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

Amit Kumar Thakur,Manni Luthra-Guptasarma

doi:10.3389/fimmu.2021.795053

Amit Kumar Thakur, Manni Luthra-Guptasarma

Open Access

https://doi.org/10.3389/fimmu.2021.795053

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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.

Highlights

Studies over the last two decades have helped to understand the link between the strong association of HLA-B27 and ankylosing spondylitis (AS)
Label-free quantitation of stable transfectants of H1299 cells carrying disease associated, HLA B*2704, and non-disease associated, HLA B*2709, was carried out. This was done to examine protein QC mechanisms operating in respect of the two subtypes towards clearance of protein aggregates and maintenance of cellular homeostasis
Considering the possibility that the aggregates in B*2704-expressing cells can possibly relieve the stress through other alternative pathways such as unfolded protein response (UPR), we examined the levels of UPR-related genes such as ATF4, BiP, and CHOP, consequent to CQ treatment; as expected, the levels of all three genes were significantly

Summary

Introduction

Studies over the last two decades have helped to understand the link between the strong association of HLA-B27 and ankylosing spondylitis (AS). It has been established that the heavy chain of HLAB27 has a tendency to misfold through the formation of either disulfide-linked dimers or oligomers/ high-molecular-weight (HMW) species [1,2,3]. Misfolded forms of HLA-B27 have been observed on cell surfaces, in the form of b2m-free homodimers. These are believed to cause pathology through binding with killer immunoglobulin-like receptors (KIRs) and leucocyte immunoglobulin-like receptors (LILRs), or through deposition within synovial tissues, resulting in activation and regulation of the immune system [5].

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