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Age-independent immune subtypes in Type 1 diabetes exhibit distinct post-onset progression rates and immunotherapeutic responses

ABSTRACT: Through analysis of >600 participants, we defined two immunologically distinct Type 1 diabetes subgroups that uniquely respond to immune intervention. Personalized prevention and treatment strategies for Type 1 diabetes (T1D), an autoimmune disease that targets the insulin-producing pancreatic β-cell, will require a deeper understanding of disease heterogeneity. We analyzed pre-intervention plasma samples, collected within 100 days of diagnosis, from 560 participants across six immunotherapy trials, using a bioassay in which plasma-induced transcription was measured in a well-controlled peripheral blood mononuclear cell population. Microarray profiling identified 2,854 transcripts exhibiting high variation in at least five of the six trials. Unsupervised analyses concordantly divided the participants into two age-independent subgroups. The observed signatures were not due to relapsing and remitting immune activity as subgroup assignments were conserved in longitudinal analysis of post-baseline samples. Phenotypic analyses and follow-up studies of an independent new-onset T1D cohort determined that subgroup 1 was enriched with participants possessing neutral or low-risk HLA haplotypes and included the youngest participants possessing the most rapid rate of C-peptide decline. This subgroup exhibited elevated plasma cytokine and chemokine levels, increased circulating CD4+ CD45RO+ memory T-cells, and a better therapeutic response to anti-CD20. Subgroup 2 was enriched with participants of Hispanic ancestry, individuals with insulin auto-antibody titers, elevated levels of plasma miR-155-5p and miR-409-3p, and a better therapeutic response to CTLA4-Ig. These analyses support the existence of immunologically distinct endotypes and the potential for biomarker-driven stratification for more targeted therapeutic interventions in T1D.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302205 | GEO | 2026/06/01

REPOSITORIES: GEO

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Age-independent immune subtypes in Type 1 diabetes exhibit distinct post-onset progression rates and immunotherapeutic responses

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