A Single Amino Acid Polymorphism Within the α2 Domain of HLA-DQα Regulates the Assembly and Expression of HLA DQ Alleles and the Potential Clinical Impact.
6 affiliations
- 1Terasaki Innovation Center, Los Angeles, CA.
- 2Southwest Immunodiagnostics, Inc., San Antonio, TX.
- 3Department of Immunology, University Hospital Zurich, Switzerland.
- 4Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
- 5Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
- 6Department of Pathology, Emory University, Atlanta, GA.
Abstract
Background
Single antigen bead testing is currently accepted as standard practice for evaluating HLA alloantibodies. However, it is well established that the expression of HLA antigens, on beads, is not representative of actual cellular expression. It is well recognized that the cellular surface expression of certain HLA loci are expressed at relatively low levels. As such, single antigen bead data may overrepresent the impact of HLA antibodies for certain loci. Importantly, for clinical assessments, the cell surface expression of target donor HLA antigens is not routinely considered unless it is a known null allele.Methods
Using a panel of variably reactive DQ4 allosera, we have evaluated DQ4 antigen assembly and surface expression on cell lines and in transfectants carrying DQ4 variants.Results
A single amino acid change at residue 137 in the α2 domain of the DQα chain can significantly affect the stability of the αβ heterodimer and result in the reduced surface expression of the affected DQ antigens, resulting in changes in anti-HLA antibody reactivity.Conclusions
A single amino acid residue in the DQα chain can influence the expression of a DQ4 molecule. Importantly, such surface expression variability does significantly impact allo-antibody reactivity. As a result, amino acid sequence variations in the α2 and β2 domains of the HLA class II serological groups and alleles within serological groups should be further investigated to understand the scope of allelic expression variability. Identifying low surface expressing HLA antigens/alleles might facilitate the understanding of certain discordant clinical observations.
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BibTeX
@article{nong2026single,
title = {{A Single Amino Acid Polymorphism Within the α2 Domain of HLA-DQα Regulates the Assembly and Expression of HLA DQ Alleles and the Potential Clinical Impact.}},
author = {Thoa Nong and Mayra Lopez-Cepero and Cathi Murphey and Jakob Nilsson and Melissa Y Yeung and Edgar L Milford and Peter W Nickerson and N Remi Shih and Robert A Bray and Jar-How Lee},
journal = {Transplantation},
year = {2026},
month = oct,
doi = {10.1097/tp.0000000000005885},
url = {https://europepmc.org/article/MED/42910568},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A Single Amino Acid Polymorphism Within the α2 Domain of HLA-DQα Regulates the Assembly and Expression of HLA DQ Alleles and the Potential Clinical Impact.
AU - Thoa Nong
AU - Mayra Lopez-Cepero
AU - Cathi Murphey
AU - Jakob Nilsson
AU - Melissa Y Yeung
AU - Edgar L Milford
AU - Peter W Nickerson
AU - N Remi Shih
AU - Robert A Bray
AU - Jar-How Lee
PY - 2026
DA - 2026/10/22
JO - Transplantation
DO - 10.1097/tp.0000000000005885
UR - https://europepmc.org/article/MED/42910568
AB - Background Single antigen bead testing is currently accepted as standard practice for evaluating HLA alloantibodies. However, it is well established that the expression of HLA antigens, on beads, is not representative of actual cellular expression. It is well recognized that the cellular surface expression of certain HLA loci are expressed at relatively low levels. As such, single antigen bead data may overrepresent the impact of HLA antibodies for certain loci. Importantly, for clinical assessments, the cell surface expression of target donor HLA antigens is not routinely considered unless it is a known null allele.Methods Using a panel of variably reactive DQ4 allosera, we have evaluated DQ4 antigen assembly and surface expression on cell lines and in transfectants carrying DQ4 variants.Results A single amino acid change at residue 137 in the α2 domain of the DQα chain can significantly affect the stability of the αβ heterodimer and result in the reduced surface expression of the affected DQ antigens, resulting in changes in anti-HLA antibody reactivity.Conclusions A single amino acid residue in the DQα chain can influence the expression of a DQ4 molecule. Importantly, such surface expression variability does significantly impact allo-antibody reactivity. As a result, amino acid sequence variations in the α2 and β2 domains of the HLA class II serological groups and alleles within serological groups should be further investigated to understand the scope of allelic expression variability. Identifying low surface expressing HLA antigens/alleles might facilitate the understanding of certain discordant clinical observations.
SN - 0041-1337
SN - 1534-6080
ER -