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

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β-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 β-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 β-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 β-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing β-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 β-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-DQ 4-8/8-4 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 β-cell autoantibody in early life.


  • Kristian F. Lynch
  • Hye-Seung Lee
  • Carina Törn
  • Kendra Vehik
  • Jeffrey P. Krischer
  • Helena Elding Larsson
  • Michael J Haller
  • William A. Hagopian
  • Marian J. Rewers
  • Jin-Xiong She
  • Olli G Simell
  • Jorma Toppari
  • Anette G. Ziegler
  • Beena Akolkar
  • Heikki Hyöty
  • Ezio Bonifacio
  • Åke Lernmark
  • TEDDY Study Group
External organisations
  • University of South Florida
  • Skåne University Hospital
  • Florida Museum Natural History
  • Pacific Northwest Diabetes Research Institute
  • University of Colorado
  • Turku University Hospital
  • University of Turku
  • Helmholtz Zentrum München
  • Klinikum rechts der Isar
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • Augusta University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes


  • Autoimmune diabetes, Autoimmunity, Glutamic acid decarboxylase, HLA, IA-2, Insulin, Type 1 diabetes, β-cell autoantibodies
Original languageEnglish
Pages (from-to)93-103
JournalJournal of Autoimmunity
Early online date2017
Publication statusPublished - 2018
Publication categoryResearch