Publications on the status of blood immune cells of the veterans exposed to SM within the day 1 up to the 7th week of exposure indicated a significant decrease in T cell count in 54 % of the patients and a marked decrease in the number of monocytes in 95 % of the patients. Also, the number of eosinophil reduced in 35 % of the veterans in the first week and in 65 % of them in the 7th week after exposure. The number of neutrophil r in 89 % and 60 % of the patients in the first week and the 7th week, respectively. B lymphocyte counts were within the normal range from day 1 to the 7th week after exposure (Razavimanesh 1988).

In case of toxicity of SM on function of innate immunity, we found a few papers on phagocytic cell function as the most important cells involved in innate immunity. In a study, neutrophil function tests of the SM exposed veterans, during 1 month after exposure showed a marked decrease, so that, in some cases the phagocytic index diminished to one fifth of normal range. These changes were returned back to normal condition after 3 months (Bahar et al. 1988). Keyhani and colleagues performed a functional test for neutrophill called NBT on 121 Iranian veterans, and they found the function of neutrophils to be decreased in a period up to 51 days after exposure in all cases. This finding might indicate lack of neutrophil function (Keyhani 1988). In contrary, Zandiyeh et al determined cell movement, chemotactic factors, and plasma and cell opsonins among the SM exposed patients and the results were within the normal range (Zandiyeh 1991). One mechanism by which the innate immune system protects human body is by the phagocytic uptake and subsequent destroying of pathogens, partly, via an oxidative bactericidal pathway called the respiratory burst. The act of ingesting a foreign particle by a phagocytic cell such as macrophage or neutrophil activates NADP oxidase that, in turn, start up the process of generation of a significant amount of highly potent bactericidal ROS from molecular oxygen. (Meydani et al. 1995; Chew and Park 2004). Thus, low levels of ROS are essential for daily survival (Boxer et al. 1979; Victor et al. 2004). On the other hand, if ROS is over-produced, or the antioxidant content is low, the cells damage. Phagocytic cells are under oxidative stress when there is an disbalance between pro-oxidants and antioxidants (Victor et al. 2004). Phagocytic cells are especially vulnerable to oxidative injury because of the high amount of polyunsaturated fatty acids in their surfaces and their high generation of ROS, which contribute to damage. As the level of these fatty acids in the surfaces is elevated, the potential for membrane lipid peroxidation mediated by ROS is also elevated. Lipid peroxidation reduces membrane fluidity, which adversely influence immune responses. Thus, the equilibrium between pro-oxidant generation and antioxidant protection is critical for an accurate cell function, whereas a disturbance in this equilibrium towards the oxidants indicates to an oxidative stress (Hughes 1999; Victor et al. 2003). Thus, oxidative stress caused by SM is probably an important mechanism of SM-induced immunotoxicity as measured/reflected by decreased phagocyte (i.e., phagocytic) functionality.

It has been reported that SM possesses a toxic effect on animal B-lymphocytes and therefore, hypogammaglobulinemia is a significant finding. In case of short term effects of SM on antibody status of veterans, Keyhani et al study is absolutely the best. In this study, the serum concentrations of IgG, IgA and IgM of SM-exposed veterans were determined from day 3 up to 1 month after exposure. The concentrations of serum IgG in veterans showed a significant decrease on day 3 after exposure to SM. On the other hand, the levels of serum IgG of the patients non-significantly increased during 4–18 days after exposure. The increase in the levels of serum IgG of veterans during 19–31 days after exposure was found to be significant as compared to controls. The concentrations of IgA in the sera of the veterans during 1 month after exposure showed fluctuations similar to those of IgG, but the variation of the patients serum IgA, were not significant in comparison to controls. The serum concentrations of patients IgM did not show any significant differences during 1 month after exposure to SM as compared to controls (Table 10.2). The justification of Keyhani and colleagues for the initial decrease in serum concentration of IgG in veterans was a possible leakage of IgG into the skin blisters and into other severely influenced parts of the body such as lungs, whereas the subsequent elevation in serum IgG was interpreted as a result of an auto-antigenic stimulation of the veterans immune systems (Keyhani et al. 2007).

