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Gramzyme A (GrA) is a serine proteinase with trypsin-like activity that is released extracellularly during the degranulation of cytotoxic cells. Among the cytotoxic cells, gamma/delta T cells participate in the early phases of the immune response and are known to express perforin and granzymes constitutively in agreement with their cytolytic pontential.GrA activity was detected using the synthetic substrate N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester in the plasma and supernatants of peripheral blood mononuclear cell cultured in the presence of Dimethylallyl pyrophosphate to obtain Vgamma9/Vdelta2 T cell expansion.Significantly high levels of GrA were found in the serum and supernatants of lymphocytes from patients with active Behçet's disease cultured in the presence of DMAPP. Levels were found to be significantly lower after remission. A positive correlation was observed between GrA levels in the supernatants and the Vgamma9/Vdelta2 T cell expansion factor.These results strongly suggest that Vgamma9/Vdelta2 T cells are active participants in the pathogenesis of the disease through their degranulation and granzyme release.

Background: It has been postulated that the beneficial effects of deep inspiration are dependent on the magnitude of airway distension by virtue of airway to parenchyma interdependence. Objective: This study was designed to examine whether the changes that occur in pulmonary fibrosis affect the beneficial effect of deep inspiration. Methods: Thirty-one subjects with scleroderma underwent lung volume and diffusion capacity assessment as well as high-resolution computed tomography. To assess the effect of deep inspiration, each subject underwent methacholine provocations in the absence of deep breaths. When the targeted change in lung function was achieved, subjects were asked to take 4 consecutive deep inspirations after which lung function measurements were repeated. The inspiratory vital capacity (IVC) was used as primary outcome. Results: Only 19 subjects attained the desired reduction in IVC in the absence of deep breaths. In those subjects, deep inspiration reversed the effect of methacholine on IVC by 48 ± 8.4%. The effect of deep inspiration correlated with DLCO% predicted (r = 0.55, p = 0.01), but not with high-resolution computed tomography abnormalities or baseline lung function measurements. When all subjects were considered, responsiveness to methacholine in the absence of deep inspiration was progressively lower with decreasing DLCO% predicted values (r = 0.51, p = 0.003). Conclusions: In systemic scleroderma, pulmonary abnormalities resulting in mild to moderate reduction in the diffusion capacity are associated with reduced ability of deep inspiration to reverse methacholine-induced early airway closure and bronchoconstriction. When diffusion capacity is severely affected, methacholine fails to produce obstructive airway changes.

This study sought to validate the Warrick score in the assessment of lung involvement in systemic sclerosis (SSc) and correlate the results with functional abnormalities. In addition, we propose the use of high resolution computed tomography (HRCT) indices of alveolitis and fibrosis to discriminate between different stages of the disease.Thirty-one patients with SSc (16 with the diffuse form and 15 with the limited form) underwent functional and HRCT evaluations of the lung. The semiquantitative evaluation of radiological involvement, as proposed by Warrick, provides a score for each lesion based on the severity and the extent of the pulmonary damage. In addition to the total score, indices for alveolitis and fibrosis were created. The association between each score and functional abnormalities was tested.The total Warrick score was 16+/-7.7 [mean+/-standard deviation (SD)]. The total score correlated inversely with total lung capacity (TLC) (percentage of predicted TLC) (r=-0.38; p=0.04), diffusion lung capacity for carbon monoxide (DLCO) (percentage of predicted DLCO) (r=-0.43; p=0.02) and with forced expiratory volume in 1 second (FEV1) (percentage of predicted FEV1) (r=-0.36; p=0.05). The alveolitis and fibrosis indices were 1.9+/-1.1 and 14.2+/-7.4, respectively. The alveolitis index correlated significantly with percentage of predicted DLCO (r=-0.46; p=0.01) but not with percentage of predicted TLC (r=-0.28; p=0.13). The fibrosis index correlated both with percentage of predicted DLCO (r=-0.38; p=0.04) and with percentage of predicted TLC (r=-0.35; p=0.05).Our findings confirm the diagnostic role of HRCT in assessing the extent of lung damage in SSc. Furthermore, the two indices (alveolitis and fibrosis) provide new tools for evaluating the relationship between pulmonary involvement and systemic impairment in SSc.