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Polymorphisms in the F Pocket of HLA-B27 Subtypes Strongly Affect Assembly, Chaperone Interactions, and Heavy-Chain

David B Guiliano1, Helen North2, Eleni Panayoitou3

  • 1Stratford Campus, University of East London, London, UK.

Arthritis & Rheumatology (Hoboken, N.J.)
|October 11, 2016
PubMed
Abstract

Insights

Specific differences in HLA-B27 subtypes affect its dimerization and assembly rate, influencing the development of inflammatory spondyloarthropathies (SpA). Understanding these molecular factors is key to SpA pathogenesis research.

Area of Science:

  • Immunogenetics
  • Molecular immunology
  • Protein biochemistry

Background:

  • The Human Leukocyte Antigen B27 (HLA-B27) is strongly associated with inflammatory spondyloarthropathies (SpA).
  • Certain HLA-B27 subtypes, like HLA-B*27:06 and HLA-B*27:09, are not linked to SpA, suggesting specific molecular differences are responsible.
  • The F-pocket residues (114 and 116) of the heavy chain and HLA-B27 dimerization during assembly are implicated in disease pathogenesis.

Purpose of the Study:

  • To investigate the molecular factors influencing dimerization differences between disease-associated and non-disease-associated HLA-B27 alleles.
  • To understand how specific amino acid residues in the F-pocket affect HLA-B27 assembly and dimerization.

Main Methods:

  • Expression of HLA-B*27:05 (disease-associated) and HLA-B*27:06/09-like (non-disease-associated) alleles in rat and human T cell lines.
  • Utilized immunoprecipitation, pulse-chase experiments, flow cytometry, and immunoblotting to analyze assembly kinetics, heavy-chain dimerization, and chaperone interactions.
  • Investigated the role of F-pocket residues and chaperones like calnexin and ERp57 in HLA-B27 processing.

Main Results:

  • A tyrosine at position 116, with or without aspartic acid at position 114, inhibited HLA-B27 dimerization and accelerated assembly rate.
  • Alterations in F-pocket residues modified interactions with early-stage MHC class I folding pathway chaperones.
  • Calnexin mediated ER stress-induced degradation of HLA-B27 dimers, while ERp57 did not significantly impact dimerization.

Conclusions:

  • Amino acid variations within the F-pocket of HLA-B27 influence its assembly process and heavy-chain dimerization.
  • These molecular events, modulated by F-pocket residues, are linked to the initiation of SpA pathogenesis.
  • The study highlights the critical role of specific HLA-B27 structural features in disease development.

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