Cytokine polymorphisms in sickle cell disease and the relationship with cytokine expression

Sickle cell disease is a chronic inflammatory condition characterized by elevated levels of inflammatory cytokines, which may be regulated by genetic polymorphisms and could be associated with diverse disease presentations and alloimmunization. The aim of this study was to evaluate Treg and Th17 cell frequencies, cytokine gene polymorphisms, and their association with cytokine expression profile in patients with sickle cell disease. For that purpose, we evaluated the IL intron 3 variable number tandem repeat (VNTR, genotypes 1.1, 1.2, 2.2, and 2.3), IL4-T590C>T, IL6-174G>C, TNFα-308G>A, IL10-819T>C, IL10-592A>C, and IL10-1082A>G polymorphisms and their correlation with TGFβ, IL4, IL6, and IL10 gene expression in sickle cell patients. We observed a significant decrease in Treg frequency together with a substantial increase in Th17 response in patients with sickle cell disease compared with healthy controls (p < 0.001 and p = 0.014, respectively). There was also a higher prevalence of the IL4-590T/T genotype in patients with sickle cell disease than in Afro-Brazilian descendent controls (p < 0.001) and higher expression of IL4 in patients with the 1.1 genotype of IL4 intron 3 VNTR (p = 0.06). Significantly greater gene expression of TGFβ, IL6, and IL10 was observed in sickle cell patients when compared with controls (p = 0.01, 0.03, and <0.001, respectively). Moreover, higher levels of interleukin-6 and -10 were observed in the group of alloimmunized patients. These new data bring insights into the deregulation in the immune system affecting sickle cell patients and must be further investigated in larger cohorts to better characterize individual variations in immune responses and new markers for disease morbidity.