Allorecognition of an HLA-A*01 Aberrant Allele by an HLA Identical Family Member Carrying the HLA-A*0101 Allele

Abstract

We identified and characterized an HLA-A1 aberrant allele (A*0118N) resulting from a novel molecular mechanism; this allele was present in an unusually informative family with a near identical parental HLA haplotype (c d) differing only by one nucleotide substitution in one HLA-A allele, A*0118N, of the maternal HLA haplotype (c) and not of the paternal HLA haplotype (a). Although serologic HLA typing showed a “blank,” DNA molecular HLA typing detected a HLA-A*0118N allele. Sequence based typing identified the substitution of guanine by cytosine at the nucleotide position 215, which resulted in the replacement of arginine by proline at position 48 of the HLA-A1 H chain. The loss of surface protein expression was also found by FACS analysis. Isoelectric-focusing analysis detected a HLA-A H chain with a unique isoelectric-focusing pattern, which does not associate with the L chain (β2-microglobulin). These results suggest that the residue 48-containing interaction site on the α1 domain plays a critical role in the association between HLA class I H chain and β2-microglobulin. Functional studies showed that the T cells of the propositus (HLA haplotypes c d) carrying this null allele recognized its wild-type counterpart, HLA-A*010101, in her HLA-identical son that carries the HLA-A*0101 heterodimer. This is the first example of the generation of cytotoxic T cells in the absence of proliferation of CD4+ T cells (mixed lymphocyte culture) and the description of an aberrant allele, A*0118N, that may behave as a minor histocompatibility Ag, with implications in allorecognition by cytolytic T cells in solid organ and stem cell transplantation.

Closing the gap: discrimination of the expression profile of HLA questionable alleles by a cytokine‐induced secretion approach using HLA‐A*32:11Q

“…Taking this into account, it is likely that the enriched HLA‐A*32:11Q is a substrate for proteasomal cleavage and provides peptide fragments for presentation to T lymphocytes enhancing the indirect allorecognition pathway. This has also been hypothesized for N alleles, for example, HLA‐A*01:18N (41) and other aberrantly expressed alleles like HLA‐B*44:02:01:02S (42), who may act as minor histocompability antigens. Mismatch transplantation with such an allele might cause GvHD or graft rejection, in particular, considering that indirect allorecognition is the driving force for long‐term graft rejection (40).…”

Next-generation sequencing: the solution for high-resolution, unambiguous human leukocyte antigen typing

“…It was found that the single amino acid difference, located in the second domain of DRB1, would not influence ARS structure or interaction with T-cell receptors or CD4 [25]. However, this does not consider indirect allorecognition whereby the mismatched amino acid, as part of a peptide, may be presented by another self HLA molecule [26]. Immune response may be different under this scenario.…”