Assessing risks of secondary immunodeficiency in children with aluminum contamination in biological media and polymorphism of the cell death gene FAS RS1159120 and the antigen-recognizing gene of the toll-like receptor TLR4 RS1927911

Secondary immunodeficiency remains an incompletely understood medical problem, and despite a significant number of international and scientific studies, there is no complete picture of the causes and consequences of this pathology. Metal cations have been proven to participate in the formation of acquired immunodeficiency. In particular, aluminum properties as an immune suppressor have been established and its targets in the body have been identified in case aluminum was present in biological media. However, no evaluations have been accomplished so far as regards the role of specific point genetic changes, that is, polymorphisms in the genes of immune system compartments that determine the risk of negative effects caused by contamination with metal cations, including aluminum. It is quite relevant to search and substantiate immunogenetic markers to create an indicator system for diagnostics and prevention of secondary immunodeficiency states in children associated with aluminum contamination in biological media. We examined 97 preschool children exposed to elevated levels of airborne aluminum (in an area influenced by a metallurgic production). The study groups were divided depending on either presence or absence of secondary immunodeficiency as immune system pathology (common variable immunodeficiency D83). Several markers of the immune system were evaluated: aluminum-specific IgG, CD3+, CD4+, CD8+, CD127-, CD95+, CD284+, and phagocytic activity; we also evaluated polymorphism of TLR4 A8595G (rs1927911) and FAS C14405T (rs1159120) genes of innate and acquired immunity. According to the results obtained by examining biological media composition, children with secondary immunodeficiency had 1.8 times higher aluminum levels in urine (0.0095 ± 0.0014 vs. 0.0054 ± 0.0009 mg/dm3, reference range 3) as opposed to their conditionally healthy peers. We established an authentic inverse dependence between the expression level of the main CD clusters (CD3+: r = -0.38; CD4+: r = -0.39; CD8+: r = -0.26) as well as indicators of phagocytic activity (r = -0.22-0.23) and the level of aluminum contamination in biological media (urine). Expression of T-mature lymphocyte clusters was found to be inhibited by 1.3-3.1 times (including T-helper, effector T-lymphocytes, NK-killers, regulatory lymphocytes) and we also detected some changes in expression of specific immunoglobulin of IgG class to aluminum. All this results in an unacceptable level of relative risk (RR = 1.23-1.63) of developing secondary immunodeficiency against increased frequency of allele C and genotype CC of FAS gene (rs1159120) by 1.2 and 1.5 times respectively, as well as minor allele G of TLR4 gene (rs1927911) by 1.8 times relative to the comparison group (OR = 4.05; CI: 1.41-11.59; p = 0.006; RR = 1.23; CI: 1.02-1.48) and (OR = 2.01; CI: 1.04-3.91; p = 0.037; RR = 1.64; CI:1.46-1.94). Toll-dependent and FAS-dependent mechanism of this risk is associated with aluminum contamination. It is recommended to use a combination of immune and genetic markers as indicator ones when evaluating the immune system state, in order to prevent the risk (RR = 1.23-1.63) of secondary immunodeficiency associated with aluminum contamination in biological media.