Distinct cellular immune responses in children en route to type 1 diabetes with different first-appearing autoantibodies

• Published in: Nature communications 2024-05, Vol.15 (1), p.3810-3810, Article 3810
• Main Authors: Starskaia, Inna, Valta, Milla, Pietilä, Sami, Suomi, Tomi, Pahkuri, Sirpa, Kalim, Ubaid Ullah, Rasool, Omid, Rydgren, Emilie, Hyöty, Heikki, Knip, Mikael, Veijola, Riitta, Ilonen, Jorma, Toppari, Jorma, Lempainen, Johanna, Elo, Laura L., Lahesmaa, Riitta
• Format: Article
• Language: English
• Subjects: 49/31; 631/250/38; 692/163/2743/137/1418; Adolescent; Antibodies; Autoantibodies; Autoantibodies - blood; Autoantibodies - immunology; Child; Child, Preschool; Children; Cytometry; Depth profiling; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - immunology; Disease Progression; Female; Glutamate decarboxylase; Glutamate Decarboxylase - immunology; Glutamic acid; Heterogeneity; Humanities and Social Sciences; Humans; Immune response; Immune response (cell-mediated); Immune system; Immunity, Cellular; Insulin; Insulin - immunology; Islets of Langerhans - immunology; Killer Cells, Natural - immunology; Leukocytes, Mononuclear - immunology; Male; multidisciplinary; Natural killer cells; Peripheral blood; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47918-w

Previous studies have revealed heterogeneity in the progression to clinical type 1 diabetes in children who develop islet-specific antibodies either to insulin (IAA) or glutamic acid decarboxylase (GADA) as the first autoantibodies. Here, we test the hypothesis that children who later develop clinical disease have different early immune responses, depending on the type of the first autoantibody to appear (GADA-first or IAA-first). We use mass cytometry for deep immune profiling of peripheral blood mononuclear cell samples longitudinally collected from children who later progressed to clinical disease (IAA-first, GADA-first, ≥2 autoantibodies first groups) and matched for age, sex, and HLA controls who did not, as part of the Type 1 Diabetes Prediction and Prevention study. We identify differences in immune cell composition of children who later develop disease depending on the type of autoantibodies that appear first. Notably, we observe an increase in CD161 expression in natural killer cells of children with ≥2 autoantibodies and validate this in an independent cohort. The results highlight the importance of endotype-specific analyses and are likely to contribute to our understanding of pathogenic mechanisms underlying type 1 diabetes development. Previous studies have reported heterogeneity in the progression to clinical type 1 diabetes in children who develop either insulin- or glutamic acid decarboxylase-specific antibodies as their first autoantibodies. Here, the authors show that children who later develop disease have distinct characteristics in early immune responses, which are dependent on the type of autoantibodies that appear first.