Mechanisms associated with Type 1 diabetes (T1D) development remain incompletely defined. Employing a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially IL-1 dependent, signatures associated with pre and recent onset (RO) T1D relative to unrelated healthy controls (uHC). To better understand inherited susceptibility in T1D families, we conducted cross-sectional and longitudinal analyses of healthy auto-antibody-negative (AA-) high HLA risk siblings (HRS, DR3 and/or DR4) and AA- low HLA risk siblings (LRS, non-DR3/non-DR4). Signatures, scored with a novel ontology-based algorithm, and confirmatory studies differentiated the RO T1D, uHC, HRS, and LRS plasma milieus. Relative to uHC, T1D family members exhibited an elevated inflammatory state, consistent with innate receptor ligation that was independent of HLA, AA, or disease status and included elevated plasma IL-1α, IL-12p40, CCL2, CCL3, and CCL4 levels. Longitudinally, signatures of T1D progressors exhibited increasing inflammatory bias. Conversely HRS possessing decreasing AA titers revealed emergence of an IL-10/TGF-β mediated regulatory state that paralleled temporal increases in peripheral activated CD4+/CD45RA-/FoxP3high regulatory T-cell frequencies. In AA- HRS, the familial innate inflammatory state was also temporally supplanted by immunoregulatory processes, suggesting a mechanism underlying the decline in T1D susceptibility with age.
- Received February 6, 2014.
- Accepted April 21, 2014.
- © 2014 by the American Diabetes Association.
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