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The most important long-term morbidity problem of sulfur mustard (SM) toxicity is pulmonary complications but the pathogenesis of these complications is not clearly understood. This study evaluates the peripheral blood mononuclear sub-sets and their correlation with pulmonary function in SM exposed civilian cases 20 years post-exposure as gathered in the context of the Sardasht-Iran Cohort Study (SICS). Samples were randomly selected from two groups, SM-exposed (n=372) and control (n=128), with the same ethnicity, culture, and demography. Three color flow cytometry was applied for peripheral blood mononuclear sub-population determination. Results indicated a significant decrease in CD45+/CD3+, CD45+/CD3+/CD4+, and an increase in CD3+/CD16+56+ percentages. It was also found that absolute count of NK cells was highly increased in peripheral blood of exposed cases. There was a significant increase in NK cell count of SM exposed group with pulmonary problems as compared to the same group without pulmonary problems (p-value<0.04) based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The findings showed a significant negative correlation between absolute numbers of T lymphocyte and FVC % and positive correlation with FEV1/FVC%. The results also demonstrated that absolute numbers of monocytes had a negative correlation with FVC %. We propose that NK and T cells are probably involved in the pathogenesis or immune reactions to the delayed pulmonary complications induced by SM. This hypothesis should be tested in a more severe pulmonary complicated group., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The serum levels of four important and well characterized inflammatory chemokines including MCP-1/CCL2, RANTES/CCL5, IL-8/CXCL8 and Fractalkine/CX3CL1 were evaluated in sulfur mustard (SM) exposed Iranian population 20 years after exposure. In this historical cohort study 372 SM exposed participants from Sardasht, and 128 unexposed participants as controls were studied. The serum concentrations of chemokines were measured by a sandwich ELISA technique. The serum concentrations in the exposed comparing to the control group were 201.86 vs 180.60 pg/ml (p=0.002), for MCP-1/CCL2, 1182.6 vs 1393.1pg/ml (p=0.021) for RANTES/CCL5, 12.61 vs 15 pg/ml (p=0.002) for IL-8/CXCL8 and 0.696 vs 0.0648 (p=0.413) for Fractalkine/CX3CL1. In conclusion, elevated levels of MCP-1/CCL2 may suggest an anti inflammatory response and decreased levels of IL-8/CXCL8 and RANTES/CCL5 may represent a different pathophysiology and diverse molecular mechanisms involved in long term clinical manifestations of SM exposure. However, further prospect into their role in the pathogenesis of SM remains to be done.

Sulfur mustard (SM) is a blistering chemical agent which has short and long term toxicity against many organs. The respiratory tract is one of the main targets, and is the most disabling long term complication of SM. Inflammatory mediators especially IL-8 and IL-6 play the primary role in the various chronic pulmonary diseases. Sardasht-Iran Cohort Study (SICS) was designed to evaluate immunological and molecular parameters in SM exposed people 20 years after exposure. In the present study, the association of the serum levels of IL-8, IL-6, C reactive protein (CRP) and rheumatoid factor (RF) with long term pulmonary involvement was evaluated. There were 348 exposed and 120 control participants. The clinical evaluations were done for all subjects and Spirometry was performed according to American Thoracic Society Criteria. Severity of pulmonary involvement was assessed by Global Initiative for chronic Obstructive Lung Disease (GOLD) classification. The serum levels of IL-8, IL-6 and RF were assessed by ELISA assay. CRP was assessed by photometric method. The serum levels of IL-8 and IL-6 significantly decreased in the SM exposed participants compared to the control group. There were no significant associations between the serum levels of IL-8 and pulmonary symptoms (chronic cough, sputum, hemoptysis, and dyspnea), pulmonary findings (crackles, rales, and wheezing) as well as spirometry parameters. IL-6 was associated with wheezing and CRP was associated with wheezing and rales in SM exposed group. We concluded the serum levels of these inflammatory mediators probably do not have any major role in pathogenesis and persistence of pulmonary complications and do not reflect the degree of severity of pulmonary involvement following SM exposure.

