A dual role for interferon-gamma in the pathogenesis of Sjogren's syndrome-like autoimmune exocrinopathy in the nonobese diabetic mouse.
Sjogren's syndrome-like autoimmune exocrinopathy (AEC) in the nonobese diabetic (NOD) mouse progresses from a preimmune phase to an immune phase, resulting in dry mouth and/or dry eyes. In the present study, the impact of the prototypical T-helper type 1 cytokine, interferon-gamma (IFN-gamma), on the onset of AEC was investigated using both the IFN-gamma and the IFN-gamma receptor gene knockout mice, NOD.IFN-gamma(-/-) and NOD.IFN-gammaR(-/-), respectively. Neither the NOD.IFN-gamma(-/-) nor the NOD.IFN-gammaR(-/-) mice exhibited increased acinar cell apoptosis and abnormal salivary protein expression, typically observed in parental NOD mice prior to disease. Without these preimmune phase abnormalities, NOD.IFN-gamma(-/-) and NOD.IFN-gammaR(-/-) mice showed no subsequent autoimmune responses against the salivary glands at 20 weeks. Interestingly, real-time polymerase chain reaction and electrophoretic gel mobility shift assays suggested that IFN-gamma and STAT1, as well as the transcriptional activity of STAT1 in NOD glands, were increased at birth. Unlike the neonatal submandibular glands of NOD or NOD-scid mice that show abnormal glandular morphogenesis at birth, the submandibular glands of the newly constructed congenic strain, NOD-scid.IFN-gamma(-/-), were found to be normal. Taken together, IFN-gamma appears to play a critical role not only during the later immune phase of AEC, but also the early preimmune phase, independent of effector functions of immune cells. How exactly IFN-gamma functions during this period remains speculative.
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Department of Oral Biology, University of Florida, Gainesville, FL 32610, USA.
Brayer
J
J
Gao
J
J
Brown
V
V
Killedar
S
S
Yasunari
U
U
Peck
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D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000502:physiology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D050794:STAT1 Transcription Factor; D012471:Salivary Proteins and Peptides / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D013363:Submandibular Gland / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
C511597:Bpifa2 protein, mouse; D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; D012471:Salivary Proteins and Peptides; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D020782:Matrix Metalloproteinases