Understanding the Pathogenesis of Spondyloarthritis.

Aigul Sharip,Jeannette Kunz

doi:10.3390/biom10101461

Abstract

Spondyloarthritis comprises a group of inflammatory diseases of the joints and spine, with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B*27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B*27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B*27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.

Highlights

Spondyloarthritis (SpA, called spondyloarthropathy) is a group of inflammatory diseases of the joints and spine with various clinical manifestations
These subtypes include ankylosing spondylitis (AS), reactive arthritis (ReA), psoriatic arthritis (PsA), arthritis associated with inflammatory bowel disease (SpA-IBD), and undifferentiated spondyloarthritis [2,3]
HLA-B*27 heavy chains homodimerize at the cell surface, where they act as pro-inflammatory ligands for humoral or cell-mediated autoimmune responses [14,22]

Summary

Introduction

Spondyloarthritis (SpA, called spondyloarthropathy) is a group of inflammatory diseases of the joints and spine with various clinical manifestations. Five major subtypes of SpA are recognized on the basis of the classification criteria proposed by the European Spondyloarthropathy Study Group (ESSG) [1]. These subtypes include ankylosing spondylitis (AS), reactive arthritis (ReA), psoriatic arthritis (PsA), arthritis associated with inflammatory bowel disease (SpA-IBD), and undifferentiated spondyloarthritis (uSpA) [2,3]. Several lines of evidence indicate that genetics plays an important role in individuals’ susceptibility, while environmental factors, resulting in infections and gut dysbiosis, contribute to SpA pathogenesis. SpA is strongly associated with the major histocompatibility complex (HMC) class I antigen, HLA-B*27. YIenrsiandiad,itaionnd, CCiinnalfflomlsaatpmmryidmlmoiubaaamttcootrdreyyriffiaascrpriltteehh,crrBiiiettrisiuss,ceffprlrleeraoqq, vuuaienednndettslGlyyiaaddrdeesivvoaee.lillTdoophpsesbaiffdcookellllgnoortwwiofiuiicnnnaggdtioiinnnfoffeoerccfttmtiihooinencsrewowbiihittahhylpaeeonnnttthtieegerrseiieccnssooirr[ngg17aath]nn.eiisssImmnysns,,oadsvsuuiduccimhthioaaonssf, CRleoAstriniddiuicmatedsiftfihcailte,thBorsuecealnlat,igaennds Gcainarbdieac. rTuhceiaildfeonrtoifnigcaotiinognjooifnmt iincflroabmiaml aatniotinge[1n8s].inTthheefasyctntohvaitusmomoef RSpeAA tiynpdeicsactaesn tbheattrtihggoseereadnbtiygebnasctcearnialbienfcercutcioianlsfoprroovnegsotihnegimjoipnotritnafnlcaemomf athtieosne [o1r8g]a.nTihsme sfaicnt SthpaAt psoamtheogSepnAestyisp. eTshcearnefboeret,riingagperperdopbryiabteacimtermiaulninefreecstpioonnssepsrotovecsomthme eimnspaol rbtaacntceerioafotrhaelsteeroartgioannsisimn sguint SmpiAcropbaitohtoagwenereesiasl.sTohperroepfoorsee,dintaopbperofapcrtioartseiinmSmpuAndeerveeslpoopnmseesntto. commensal bacteria or alterations in gut microbiota were proposed to be factors in SpA development

Models of SpA Pathogenesis

Arthritogenic Peptide Hypothesis

The Unfolded Protein Response Hypothesis

The ERAP Polymorphism Hypothesis

Findings

Gut Inflammation and Dysbiosis Hypothesis