The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis

Abstract

Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. AS patients are predominantly young men, and the disease is characterized by inflammation and ankylosis, mainly at the cartilage–bone interface and enthesis. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years. Despite advances made in the past few years, progress in the search for non-human leukocyte antigen susceptibility genes has been hampered by the heterogeneity of the disease. Compared to other complex diseases, such as inflammatory bowel disease (IBD), fewer susceptibility loci have been identified in AS. Furthermore, non-major histocompatibility-complex susceptibility loci discovered, such as ERAP1 and IL23R, are likely contributors to joint inflammation. Identification and confirmation of functional variants remains a significant challenge of investigations involving genome-wide association studies (GWAS). It remains unclear why none of the AS-susceptibility genes identified in GWAS appear to be directly involved in the ankylosing process. Numerous reviews have recently been published on the genetics of AS. Therefore, aside from a brief summary of what AS GWAS has successfully achieved thus far, this review will focus on directions that could address unanswered questions raised by GWAS.

Clinical Role of Human Leukocyte Antigen in Health and Disease

“…The presence of amino acid Asp or histidine (His) at position 116 is the only difference between B*2705 and B*2709. There are three principle features of HLA-B27 that are known to distinguish it from other HLA class I molecules such as the peptide-binding specificity, the tendency to misfold and the predilection for forming heavy chain homodimers during cell-surface recycling [177,180,182]. The current hypotheses linking HLA-B27 to spondyloarthritis pathogenesis includes (1) Arthritogenic peptides: self-peptides selected and presented by properly folded forms of HLA-B27 complexed with b2 m have been hypothesized to be the target of autoreactive CD8 + T cells and serve as an upstream initiator of inflammation, (2) recognition of non-canonical HLA-B27: naturally occurring cell-surface HLA-B27 dimers are hypothesized to be recognized by killer immunoglobulin receptors (such as KIR3DL2) in the leucocyte immunoglobulin-like receptor family (LILR) and trigger inflammation and (3) HLA-B27 misfolding: the formation of misfolded oligomers and BiP binding by newly synthesized HLA-B27 heavy chains causes ER stress, which has intrinsic effects on cellular function that are hypothesized to promote development of spondyloarthritis.…”

“…The current hypotheses linking HLA-B27 to spondyloarthritis pathogenesis includes (1) Arthritogenic peptides: self-peptides selected and presented by properly folded forms of HLA-B27 complexed with b2 m have been hypothesized to be the target of autoreactive CD8 + T cells and serve as an upstream initiator of inflammation, (2) recognition of non-canonical HLA-B27: naturally occurring cell-surface HLA-B27 dimers are hypothesized to be recognized by killer immunoglobulin receptors (such as KIR3DL2) in the leucocyte immunoglobulin-like receptor family (LILR) and trigger inflammation and (3) HLA-B27 misfolding: the formation of misfolded oligomers and BiP binding by newly synthesized HLA-B27 heavy chains causes ER stress, which has intrinsic effects on cellular function that are hypothesized to promote development of spondyloarthritis. HLA-B27 can exhibit all three of these behaviours in the same cell and these concepts are not mutually exclusive [182].…”

Genética, HLA-B27 y espondilitis anquilosante: 40 años

“…Existen evidencias de la eficacia de tratamientos con ustekinumab (anticuerpo anti-IL-12p40, una de las subunidades de IL-23) y secukimumab (anticuerpo anti-IL-17) en EA, y ensayos con tofacitinib (inhibidor JAK) y fostamatinib (inhibidor TYK2) están en marcha en la actualidad. Con el objetivo de explorar nuevas terapias para pacientes con EA, especialmente para los pacientes que no responden a inhibidores de TNF-α, más estudios tienen que ser llevados a cabo 50 . Los GWAS han supuesto una herramienta vital a la hora de localizar asociaciones no-HLA en EA (Tabla 2).…”

Evaluation of MIF -173 G/C Polymorphism in Turkish Patients with Ankylosing Spondylitis

“…AS is characterized by sacroiliac joint inflammation, peripheral inflammatory arthropathy and a totally lack or low levels of rheumatoid factor (1,2). It influences EXTRA-ARTICULAR organs such as eye, skin and cardiovascular system organs less frequently.…”

“…It influences EXTRA-ARTICULAR organs such as eye, skin and cardiovascular system organs less frequently. The prevalence of AS is about 0.1-1.4% (2). Most patients develop first symptoms in the second or third decade.…”