Differences in Cellular Clearing Mechanisms of Aggregates of Two Subtypes of HLA-B27

Front Immunol. 2022 Jan 10:12:795053. doi: 10.3389/fimmu.2021.795053. eCollection 2021.

Abstract

Ankylosing spondylitis (AS) belongs to a group of diseases, called spondyloarthropathies (SpA), that are strongly associated with the genetic marker HLA-B27. AS is characterized by inflammation of joints and primarily affects the spine. Over 160 subtypes of HLA-B27 are known, owing to high polymorphism. Some are strongly associated with disease (e.g., B*2704), whereas others are not (e.g., B*2709). Misfolding of HLA-B27 molecules [as dimers, or as high-molecular-weight (HMW) oligomers] is one of several hypotheses proposed to explain the link between HLA-B27 and AS. Our group has previously established the existence of HMW species of HLA-B27 in AS patients. Still, very little is known about the mechanisms underlying differences in pathogenic outcomes of different HLA-B27 subtypes. We conducted a proteomics-based evaluation of the differential disease association of HLA B*2704 and B*2709, using stable transfectants of genes encoding the two proteins. A clear difference was observed in protein clearance mechanisms: whereas unfolded protein response (UPR), autophagy, and aggresomes were involved in the degradation of B*2704, the endosome-lysosome machinery was primarily involved in B*2709 degradation. These differences offer insights into the differential disease association of B*2704 and B*2709.

Keywords: HLA-B27 alleles; aggregates; clearance; high molecular weight (HMW); proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics
  • Autophagy / immunology
  • Cell Line, Tumor
  • Chromatography, Liquid / methods
  • Endosomes / immunology
  • Endosomes / metabolism
  • Genetic Predisposition to Disease*
  • HLA-B27 Antigen / genetics
  • HLA-B27 Antigen / immunology*
  • HLA-B27 Antigen / metabolism
  • Humans
  • Lysosomes / immunology
  • Lysosomes / metabolism
  • Mass Spectrometry / methods
  • Polymorphism, Genetic / genetics
  • Polymorphism, Genetic / immunology*
  • Protein Aggregates / genetics
  • Protein Aggregates / immunology
  • Proteome / genetics
  • Proteome / immunology
  • Proteome / metabolism
  • Proteomics / methods*
  • Spondylitis, Ankylosing / genetics
  • Spondylitis, Ankylosing / immunology*
  • Spondylitis, Ankylosing / metabolism
  • Unfolded Protein Response / genetics
  • Unfolded Protein Response / immunology

Substances

  • HLA-B*27:04 antigen
  • HLA-B27 Antigen
  • Protein Aggregates
  • Proteome