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

• Published in: Journal of autoimmunity Vol. 86; pp. 93 - 103
• Main Authors: Lynch, Kristian F., Lee, Hye-Seung, Törn, Carina, Vehik, Kendra, Krischer, Jeffrey P., Larsson, Helena Elding, Haller, Michael J., Hagopian, William A., Rewers, Marian J., She, Jin-Xiong, Simell, Olli G., Toppari, Jorma, Ziegler, Anette-G., Akolkar, Beena, Hyöty, Heikki, Bonifacio, Ezio, Lernmark, Åke
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-01-2018
• Subjects: Autoantibodies - metabolism; Autoimmune diabetes; Autoimmunity; Clinical Medicine; CTLA-4 Antigen - metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Gestational Age; Glutamate Decarboxylase - immunology; Glutamic acid decarboxylase; HLA; HLA-DQ Antigens - genetics; HLA-DQ Antigens - metabolism; HLA-DR Antigens - genetics; HLA-DR Antigens - metabolism; Humans; IA-2; Infant; Insulin; Insulin - immunology; Insulin-Secreting Cells - immunology; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; 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; Type 1 diabetes; β-cell autoantibodies; Autoimmunity; Type 1 diabetes; β-cell autoantibodies; Autoimmune diabetes; Glutamic acid decarboxylase; HLA; Insulin; IA-2
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2017.09.005

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.
•The first β-cell autoantibody to appear in children depends on T1D-associated genes.•IAA as first appears in younger children, GADA-first in children older than 2 years.•Gestational respiratory infections (G-RI) protective of IAA-first among CTLA4-G children.•Strong HLA association with IAA-first and GADA-first not observed if a G-RI reported.•G-RI role in early life depends on offspring HLA and CTLA-4 alleles.