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Selective Autoantibody Production against CCL3 Is Associated with Human Type 1 Diabetes Mellitus and Serves As a Novel Biomarker for Its Diagnosis¹

Naim Shehadeh^,, Shirly Pollack, Gizi Wildbaum^*,, Yaniv Zohar^*,, Itay Shafat, Reem Makhoul, Essam Daod, Fahed Hakim, Rina Perlman and Nathan Karin^2,*,,

^* Department of Immunology, Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

We have recently demonstrated that patients suffering from chronic autoimmune diseases develop an autoantibody response against key mediators that participate in the initiation and progression of these diseases. In this paper, we show that patients with type 1 diabetes mellitus (T1DM), but not those suffering from several other inflammatory autoimmune diseases, display a selective autoantibody titer to a single CC chemokine named CCL3. From the diagnostic point we show that this response could be used as a biomarker for diagnosis of T1DM, a disease that is currently diagnosed by autoantibodies to competitive anti-insulin Abs, islet cell Abs, and glutamic acid decarboxylase Abs. We show that our currently suggested biomarker is more reliable than each of the above alone, including diagnosis of T1DM at its preclinical stage, and could therefore be used as a novel way for diagnosis of T1DM. These Abs were found to be neutralizing Abs. It is possible, though hard to prove, that these Abs participate in the natural regulation of the human disease. Hence, it has previously been shown by others that selective neutralization of CCL3 suppresses T1DM in NOD mice. Theses results together with ours suggest CCL3 as a preferential target for therapy of 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 The study was supported by the Israel Science Foundation and by a research grant of Micro-Medic (Israel).

² Address correspondence and reprint requests to Dr. Nathan Karin, Bruce Rappaport Faculty of Medicine, Technion, P.O.B. 9697, Haifa 31096, Israel. E-mail address: nkarin{at}tx.technion.ac.il

³ Abbreviations used in this paper: RA, rheumatoid arthritis; CF, cystic fibrosis; CIAA, competitive anti-insulin Ab; GAD, glutamic acid decarboxylase; ICA, islet cell Ab; JRA, juvenile RA; ROC, receiver operating characteristic; T1DM, type 1 diabetes mellitus.