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* 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
Children’s Hospital of Wisconsin Diabetes Center, Pediatric Endocrinology and Metabolism, Medical College of Wisconsin, Milwaukee WI 53226
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering Grant EB001421, National Institute of Allergy and Infectious Diseases Grant P01-AI-42380, General Clinical Research Centers Grant M01-RR00058, as well as Advancing a Healthier Wisconsin Initiative Grant 5520065, and The Children’s Hospital of Wisconsin Foundation.
2 Address correspondence and reprint requests to Dr. Martin J. Hessner, Department of Pediatrics, The Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail address: mhessner{at}mcw.edu
3 Abbreviations used in this paper: T1DM, type 1 diabetes mellitus; AR, at risk; FDR, false discovery rate; GAD, glutamic acid decarboxylase; HC, healthy control; IA2, protein tyrosine phosphatase-2; JRA, juvenile rheumatoid arthritis; LS, long standing; MDS, multiple dimensional scaling; qRT-PCR, quantitative RT-PCR; RO, recent onset.
4 The online version of this article contains supplemental material.
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