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

J Autoimmun. 2018 Jan;86:93-103. doi: 10.1016/j.jaut.2017.09.005. Epub 2017 Sep 21.


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.

Keywords: Autoimmune diabetes; Autoimmunity; Glutamic acid decarboxylase; HLA; IA-2; Insulin; Type 1 diabetes; β-cell autoantibodies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Autoantibodies / metabolism
  • CTLA-4 Antigen / metabolism*
  • Female
  • Gestational Age
  • Glutamate Decarboxylase / immunology
  • HLA-DQ Antigens / genetics
  • HLA-DQ Antigens / metabolism
  • HLA-DR Antigens / genetics
  • HLA-DR Antigens / metabolism
  • Humans
  • Infant
  • Insulin / immunology
  • Insulin-Secreting Cells / immunology*
  • Male
  • Polymorphism, Genetic
  • Pregnancy
  • Prenatal Exposure Delayed Effects / epidemiology
  • Prenatal Exposure Delayed Effects / immunology*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / immunology
  • Respiratory Tract Infections / epidemiology
  • Respiratory Tract Infections / immunology*


  • Autoantibodies
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • HLA-DQ Antigens
  • HLA-DR Antigens
  • Insulin
  • PTPRN protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2