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PMID: 17360338 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 12 ·2007-03-20 ·Pages 5115-20

Dotta F, Censini S, van Halteren AG, Marselli L, Masini M, Dionisi S, Mosca F, Boggi U, Muda AO, Del Prato S, Elliott JF, Covacci A, Rappuoli R, Roep BO, Marchetti P

Abstract

Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic beta cells. Several studies have suggested an association between Coxsackie enterovirus seroconversion and onset of disease. However, a direct link between beta cell viral infection and islet inflammation has not been established. We analyzed pancreatic tissue from six type 1 diabetic and 26 control organ donors. Immunohistochemical, electron microscopy, whole-genome ex vivo nucleotide sequencing, cell culture, and immunological studies demonstrated Coxsackie B4 enterovirus in specimens from three of the six diabetic patients. Infection was specific of beta cells, which showed nondestructive islet inflammation mediated mainly by natural killer cells. Islets from enterovirus-positive samples displayed reduced insulin secretion in response to glucose and other secretagogues. In addition, virus extracted from positive islets was able to infect beta cells from human islets of nondiabetic donors, causing viral inclusions and signs of pyknosis. None of the control organ donors showed signs of viral infection. These studies provide direct evidence that enterovirus can infect beta cells in patients with type 1 diabetes and that infection is associated with inflammation and functional impairment.

MeSH Terms
Adolescent Adult Autoimmunity/immunology Child, Preschool Coxsackievirus Infections/pathology Diabetes Mellitus, Type 1/virology Enterovirus/isolation & purification,physiology Female Glucose/metabolism Humans Inflammation Insulin/metabolism Insulin Secretion Insulin-Secreting Cells/pathology,ultrastructure,virology Interleukin-10/metabolism Killer Cells, Natural/pathology Male Middle Aged Molecular Sequence Data T-Lymphocytes/immunology Transplantation, Homologous Tumor Necrosis Factor-alpha/metabolism Viral Proteins/metabolism
Chemicals
Insulin Tumor Necrosis Factor-alpha Viral Proteins Interleukin-10 Glucose
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Dotta Francesco
Department of Internal Medicine, Endocrine and Metabolic Sciences, and Biochemistry, University of Siena, 53100 Siena, Italy.
Censini Stefano
van Halteren Astrid G S
Marselli Lorella
Masini Matilde
Dionisi Sabrina
Mosca Franco
Boggi Ugo
Muda Andrea Onetti
Del Prato Stefano
Elliott John F
Covacci Antonello
Rappuoli Rino
Roep Bart O
Marchetti Piero
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0700442104
Published
2007-03-20
Epub
2007-00-14
Pages
5115-20
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1829272
Subset
IM
Databases
GENBANK
DQ480420
External Links
PubMed source DOI: 10.1073/pnas.0700442104 PMC Full Text View journal details
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