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Identification of a Molecular Signature in Human Type 1 Diabetes Mellitus Using Serum and Functional Genomics

Xujing Wang, Shuang Jia, Rhonda Geoffrey, Ramin Alemzadeh, Soumitra Ghosh and Martin J. Hessner
J Immunol February 1, 2008, 180 (3) 1929-1937; DOI: https://doi.org/10.4049/jimmunol.180.3.1929
Xujing Wang
*Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at Medical College of Wisconsin and Children’s Research Institute of Children’s Hospital of Wisconsin,
†Human and Molecular Genetics Center, Medical College of Wisconsin, and
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Shuang Jia
*Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at Medical College of Wisconsin and Children’s Research Institute of Children’s Hospital of Wisconsin,
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Rhonda Geoffrey
*Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at Medical College of Wisconsin and Children’s Research Institute of Children’s Hospital of Wisconsin,
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Ramin Alemzadeh
‡Children’s Hospital of Wisconsin Diabetes Center, Pediatric Endocrinology and Metabolism, Medical College of Wisconsin, Milwaukee WI 53226
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Soumitra Ghosh
*Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at Medical College of Wisconsin and Children’s Research Institute of Children’s Hospital of Wisconsin,
†Human and Molecular Genetics Center, Medical College of Wisconsin, and
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Martin J. Hessner
*Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at Medical College of Wisconsin and Children’s Research Institute of Children’s Hospital of Wisconsin,
†Human and Molecular Genetics Center, Medical College of Wisconsin, and
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Abstract

Understanding active proinflammatory mechanisms at and before type 1 diabetes mellitus (T1DM) onset is hindered in humans, given that the relevant tissues are inaccessible and pancreatic immune responses are difficult to measure in the periphery by traditional approaches. Therefore, we investigated the use of a sensitive and comprehensive genomics strategy to investigate the presence of proinflammatory factors in serum. The sera of recent onset diabetes patients (n = 15, 12 possessing and 3 lacking islet cell autoantibodies), long-standing diabetes patients (n = 12), “at risk” siblings of diabetes patients (n = 9), and healthy controls (n = 12) were used to induce gene expression in unrelated, healthy PBMC. After culture, gene expression was measured with microarrays and normalized expression data were subjected to hierarchical clustering and multidimensional scaling. All recent onset sera induced an expression signature (192 UniGenes; fold change: >1.5, p < 0.01; false discovery rate: <0.01) that included IL-1 cytokine family members and chemokines involved in monocyte/macrophage and neutrophil chemotaxis, as well as numerous receptors and signaling molecules. This molecular signature was not induced with the sera of healthy controls or long standing diabetes patients, where longitudinal analysis of “at risk” siblings (n = 3) before and after onset support the hypothesis that the signature emerges years before onset. This study supports prior investigations of serum that reflect disease processes associated with progression to T1DM. Identification of unique inflammatory mediators may improve disease prediction beyond current islet autoantibodies. Furthermore, proinflammatory serum markers may be used as inclusion criteria or endpoint measures in clinical trials aimed at preventing T1DM.

  • Received August 16, 2007.
  • Accepted November 15, 2007.
  • Copyright © 2008 by The American Association of Immunologists
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The Journal of Immunology: 180 (3)
The Journal of Immunology
Vol. 180, Issue 3
1 Feb 2008
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Identification of a Molecular Signature in Human Type 1 Diabetes Mellitus Using Serum and Functional Genomics
Xujing Wang, Shuang Jia, Rhonda Geoffrey, Ramin Alemzadeh, Soumitra Ghosh, Martin J. Hessner
The Journal of Immunology February 1, 2008, 180 (3) 1929-1937; DOI: 10.4049/jimmunol.180.3.1929

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Identification of a Molecular Signature in Human Type 1 Diabetes Mellitus Using Serum and Functional Genomics
Xujing Wang, Shuang Jia, Rhonda Geoffrey, Ramin Alemzadeh, Soumitra Ghosh, Martin J. Hessner
The Journal of Immunology February 1, 2008, 180 (3) 1929-1937; DOI: 10.4049/jimmunol.180.3.1929
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