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Differential Impact of HLA-B*44 Allelic Mismaches at Position 156 on Peptide Binding Specificities and T-Cell Diversity

Soumya Badrinath, Trevor Huyton, Heike Kunze-Schumacher, Holger Andreas Elsner, Rainer Blasczyk and Christina Bade Doeding

The molecular understanding of how we can mismatch patients and donors and still have successful clinical outcomes will help to guide the future of unrelated bone-marrow transplantation. Single amino acid mismatches at position 156 on the alpha 2 helix of B*44 variants have been described to cause immunological episodes. The magnitude of permissivity between B44/156 variants differs from peptide presentation independent of the peptide loading complex (B*44:28) to influencing clinical episodes (B*44:02 vs. B*44:03). We here investigated if the single exchange of an Asp>Glu as occurring in B*44:35 at residue 156 would force an immune response in vitro. We developed an in vitro system by recombinant co-expression of a single membrane-bound allogeneic HLA class I molecule in donor cells and co-incubating these cells with autologous T-cells. This strategy enables the study of single HLA class I mismatches and excludes the influence of minor antigens. We found these T-cells to be able to differentially discriminate between mismatched B*44 subtypes and their micropolymorphism. To understand how certain pHLA landscapes shaping the alloreactive immune response, we sequenced the individual peptides derived from B*44/156 subtypes using LC-ESI-MS/MS technology. Based on the peptide data we modeled the structure of the B*44:35 variant and can describe the unexpected immunological reaction of the mismatched B*44 subtypes through structural manipulation of the heavy chain. The meticulous characterization of peptide-binding profiles for key alleles, as well as the evaluation of T-cell responses and structural analysis in the context of one-allele mismatches will open the door to a new era in bonemarrow transplantation.