported (G-RI*HLA-DR-DQ interaction, p = 0.03). The role of G-RI may depend on offspring HLA and CTLA-4 alleles and supports a bidirectional trigger for IAA or GADA as a first appearing beta-cell autoantibody in early life. (C) 2017 Elsevier Ltd. All rights reserved.

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