Enterovirus Infection, CXC Chemokine Ligand 10 (CXCL10), and CXCR3 Circuit
A Mechanism of Accelerated β-Cell Failure in Fulminant Type 1 Diabetes
- Shoichiro Tanaka1,
- Yoriko Nishida1,
- Kaoru Aida1,
- Taro Maruyama2,
- Akira Shimada3,
- Masako Suzuki4,
- Hiroki Shimura1,
- Soichi Takizawa1,
- Masashi Takahashi1,
- Daiichiro Akiyama1,
- Sayaka Arai-Yamashita1,
- Fumihiko Furuya1,
- Akio Kawaguchi1,
- Masahiro Kaneshige1,
- Ryohei Katoh5,
- Toyoshi Endo1 and
- Tetsuro Kobayashi1
- 1Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan;
- 2Department of Internal Medicine, Saitama Social Insurance Hospital, Saitama, Japan;
- 3Department of Internal Medicine, Keio University, Tokyo, Japan;
- 4Department of Pathology, Sayama Hospital, Saitama, Japan;
- 5Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
- Corresponding author: Tetsuro Kobayashi, tetsurou{at}yamanashi.ac.jp.
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S.Tan., Y.N., and K.A. contributed equally to this article.
Abstract
OBJECTIVE Fulminant type 1 diabetes is characterized by the rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetes complications. Causative mechanisms for accelerated β-cell failure are unclear.
RESEARCH DESIGN AND METHODS Subjects comprised three autopsied patients who died from diabetic ketoacidosis within 2–5 days after onset of fulminant type 1 diabetes. We examined islet cell status, including the presence of enterovirus and chemokine/cytokine/major histocompatibility complex (MHC) expressions in the pancreata using immunohistochemical analyses and RT-PCR.
RESULTS Immunohistochemical analysis revealed the presence of enterovirus-capsid protein in all three affected pancreata. Extensive infiltration of CXCR3 receptor–bearing T-cells and macrophages into islets was observed. Dendritic cells were stained in and around the islets. Specifically, interferon-γ and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including β-cells and α-cells. No CXCL10 was expressed in exocrine pancreas. Serum levels of CXCL10 were increased. Expression of MHC class II and hyperexpression of MHC class I was observed in some islet cells.
CONCLUSIONS These results strongly suggest the presence of a circuit for the destruction of β-cells in fulminant type 1 diabetes. Enterovirus infection of the pancreas initiates coexpression of interferon-γ and CXCL10 in β-cells. CXCL10 secreted from β-cells activates and attracts autoreactive T-cells and macrophages to the islets via CXCR3. These infiltrating autoreactive T-cells and macrophages release inflammatory cytokines including interferon-γ in the islets, not only damaging β-cells but also accelerating CXCL10 generation in residual β-cells and thus further activating cell-mediated autoimmunity until all β-cells have been destroyed.
Footnotes
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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.
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- Received January 21, 2009.
- Accepted July 7, 2009.
- © 2009 by the American Diabetes Association.