In our search we found one study regarding short-term effects of SM on complement system showing normal level of C3, C4 and CH50 during the first week and up to the 6 months after SM exposure.

Sulfur mustard is a debilitating agent with long-term adverse effects on the immune system. Several studies have tried to investigate the potential of sulfur mustard to induce delayed outcomes of SM on cellular components of the immune system. In this field, there are numbers of contradictory studies related to delayed effects of SM on immune cells that some of them will be discussed.

In a study, all poisoned patients that had been exposed to SM 16–20 years prior to this study and had severe clinical complications were studied (Mahmoudi et al. 2005). The analysis of blood immune cells for the patients and 35 healthy age-matched controls showed that the percentages of monocytes and T-cells were significantly higher and the percentage of natural killer cells was significantly lower in patients. According to Mahmoudi et al the impaired innate immunity due to a decrease in the number of blood NK cells is probably responsible for the increased risk of infections in these patients (Table 10.3).

Similar study was performed by Ghotbi and Hassan investigating a total of 75 veterans with an average age of 40. They all had been exposed to SM about 10 years before the study begins. They classified the patients into mild, moderate and severe groups. It was shown that the percentage of NK cells was significantly lower in severe patients. The results also showed that the function of NK cells in severe group is appreciably higher in comparison to the control (Ghotbi and Hassan 2002). They proposed that a marked reduction in the absolute counts of NK cells in severe patients is likely due to the harmful effect of SM on NK cell precursors of bone marrow. Their other conclusion was that the function of NK cells has increased to compensate the reduction in the number of these cells. Finally, they concluded that their results indicate that higher risk of cancer and also recurrent infections in SM-exposed veterans might be due to the reduction of NK cell number.

According to a comprehensive study (Sardasht-Iran Cohort Study) on the immune and pulmonary system of SM exposed civilian cases 20 years after exposure, performed by Ghazanfari and colleagues, results indicated a significant decrease in T lymphocytes and T helpers percentages. It was also shown that peripheral blood NK cell counts were highly elevated in exposed patients. The data demonstrated a marked negative correlation between T lymphocyte counts and FVC percentage and positive correlation with FEV1/FVC%. It was also showed that blood monocytes counts had a negative correlation with FVC%. They concluded that NK and T cells are likely to be involved in the pathogenesis or immune reactions to the long term pulmonary problems induced by SM. (Ghazanfari et al. 2013).

In another study conducted by Akbari et al., the potential delayed toxic effects of sulfur mustard on white blood cells was investigated on 113 Iranian veterans, nearly 25 years after exposure. Total leukocyte counts and percentage of polymorphonuclear cells were significantly higher in exposed patients. The analysis showed that the percentages of T helpers were significantly lower in exposed veterans whereas, T cytotoxic lymphocyte percentage and CD4+/CD8+ ratio statistically remained unchanged (Mohammadhoseiniakbari et al. 2008). They concluded that blood diathesis is still present in sulfur-mustard–exposed veterans 25 years after exposure.

Shaker and colleagues in another study determined the total leukocyte and the status of T helper and T cytotoxic cells on 75 exposed veterans 10 years after exposure to SM. Their results showed that leukocyte percentages were normal in all patients while the percentage of T helper and T cytotoxic cells showed a significant decrease in the severely affected patients as compared to mild contaminated group. Also the CD4+/CD25+ cells in the most severely affected patients were statistically increased in comparison with the mildly and moderately affected groups (Shaker et al. 2003). Therefore, in their opinion, 10 years after exposure to SM, the immune system of the veterans is still impaired.

The long–term effects of SM on molecular components of immune system of veterans 16–20 years after exposure was completely studied by Mahmoudi and colleagues. Serum levels of IgA, IgG, IgM, IgE, and complement components C3 and C4 were measured. Other factor included plasma protein electrophoresis. In this study, serum IgA, IgE, and C4 did not show any significant changes in comparison to control, whereas IgM and C3 concentrations were significantly higher in veterans. Regarding plasma protein analysis, the serum absolute levels of α₁-globulin, α₂-globulin and β-globulin in veterans were higher than control. The albumin/globulin ratio of patients was also elevated. They concluded that these protein changes might be related to the acute phase response to frequent infections (Table 10.4) (Mahmoudi et al. 2005).