Life-threatening graft-versus-host disease (GVHD) limits the use of HLA-C-mismatched unrelated donors in transplantation. Clinicians lack criteria for donor selection when HLA-C-mismatched donors are a patient's only option for cure. We previously elucidated the range of expression across HLA-C allotypes. Each serologically defined HLA-C allotype has a characteristic median fluorescence intensity (MFI) of cell surface expression that is reproducible in both healthy and HIV-infected cells in vitro. Expected levels of HLA-C cell surface expression based on the sum of the 2 allelic MFI coefficients was shown to predict observed HLA-C expression levels among individuals in 2 cohorts, indicating that MFI coefficients can be assigned to each HLA-C allotype in lieu of direct ascertainment of expression. Thus, the clinical importance of HLA-C expression can be determined in large-scale retrospective outcome studies where appropriate materials for measuring HLA-C expression directly are not available. Using this approach, we showed that higher MFI levels correlated with better control of HIV viral load and slower progression to HIV-AIDS across ethnic groups, but with increased susceptibility to Crohn disease, solidifying the role for HLA-C expression levels in modulating the strength of immune responses. In collaboration with Dr. Effie Petersdorf at the FHCRC, Washington University, we applied the MFI as a quantitative proxy of HLA-C expression level to assess the clinical significance of the level of HLA-C expression in an exceptionally large international population of patients and unrelated transplant donors whose only HLA mismatch was a single HLA-C allotype. The association of outcome with the level of expression of patients' and donors' HLA-C allotypes was evaluated in multivariable models. Increasing expression level of the patient's mismatched HLA-C allotype was associated with increased risks of grades III to IV acute GVHD, nonrelapse mortality, and mortality. This study provides new insight into the strength of the immune response of HLA-C in transplantation. Application of the findings can be envisioned for future patients who do not have HLA-matched donors as an option. The effects of differential allotype expression levels at other HLA loci may further delineate and broaden the pool of acceptable donors for patients, and given the above results, characterizing such effects is warranted. Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. As part of a collaborative effort with the International Inflammatory Bowel Disease Genetics Consortium, high-density SNP typing of the MHC in 32,000 individuals with IBD was performed along with HLA genotyping of a subset of samples. Data analysis showed an association with multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Overall, the contribution of class I and class II HLA variants to disease risk was relatively equivalent in Crohn's disease, whereas HLA class II variation was more important in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD. In addition, most associated HLA alleles have a predominant role in either Crohn's disease or ulcerative colitis, with very few conferring shared IBD risk.Some individuals naturally control HIV replication in the absence of antiretroviral therapy, and this ability to control is strongly correlated with the HLA class I alleles that they express. In collaboration with Dr. Bruce Walker at the Ragon Institute, we demonstrated that this correlation is mediated largely by the targeting of specific CD8+ T-cell epitopes. Eight epitopes that are most likely to cause control were identified by ELISPOT analysis. In addition, using an in silico analysis we were able to show that control occurs because mutations within these epitopes change the stability of the protein structures. Additional epitopes that are not typically targeted in natural infection but may lead to control when included in a vaccine, were also identified by in silico analysis. These observations argue for the inclusion of specific epitopes in a vaccine, rather than whole viral proteins that may result in unfocused and unhelpful targeting, suggest that a hallmark of protective epitopes is a reduced capacity to escape the immune response through viral mutation, and provide an approach to identify additional protective epitopes.
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