Molecular signatures differentiate immune states in type 1 diabetic families.
Mechanisms associated with type 1 diabetes (T1D) development remain incompletely defined. Using a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially interleukin (IL)-1-dependent signatures associated with preonset and recent onset (RO) T1D relative to unrelated healthy control subjects (uHC). To better understand inherited susceptibility in T1D families, we conducted cross-sectional and longitudinal analyses of healthy autoantibody-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/transforming growth factor-β-mediated regulatory state that paralleled temporal increases in peripheral activated CD4(+)/CD45RA(-)/FoxP3(high) regulatory T-cell frequencies. In AA(-) HRS, the familial innate inflammatory state also was temporally supplanted by immunoregulatory processes, suggesting a mechanism underlying the decline in T1D susceptibility with age.
The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI.
Yi-Guang
YG
Chen
The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI.
Susanne M
SM
Cabrera
The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI.
Shuang
S
Jia
The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI.
Mary L
ML
Kaldunski
The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI.
Joanna
J
Kramer
Department of Mathematical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI.
Sami
S
Cheong
The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI.
Rhonda
R
Geoffrey
The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI.
Mark F
MF
Roethle
Flow Cytometry and Cell Separation Facility, Bindley Bioscience Center, Purdue University, West Lafayette, IN.
Jeffrey E
JE
Woodliff
Diabetes Research Program, Benaroya Research Institute, Seattle, WA.
Carla J
CJ
Greenbaum
Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Xujing
X
Wang
The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI mhessner@mcw.edu.
Martin J
MJ
Hessner
D000293:Adolescent; D000328:Adult; D018932:Chemokine CCL2 / Q000097:blood; D054405:Chemokine CCL3 / Q000097:blood; D054407:Chemokine CCL4 / Q000097:blood; D002648:Child; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D053762:Interleukin-12 Subunit p40 / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D055815:Young Adult
D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D007375:Interleukin-1; D053762:Interleukin-12 Subunit p40; D016753:Interleukin-10