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Aims/hypothesis <p>The development of improved prevention and treatment strategies for type 1 diabetes requires a deeper understanding of its heterogeneity. Our aim was to measure immunological heterogeneity among individuals with new-onset type 1 diabetes using plasma-induced transcription, bioinformatics tools and targeted follow-up analyses.</p> Methods <p>We analysed pre-intervention samples from 560 participants across six immunotherapy trials, using a plasma-induced transcriptional bioassay and a standardised reporter cell population.</p> Results <p>Transcriptomic profiling at baseline identified 2854 transcripts with high variation in at least five trials. Unsupervised clustering divided the participants into two subgroups that did not differ in mean age and whose classifications remained stable in post-baseline longitudinal samples, suggesting that subgroup assignments were not driven by transient relapsing and remitting immune activity (<i>p</i>=1.4&#xa0;×&#xa0;10<sup>−14</sup>). Phenotypic analyses and an independent new-onset type 1 diabetes cohort found subgroup 1 enriched for participants with neutral or low-risk HLA haplotypes and the youngest participants possessing the most rapid rate of C-peptide decline (<i>p</i>&lt;0.05). This subgroup showed elevated plasma cytokine and chemokine levels, increased circulating CD4<sup>+</sup>CXCR3<sup>+</sup>CCR6<sup>−</sup> Th1 T cells (<i>p</i>&lt;0.05) and better therapeutic responses to anti-CD20. Subgroup 2 was enriched for individuals possessing insulin autoantibody titres, higher plasma miR-155-5p and miR-409-3p (<i>p</i>&lt;0.05) and a better therapeutic response to CTLA4-Ig that was linked to a greater reduction in CD4<sup>+</sup>CD45RO<sup>+</sup>CD62L<sup>+</sup> central memory T cells (<i>p</i>=8.1&#xa0;×&#xa0;10<sup>−5</sup>) and retention of regulatory T cells (<i>p</i>=0.02).</p> Conclusions/interpretation <p>These findings support the existence of immunologically distinct type 1 diabetes subgroups and the possibility of future targeted therapeutic interventions.</p> Data availability <p>All microarray gene expression data files have been deposited at The National Center for Biotechnology Information Gene Expression Omnibus (accession no. GSE302205).</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Amina Bedrat,
  • Nathan A. Truchan,
  • Tarun Pant,
  • Shuang Jia,
  • Mark F. Roethle,
  • Yi-Guang Chen,
  • Chien-Wei Lin,
  • Martin J. Hessner

摘要

Aims/hypothesis

The development of improved prevention and treatment strategies for type 1 diabetes requires a deeper understanding of its heterogeneity. Our aim was to measure immunological heterogeneity among individuals with new-onset type 1 diabetes using plasma-induced transcription, bioinformatics tools and targeted follow-up analyses.

Methods

We analysed pre-intervention samples from 560 participants across six immunotherapy trials, using a plasma-induced transcriptional bioassay and a standardised reporter cell population.

Results

Transcriptomic profiling at baseline identified 2854 transcripts with high variation in at least five trials. Unsupervised clustering divided the participants into two subgroups that did not differ in mean age and whose classifications remained stable in post-baseline longitudinal samples, suggesting that subgroup assignments were not driven by transient relapsing and remitting immune activity (p=1.4 × 10−14). Phenotypic analyses and an independent new-onset type 1 diabetes cohort found subgroup 1 enriched for participants with neutral or low-risk HLA haplotypes and the youngest participants possessing the most rapid rate of C-peptide decline (p<0.05). This subgroup showed elevated plasma cytokine and chemokine levels, increased circulating CD4+CXCR3+CCR6− Th1 T cells (p<0.05) and better therapeutic responses to anti-CD20. Subgroup 2 was enriched for individuals possessing insulin autoantibody titres, higher plasma miR-155-5p and miR-409-3p (p<0.05) and a better therapeutic response to CTLA4-Ig that was linked to a greater reduction in CD4+CD45RO+CD62L+ central memory T cells (p=8.1 × 10−5) and retention of regulatory T cells (p=0.02).

Conclusions/interpretation

These findings support the existence of immunologically distinct type 1 diabetes subgroups and the possibility of future targeted therapeutic interventions.

Data availability

All microarray gene expression data files have been deposited at The National Center for Biotechnology Information Gene Expression Omnibus (accession no. GSE302205).

Graphical Abstract