Immunologic significance of HLA class I genes in measles virus-specific IFN-γ and IL-4 cytokine immune responses

Abstract

The variability of immune responses modulated by human leukocyte antigen (HLA) genes and secreted cytokines is a significant factor in the development of a protective effect of measles vaccine. We studied the association between type 1 helper T cells (Th1)- and Th2-like cytokine immune responses and HLA class I alleles among 339 schoolchildren who previously received two doses of the measles vaccine. Median values for measles-specific interferon gamma (IFN-gamma) and interleukin-4 (IL-4) cytokines were 40.7 pg/ml [interquartile range (IQR) 8.1-176.7] and 9.7 pg/ml (IQR 2.8-24.3), respectively. Class I HLA-A (*0101 and *3101) and HLA-Cw (*0303 and *0501) alleles were significantly associated with measles-virus-induced IFN-gamma secretion. HLA-A*3101 and Cw*0303 were associated with a higher median IFN-gamma response, while A*0101 and Cw*0501 were associated with lower measles-specific IFN-gamma response. We found limited associations between HLA class I gene polymorphisms and Th2-like (IL-4) immune responses after measles vaccination, indicating that HLA class I molecules may have a limited effect on measles-vaccine-induced IL-4 secretion. Understanding the genetic factors that influence variations in cytokine secretion following measles vaccination will provide insight into the factors that influence both cell-mediated and humoral immunity to measles.

Human leukocyte antigen and interleukin 2, 10 and 12p40 cytokine responses to measles: Is there evidence of the HLA effect?

“…Prior population-based studies found associations with both class I and class II alleles and measles vaccine immune response [22][23][24]. Subsequent studies suggest the significance of HLA genes in measles virus-specific IFN-γ and IL-4 cytokine immune responses [25,26]. The class I HLA-A (*0101 and *3101) and HLA-Cw (*0303 and *0501) alleles have been significantly associated with measles virus-induced IFN-γ secretion [25].…”

“…Subsequent studies suggest the significance of HLA genes in measles virus-specific IFN-γ and IL-4 cytokine immune responses [25,26]. The class I HLA-A (*0101 and *3101) and HLA-Cw (*0303 and *0501) alleles have been significantly associated with measles virus-induced IFN-γ secretion [25]. Likewise, class II HLA-DRB1 (*0301, *0901 and *1501) and DRB1 (*0103, *0701 and *1101) alleles were associated with IFN-γ and IL-4 secretion, respectively.…”

“…Peripheral blood mononuclear cells (PBMC) were immediately separated from heparinized venous blood by Ficoll-Hypaque (Sigma, St. Louis, MO) density gradient centrifugation as described elsewhere [25,26]. Cells were resuspended in RPMI 1640 culture media (Celox Laboratories Inc., St. Paul, MN) containing 10% dimethyl sulfoxide (Sigma) and 20% fetal calf serum (FCS; Hyclone, Logan, UT), frozen at −80°C, and stored in liquid nitrogen.…”

“…Cells were resuspended in RPMI 1640 culture media (Celox Laboratories Inc., St. Paul, MN) containing 10% dimethyl sulfoxide (Sigma) and 20% fetal calf serum (FCS; Hyclone, Logan, UT), frozen at −80°C, and stored in liquid nitrogen. After cryopreservation, PBMC were thawed, resuspended in RPMI 1640 culture media supplemented with 10% normal human serum (NHS; Irvine Scientific, Santa Ana, CA), 100 U/ml penicillin (Sigma), and 100 g/ml streptomycin (Sigma) as previously described [25,26]. For determination of secreted IL-2 and IL-10, PBMC (4×10 5 cells/well) were cultured in duplicate with or without the Edmonston B vaccine strain of measles virus (multiplicity of infection [MOI] of 0.1) diluted in RPMI 1640 culture media supplemented with 1% NHS.…”

“…Further, we demonstrated that the HLA genes may also play a role in measles-specific cytokine responses and demonstrated significant associations with measles-induced IFN-γ and IL-4 secretion and HLA alleles [25,26]. We hypothesized that variations in IL-2, IL-10, and IL-12p40 cytokine responses to measles vaccine are associated in part with genetic polymorphisms of the HLA genes.…”