Sequencing based typing for HLA-C. Identification of three new alleles: Cw*0307, Cw*0502 and Cw*0504
S Santos1, J L Vicario, F Garcia-Sanchez
1Laboratory of Histocompatability, Regional Transfusion Centre, Menendez-Pelayo 85, 28009 Madrid, Spain.
Insights
Sequencing-based typing identified three novel Human Leukocyte Antigen C (HLA-C) alleles in Spanish bone marrow donors. This finding highlights significant hidden HLA-C diversity, crucial for transplantation compatibility.
Area of Science:
- Immunogenetics
- Molecular Biology
- Transplantation Science
Background:
- Human Leukocyte Antigen C (HLA-C) is a critical transplantation locus.
- High mismatch rates are observed in HLA-A, -B, and -DRB1 compatible bone marrow transplant pairs.
- Sequencing-based typing (SBT) offers high-resolution HLA allele identification.
Purpose of the Study:
- To investigate HLA-C allele diversity in a cohort of bone marrow transplant recipients and donors.
- To identify novel HLA-C alleles using high-resolution sequencing-based typing.
- To assess the extent of hidden HLA-C diversity within the Spanish population.
Main Methods:
- Application of sequencing-based typing (SBT) for HLA-C locus analysis.
- Study of 40 bone marrow recipient-donor pairs matched for HLA-A, -B, -DRB1, -DRB3/4/5, and -DQB1.
- Detailed analysis of nucleotide and amino acid variations in identified HLA-C alleles.
Main Results:
- Discovery of three new HLA-C alleles: Cw*0307, Cw*0502, and Cw*0504.
- Cw*0307 exhibited distinct amino acid changes at the NK motif compared to other Cw*03 alleles.
- Cw*0502 and Cw*0504 showed variations from Cw*0501, including nucleotide and amino acid differences impacting the peptide binding site.
Conclusions:
- The study reveals a high degree of previously unrecognized HLA-C diversity in the Spanish population.
- Novel HLA-C alleles were identified even within well-defined serologic specificities.
- These findings underscore the importance of high-resolution HLA typing for optimizing bone marrow transplantation outcomes.
Abstract:
HLA-C has been described as a transplantation locus in the unrelated bone marrow transplantation setting, and noticeably the number of mismatches between HLA-A,-B,-DRB1 compatible pairs is considerably high. Sequencing based typing (SBT) is an accurate and efficient methodology utilised in the HLA class I and II allele level of resolution. SBT for HLA-C locus was applied on a sample of 40 HLA-A,B,DRB1,DRB3/4/5,DQB1-compatible bone marrow recipient-donor pairs, and 3 new HLA-C alleles have been found. Cw*0307, well defined by serology as Cw3, showed two amino acid changes at the NK motif 77-80 regarding all described Cw*03 alleles, N77K80 instead of S77N80. Two new Cw*05 alleles were described, Cw*0502 properly typed by serology, and Cw*0504 that behaves as a short antigen. Cw*0502 differed from Cw*0501 by only one nucleotide at exon 3, that generated an amino acid replacement at codon 177, K to E. Cw*0504 differs from Cw*0501 by two clustered amino acid positions (114 and 116) placed at the peptide binding site. The rate of new HLA-C alleles found in this small series evidences a high grade of hidden HLA-C diversity in the Spanish population, particularly in the well-defined serologic specificities.
