Sjögren'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-g), on the onset of AEC was investigated using both the IFN-g and the IFN-g receptor gene knockout mice, NOD.IFN-g -/-and NOD.IFN-gR -/-, respectively. Neither the NOD.IFN-g -/-nor the NOD.IFN-gR -/-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-g -/-and NOD.IFN-gR -/-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 IFNg 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-g -/-, were found to be normal. Taken together, IFN-g 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-g functions during this period remains speculative.
Objective. The NOD mouse is genetically predisposed to the development of at least 2 autoimmune diseases, autoimmune diabetes and autoimmune exocrinopathy (AEC). More than 19 chromosomal intervals (referred to as Idd regions) that contribute to diabetes susceptibility in the NOD mouse model have been identified, but only 2 chromosomal intervals (associated with Idd3 and Idd5) have been shown to control sialadenitis. In the present study, we bred the Idd3 and Idd5 chromosomal intervals from NOD mice into nonautoimmune C57BL/6 mice to determine if these intervals recreate a Sjögren's syndrome (SS)-like phenotype.Methods. C57BL/6.NODc3 mice carrying Idd3 and C57BL/6.NODc1t mice carrying Idd5 were crossed and intercrossed to generate a C57BL/6.NODc3.NODc1t mouse line homozygous for the Idd3 and Idd5 chromosomal intervals on an otherwise disease-resistant genetic background. C57BL/6.NODc3.NODc1t mice were evaluated for biochemical, pathophysiologic, and immunologic markers characteristic of the SS-like phenotype present in the NOD mouse.Results. C57BL/6.NODc3.NODc1t mice fully manifested the SS-like phenotype of the NOD mouse, including decreased salivary and lacrimal gland secretory flow rates, increased salivary protein content due in part to less fluid, aberrant proteolytic enzyme activity, decline in amylase activity, appearance of autoantibodies to exocrine gland proteins, and glandular lymphocytic focal infiltrates. Loss of secretory function occurred more rapidly in C57BL/6.NODc3.NODc1t mice (by 12 weeks of age) than in NOD mice (by 16 weeks of age). No signs of insulitis or autoimmune (type 1) diabetes were observed in the C57BL/6.NODc3.NODc1t mice.Conclusion. Genes located within the 2 chromosomal intervals Idd3 and Idd5 appear necessary and sufficient for manifestation of AEC. We propose that this murine model of SS-like disease be designated C57BL/6.NOD-Aec1Aec2. Identification of specific genes within the Aec1 and Aec2 genetic regions should help elucidate the mechanism(s) underlying SS-like disease.
Porphyromonas gingivalis is a periodontal pathogen that promotes a proatherogenic response in endothelial cells. Cell death responses of human aortic endothelial cells to P. gingivalis at various multiplicities of infection (MOI) were investigated by assessment of cell detachment, histone-associated DNA fragmentation, lactate dehydrogenase release and ADP:ATP ratio. Porphyromonas gingivalis at MOI 1:10-1:100 did not have a cytotoxic effect, but induced apoptotic cell death at MOI 1:500 and 1:1000. Monocyte chemoattractant protein-1 production was significantly enhanced by P. gingivalis at MOI 1:100. At higher MOI, at least in vitro, P. gingivalis mediates endothelial apoptosis, thereby potentially amplifying proatherogenic mechanisms in the perturbed vasculature.
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