TY - JOUR
T1 - Coxsackie B4 virus infection of β cells and natural killer cell insulitis in recent-onset type 1 diabetic patients
AU - Dotta, Francesco
AU - Censini, Stefano
AU - Van Halteren, Astrid G.S.
AU - Marselli, Lorella
AU - Masini, Matilde
AU - Dionisi, Sabrina
AU - Mosca, Franco
AU - Boggi, Ugo
AU - Muda, Andrea Onetti
AU - Del Prato, Stefano
AU - Elliott, John F.
AU - Covacci, Antonello
AU - Rappuoli, Rino
AU - Roep, Bart O.
AU - Marchetti, Piero
PY - 2007/3/20
Y1 - 2007/3/20
N2 - Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic β cells. Several studies have suggested an association between Coxsackie enterovirus seroconversion and onset of disease. However, a direct link between β 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 β 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 β 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 β cells in patients with type 1 diabetes and that infection is associated with inflammation and functional impairment.
AB - Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic β cells. Several studies have suggested an association between Coxsackie enterovirus seroconversion and onset of disease. However, a direct link between β 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 β 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 β 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 β cells in patients with type 1 diabetes and that infection is associated with inflammation and functional impairment.
KW - Coxsackie B4 enterovirus
KW - Type 1 diabetes
UR - http://www.scopus.com/inward/record.url?scp=34247627376&partnerID=8YFLogxK
U2 - 10.1073/pnas.0700442104
DO - 10.1073/pnas.0700442104
M3 - Article
C2 - 17360338
AN - SCOPUS:34247627376
SN - 0027-8424
VL - 104
SP - 5115
EP - 5120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -