Comparative study of the diversity of amino acids on human leucocyte antigen class II molecules in patients with acquired aplastic anaemia
Jun Qi
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorTianju Wang
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorManni Wang
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorPengcheng He
Department of Hematology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi Province, China
Search for more papers by this authorYuhui Li
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorLixia Shang
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorLe Chen
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorXiaofang Wang
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorCorresponding Author
Hua Xu
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Correspondence
Chaofeng Ma and Hua Xu, HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Zhuque Road 407, Xi'an, Shaanxi Province 710061, China.
Email: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Chaofeng Ma
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Correspondence
Chaofeng Ma and Hua Xu, HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Zhuque Road 407, Xi'an, Shaanxi Province 710061, China.
Email: [email protected] and [email protected]
Search for more papers by this authorJun Qi
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorTianju Wang
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorManni Wang
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorPengcheng He
Department of Hematology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi Province, China
Search for more papers by this authorYuhui Li
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorLixia Shang
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorLe Chen
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorXiaofang Wang
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Search for more papers by this authorCorresponding Author
Hua Xu
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Correspondence
Chaofeng Ma and Hua Xu, HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Zhuque Road 407, Xi'an, Shaanxi Province 710061, China.
Email: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Chaofeng Ma
HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Xi'an, Shaanxi Province, China
Correspondence
Chaofeng Ma and Hua Xu, HLA Laboratory, Shaanxi Province Blood Center, Institute of Xi'an Blood Bank, Zhuque Road 407, Xi'an, Shaanxi Province 710061, China.
Email: [email protected] and [email protected]
Search for more papers by this authorChaofeng Ma and Hua Xu contributed equally to this work.
Summary
Human leucocyte antigen (HLA) class II molecules are critically involved in the pathology of acquired aplastic anaemia (AA) by regulating the immune response and autoreactive T cell-mediated haematopoietic cell death. In the study, amino acid residue variation and molecular structure of HLA class II have been initially investigated in 96 patients with AA. The frequencies of residues 9 and 57 in pocket 9 (P9) in DQB1, and amino acid positions 9, 11, 13, 16, 26, 38, 67 and 71 in the P4, P6 and P9 pockets in DRB1 were more prevalent among AA patients. By applying a multivariate recursive approach, the DRβ-Gln-16 (OR = 3.003, 95% CI = 1.468–6.145, pc = 0.003), DRβ-Ala-71 (OR = 1.924, 95% CI = 1.233–3.002, pc = 0.004) in P4/P7 and DQβ-Asp-57 (OR = 3.483, 95% CI = 1.079–11.242, pc = 0.037) in P9, these critical residues were significantly discovered as risk amino acid residues on the onset of AA, as well as associated with PNH-type cells and pathological somatic or cytogenetic mutations. In silico structural model analysis showed that identified DRβ-Ala-71 and DQβ-Asp-57 within the antigen-binding groove interacting with a more variable antigenic segments, may impact the repertoire of peptides presented, influence the interface HLA-antigen-T-cell receptor β (TCR β). These findings provided light on the immunogenetic pathophysiology of AA aetiology and their potential impact on upcoming immunotherapies.
Graphical Abstract
As an immunogenetic disease susceptibility factor, human leucocyte antigen (HLA) class II loci involve in the pathophysiology of acquired aplastic anaemia (AA) by regulating the immune response and autoreactive T-cell-mediated haematopoietic cell death. Distinctive amino acid configurations encoded by the at-risk HLA alleles enriched in AA patients impact the immune presentation of the peptide repertoire derived from haematopoietic stem/progenitor cells. DRβ-Ala-71, DQβ-Asp-57 and DRβ-Gln-16 are discovered as crucial risk amino acid residues in HLA II class proteins on the onset of AA, as well as associated with paroxysmal nocturnal haemoglobinuria (PNH)-type cells and pathological somatic or cytogenetic mutations. DRβ-Ala-71 and DQβ-Asp-57 within the antigen-binding groove interacting with a more variable antigenic segments, may impact the repertoire of peptides presented, influence the interface HLA-antigen-T-cell receptor β (TCR β).
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data used to support the findings of this study are available from the corresponding author upon request.
Supporting Information
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Table S1. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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