HLA haplotype and supertype associations with cellular immune responses and cytokine production in healthy children after rubella vaccine

Secreted rubella virus-specific cytokines reflect the immunologic mechanisms underlying adoptive immune responses and are significant markers of immunity to rubella. We studied the association between measures of cellular (cytokine and frequency of cytokine-secreted cells) immune responses and HLA haplotypes (with frequencies of ≥1%) and supertypes among 738 healthy children following two doses of rubella vaccine. Haplotype effects were estimated while accounting for linkage phase ambiguity via an expectation maximization algorithm. Importantly, the majority of HLA class I and class II haplotype associations with different cytokines were consistent between Th1, Th2 and/or innate/proinflammatory cytokine groups. We found few class I supertypes (A1, A2, A3, and B7) with potential associations with IL-10 ELISPOT counts and rubella-specific IL-2, IL-10, TNF-α, and IL-6 cytokine secretion levels. Our data indicate that the presence or absence of certain HLA haplotypes and/or supertypes may influence the cytokine immune response to rubella vaccine, and represents a more advanced analysis compared to individual candidate gene association studies.