# Autoantibodies directed to islet cell surface antigens and their pathologic roles in type-1 diabetes

> **NIH NIH R56** · JOHNS HOPKINS UNIVERSITY · 2020 · $163,750

## Abstract

Islet autoantibodies (AAs) are reliable biomarkers of pancreatic autoimmunity. Serum AAs against four major
biochemical antigens (insulin, GAD, IA-2, and ZnT8) are routinely used in clinical research as key metrics for
diagnostics and prognostics in patients with type-1 diabetes (T1D), and for disease prediction in at-risk
individuals before T1D onset. Robust biochemical assays have been developed to detect AAs recognizing
soluble antigens or soluble domains of membrane-bound antigens. Detection of AAs to membrane-bound
antigens, however, is challenged by technical difficulties in adaption of their insoluble transmembrane domains
(TMD) to solution-based assay platforms. At present, we have no knowledge of the prevalence and first
appearance of AAs targeting any TMD antigens. Among the four major biochemical antigens, the islet-specific
ZnT8 is unique in having a major TMD that encompasses two thirds protein sequence in a full-length ZnT8. Our
recent works showed that ZnT8 is trafficked to the surface of pancreatic β-cells following insulin secretion, and
the surfaced TMD is highly antigenic, recognized by serum ZnT8 AAs in patients with T1D. These findings
suggest that the TMD in ZnT8 is a novel immunogenic domain for surfaced-targeted AAs, and its display on the
cell surface may promote antibody-mediated cytotoxicity contributing directly to β-cell autoimmune destruction.
To test these hypotheses, we will (i) validate AAs directed to the TMD of ZnT8 (TMDAs) in patients progressing
to T1D, and (ii) establish TMDAs as direct-targeting AAs, as such, bind directly to live pancreatic β cells to
modulate their functions and survival. The proposed research is expected to validate a completely new class of
AAs targeting a recently identified islet cell surface antigen, illuminating the roles of TMDAs in the natural history
of T1D (Aim 1) and disease pathogenesis (Aim 2). The knowledge gained will be translated to novel diagnostic
tools and potential therapeutic interventions.

## Key facts

- **NIH application ID:** 10161015
- **Project number:** 1R56DK123435-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Dax Fu
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $163,750
- **Award type:** 1
- **Project period:** 2020-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10161015

## Citation

> US National Institutes of Health, RePORTER application 10161015, Autoantibodies directed to islet cell surface antigens and their pathologic roles in type-1 diabetes (1R56DK123435-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10161015. Licensed CC0.

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