Mustard gas, even in low doses, has the ability to inflict damage in multiple organs especially the skin, eyes, as well as the respiratory tract. This damage may cause many complications which persist during the lifespan of exposed subjects. Pro-inflammatory cytokines including TNF, IL-1alpha, IL-1beta and IL-1Ra cause systemic inflammatory reactions and numerous changes including altered cell signaling and migration, changes in cytokine production and fever. The aim of this study was to determine the serum levels of these cytokines in subjects who were exposed to mustard gas 20 years ago in comparison with an unexposed control group. In this historical cohort study 368 sulfur mustard (SM) exposed participants from Sardasht and 126 age-matched unexposed volunteers from Rabat (a nearby town) as controls were chosen by a random systematic sampling. The serum concentrations of IL-1alpha, IL-1beta, IL-1Ra and TNF were measured by a sandwich ELISA technique. Median of the serum levels of cytokines TNF, IL-1alpha, IL-1beta and IL-1Ra in the control group was 23.79, 1.89, 1.91 and 32.9 pg/ml respectively, while in the SM-exposed participants these values were 11.11, 0.81, 1.73 and 26.7 pg/ml respectively. The serum pro-inflammatory cytokine levels were significantly lower in the exposed group than in controls (p<0.01). There was also significant positive correlation between concentration of all of mentioned cytokines, the strongest being between IL-1beta and TNF (r=0.809 in the control group). The observed down-regulation of pro-inflammatory cytokines should be considered in interpretation of diagnosis and therapeutic measures taken to improve clinical complications.

Sulfur mustard (SM) has short- and long-term toxicity against various organs including the respiratory system. However, the basic and molecular mechanisms of SM long-term toxicity have not clearly been defined. Thus, the aim of this study was to evaluate the association of soluble Fas ligand (sFasL) as well as nitric oxide (NO) serum levels with long-term pulmonary complications in a SM exposed population 20 years after SM exposure. In this historical cohort study 372 male SM exposed subjects and 128 age-matched unexposed controls were studied. Clinical evaluation and pulmonary function tests were carried out for all participants and serum concentrations of sFasL and NO measured. According to our results, the serum levels of sFasL and NO were not significantly different between the exposed and control groups. However, the serum levels of sFasL in the exposed group with pulmonary problems were significantly higher than their corresponding in the control group (116.711+/-81.166 vs 86.027+/-30.199 and p=0.028). Furthermore a significant elevation in sFasL levels was found in the exposed subjects with pulmonary problems compared to those exposed participants without pulmonary problems (116.711+/-81.166 vs 90.692+/-57.853 and p=0.004). Based on Global Initiative for chronic Obstructive Lung Disease (GOLD) classification analysis a positive correlation was observed between sFasL levels and pulmonary problems. There was also a significant negative correlation between sFasL and the white blood cell (WBC) count in the SM exposed cohort, but not in the control group. No significant association was shown between NO and pulmonary impairment in the SM exposed subjects. Thus, our results indicate that elevated serum levels of sFasL may be associated with progression of pulmonary diseases in the SM exposed subjects.

Together with poloxamer 407 as adjuvant the recombinant type I (rCPB) or type II (rCPA) cysteine proteinases of Leishmania major were screened as potential vaccines against L. major in a mouse model. The vaccines were delivered subcutaneously twice at 3 weeks intervals. Three weeks after booster injection, 5x10(5) stationary phase L. major promastigotes were inoculated subcutaneously in one footpad. Using the footpad thickness increase to monitor the clinical outcome/cutaneous lesion at site of L. major delivery, it was possible to document that rCPB but not rCPA allowed BALB/c mice to mount a partial protective response: indeed over the period under study (weeks 1-12) a clear delay was noticed after the immunization with rCPB. This partial protective effect was no more detectable if CD8 depleting antibody was given intravenously to rCPB-immunized mice, at the time of parasite challenge. Seven weeks after challenge, the draining lymph nodes were monitored for their frequencies of IFN-gamma positive CD4(+) and CD8(+) T lymphocytes using PMA and ionomycin as re-activating signals: interestingly the partial protection achieved in BALB/c mice immunized with rCPB together with poloxamer was correlated only to one immunological parameter, namely the higher frequency of IFN-gamma producing CD8(+) T lymphocytes. Of note also, in the lymph node draining the L. major-loaded footpad of C57BL/6 mice otherwise known to develop a transient lesion, the frequency of IFN-gamma producing CD8(+) T lymphocytes reach similar value 7 weeks after challenge and in absence of any prior immunization. Taken together, it was shown that the induced partial protection was mainly dependent on IFN-gamma producing CD8(+) T cells.