title: Revisiting the structural basis and energetic landscape of susceptibility difference between HLA isotypes to allergic rhinitis.
abstract: The human leukocyte antigen class II (HLA II) molecules are implicated in the immunopathogenesis of allergic rhinitis (AR). The HLA II contains three allelic isotypes HLA-DR, -DQ, and -QP that exhibit considerably different susceptibility to AR. Here, we investigated the structural basis and energetic landscape of the susceptibility difference between the three HLA II isotypes to AR by combining computational analysis and experimental assay. Multiple sequence alignment revealed a low conservation among the three subtypes with sequence identity of ∼10% between them, suggesting that the peptide repertoires presented by HLA-DR, -DP and -DQ are not overlapped to each other, and they may be involved in different immune functions and dysfunctions. Structural analysis imparted that the antigenic peptides are rooted on the peptide-binding groove of HLA molecules and hold in a PPII-like helical conformation. Subsequently, the interaction behavior of 17 AR allergen-derived peptides with HLA-DR, -DP and -DQ was investigated using a statistics-based quantitative structure-activity relationship (QSAR) predictor. It was found a significant difference between the binding capabilities of these antigenic peptides to HLA-DR and to HLA-DP/-DQ; the former showed a generally higher affinity than the latter with p-value of 0.02 obtained from 2-tailed Student's t-test. The computational findings were then confirmed by HLA II-peptide stability assay, which demonstrated that the AR allergen-derived peptides have a high in vitro selectivity for HLA-DR over HLA-DP/-DQ. Thus, the HLA-DR isotype, rather than HLA-DP and -DQ, is expected to associate with the pathological process of AR.
authors.affiliation: Department of Otorhinolaryngology (E.N.T.), Taizhou Hospital of Zhejiang Provience, Linhai 317000, China.
authors.forename: Xin-Li
authors.initials: XL
authors.lastname: Mao
authors.affiliation: Department of Otorhinolaryngology (E.N.T.), Taizhou Hospital of Zhejiang Provience, Linhai 317000, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Otorhinolaryngology (E.N.T.), Taizhou Hospital of Zhejiang Provience, Linhai 317000, China.
authors.forename: Zhao-Hu
authors.initials: ZH
authors.lastname: Pan
authors.affiliation: Department of Otorhinolaryngology (E.N.T.), Taizhou Hospital of Zhejiang Provience, Linhai 317000, China.
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Wu
authors.affiliation: Department of Otorhinolaryngology (E.N.T.), Taizhou Hospital of Zhejiang Provience, Linhai 317000, China. Electronic address: zhuhy9@163.com.
authors.forename: Hong-Yuan
authors.initials: HY
authors.lastname: Zhu
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004198:Disease Susceptibility; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D065631:Rhinitis, Allergic / Q000235:genetics / Q000276:immunology*
chemical_list: D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007132:Immunoglobulin Isotypes
keywords: Allergen peptide; Allergic rhinitis; HLA isotype; Immune