Specific Aim 1

Specific Aim 1

Identify novel and subgroup-associated islet autoantigens and therapeutic targets for T1D to innovate potential cures.

Specific Aim 1 – Year 2 Highlights

  • Advanced HLA typing and autoantibody analyses in Asian and comparator groups.
  • Expanded antibody discovery and immune-repertoire studies to better characterize T1D mechanisms in Asian populations.
  • Compare the autoantibody profile across T1D and T2D patients and determine similarity and differences.
  • Understand the underlying biology which is causing the elicitation of these autoantibodies in T1D patients which are missing in healthy controls.
  • Strengthened cross-laboratory collaboration across immunology, genetics, proteomics, and antigen discovery teams.

HLA-type Subjects in DIMC Endo Biorepository to Identify Diabetes-Susceptible HLA-types Among Asians with T1D – Retrospective vs Prospective Analysis

Principal Investigator and Collaborators: Everett Meyer, MD; Kent Jensen, PhD; David Maahs, MD, PhD, MA; Anna L. Gloyn, DPhil; Holden Maecker, PhD

Year 2 Highlights: This project advanced HLA characterization of Asian individuals with T1D and comparator groups using biorepository samples. The team completed a preliminary review draft and performed HLA typing on 180 subjects, including Asian T1D, Asian T2D, White T1D, Hispanic T1D, and additional comparator groups. This work supports a more detailed understanding of HLA patterns associated with diabetes susceptibility in Asian populations and helps build the foundation for ancestry-aware autoimmune diabetes research.

Looking Ahead: The team will complete the remaining review sections, compare HLA typing results with genomic array data, and further stratify HLA-A, HLA-B, HLA-DQ, and HLA-DR patterns by Asian subgroups.

Testing subjects in DIMC Endo Biorepository to determine whether Asians diagnosed with T1D or T2D are positive for Tetraspanin AutoAb

Principal Investigator and Collaborators: Everett Meyer, MD; Kent Jensen, PhD, Tobias Lanz, MD; David Maahs, MD, PhD, MA; Anna L. Gloyn, DPhil; Holden Maecker, PhD

Year 2 Highlights: Year 2 work continued testing biorepository samples for tetraspanin autoantibodies among Asian participants diagnosed with Type 1 or Type 2 diabetes. Preliminary findings showed positive reactivity in both T1D and T2D cohorts, suggesting that tetraspanin autoantibodies may help identify autoimmune mechanisms and possible diabetes misclassification among Asian patients. These results strengthen ADVANCE’s efforts to improve precision diagnosis and better distinguish diabetes subtypes in understudied Asian populations.

Looking Ahead: Next steps include correlating tetraspanin autoantibody results with HLA findings and other diabetes autoantibodies to more clearly characterize diabetes subtypes in Asian populations.

Auto-Antibody Discovery and Role of EBV in T1D among Asians in SF Bay Area

Principal Investigator and Collaborators: Bill Robinson, MD, PhD; Everett Meyer, MD

Year 2 Highlights: This continuing Aim 1 project remains focused on identifying novel autoantibody patterns and exploring the possible role of Epstein-Barr virus in T1D among Asian individuals in the San Francisco Bay Area. The project continued as part of the broader ADVANCE antibody discovery portfolio, linking immunology, autoantibody profiling, and subgroup-specific diabetes research. This project complements ongoing HLA, tetraspanin, and immune-repertoire studies by helping define immune signatures that may be distinct or enriched among Asian populations.

Looking Ahead: The next phase will clarify the detailed workplan and milestone timeline with the project team and align this effort with broader ADVANCE antibody discovery and manuscript development activities.

B & T Cell Receptor (BCR & TCR) Usage in T1D Among Asians in SF Bay Area

Principal Investigator and Collaborators: Holden Maecker, PhD; Everett Meyer, MD; Kent Jensen, PhD

Year 2 Highlights: Submission of TEMPUS RNA samples from more than 200 Asian, White, and Latinx participants for BCR/TCR repertoire analysis. Bulk BCR/TCR sequencing and single-cell RNA sequencing studies are underway to identify autoreactive B- and T-cell receptor patterns and novel beta-cell antigens associated with T1D across Asian and non-Asian populations. A manuscript writing group has also been established, supporting the translation of these immune-repertoire analyses into scientific outputs.

Looking Ahead: The team will complete BCR/TCR repertoire analyses, compare immune receptor patterns across Asian and non-Asian participants, obtain additional biorepository samples for sequencing, and prepare an abstract and manuscript on immune mechanisms contributing to T1D.

Identify novel and subgroup-associated islet autoantigens and therapeutic targets for T1D to innovate potential cures

Lead Postdoctoral Researcher: Shiva Pathak, PhD, MS

Year 2 Highlights: Building on earlier work examining genetic and immune differences in type 1 diabetes, the team advanced studies of HLA variation and islet autoantibodies across diverse populations. HLA typing was completed for 180 participants, including Asian, White, and Hispanic individuals with type 1 diabetes and additional comparison groups, creating an important foundation for investigating population-specific patterns of genetic risk and autoimmunity. The team also advanced a review examining HLA haplotypes and islet autoantibodies in Asian individuals with type 1 diabetes and strengthened collaborative efforts across the ADVANCE Specific Aim 1 Antibody Discovery Project Group. Together, these efforts are helping clarify how genetic susceptibility and autoimmune responses may differ across Asian populations and other groups.

Looking Ahead: The team will compare HLA-typing results with genomic array data, examine HLA patterns across East Asian, South Asian, and Southeast Asian subgroups, and further investigate relationships between genetic variation and islet autoantibody profiles. This work will contribute to broader collaborative efforts to identify population-specific immune mechanisms, novel autoantigens, and potential therapeutic targets for type 1 diabetes.

Antibody Discovery Project Group

Principal Investigator and Collaborators: Michael Snyder, PhD; Everett Meyer, MD; Holden Maecker, PhD; Kent Jensen, PhD; Anna Gloyn, DPhil; Daniel Panyard, PhD; Shiva Pathak, PhD, MS; Mahasish Shome, PhD

Year 2 Highlights: The Antibody Discovery Project Group continued advancing studies of diabetes-related autoantibodies, novel islet antigens, and immune mechanisms in Asian populations. The group coordinated age- and sex-matched healthy control collection, progressed T1D/T2D sample processing, and completed quality control and analysis on a subset of samples. Early analyses also identified strong antibody signals for novel targets. These efforts strengthen ADVANCE’s ability to discover immune markers that may improve diabetes classification, risk assessment, and future therapeutic target identification. We would like to verify if these autoantibodies are specific for race / ethnicity. In addition, we will dissect the data using age and biological sex to determine their possible influence.

Looking Ahead: The group will complete remaining sample processing and analyses, expand healthy control collection, evaluate associations with diabetes subtype and clinical characteristics, and advance promising antibody targets toward validation and future abstracts or manuscripts.