Th17 Cells Expressing KIR3DL2+ and Responsive to HLA-B27 Homodimers Are Increased in Ankylosing Spondylitis

Bowness, Paul; Ridley, A; Shaw, Jacqueline; Chan, Antoni; Wong‐Baeza, Isabel; Fleming, Myles; Cummings, Fraser; McMichael, Andrew J.; Kollnberger, Simon

doi:10.4049/jimmunol.1002653

Cited by 278 publications

(266 citation statements)

References 33 publications

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“…It is interesting to speculate that there may be preferential recruitment of granzymeproducing subsets of these cells to the site of inflammation, as observed with killer cell immunoglobulin-like receptor 3DL2-positive Th17 cells (30). We further detected a reduction in a number of T cell receptor (TCR) signaling-related molecules, including CD81, TARP (CD3g), and CD247 (CD3z), and TCR signal strengthmodulating IL-2R (IL2RB) (31).…”

Section: Discussionmentioning

confidence: 65%

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Gracey

Yao

Green

et al. 2016

Arthritis & Rheumatology

145

101

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ObjectiveTo identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS).MethodsCohorts of male and female patients with AS and age‐ and sex‐matched healthy control subjects were selected, and the levels of serum cytokines (interferon‐γ [IFNγ], tumor necrosis factor α, interleukin‐17A [IL‐17A], and IL‐6) were examined by enzyme‐linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches.ResultsThe frequency of IL‐17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS. In contrast, AS‐associated alterations in the Th1 axis, such as the frequency of IFNγ and Th1 cells in serum, were independent of a patient's sex. Results of microarray analysis supported an altered Th17 axis in male patients, with a specific increase in IL17RA. In addition, male and female patients with AS displayed shared gene expression patterns, while male patients with AS had additional alterations in gene expression that were not seen in female patients with AS. The differential sex‐related immune profiles were independent of HLA–B27 status, clinical disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index), or treatment (with nonsteroidal antiinflammatory drugs or biologic agents), implicating intrinsic sexual dimorphism in AS.ConclusionThe results of this study demonstrate distinct sexual dimorphism in the activation status of the immune system in patients with AS, particularly in the Th17 axis. This dimorphism could underlie sex‐related differences in the clinical features of AS and could provide a rationale for sex‐specific treatment of AS.

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Section: Discussionmentioning

confidence: 65%

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Gracey

Yao

Green

et al. 2016

Arthritis & Rheumatology

145

101

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“…Additionally, HLA-B27 homodimer expressing APCs have been shown to stimulate the survival, proliferation and IL-17 production of Th17 cells that express the NK-receptor KIR3DL2 in AS patients. 65 This observation provides a link between HLA-B27 and the IL-23 signalling pathway, which will be discussed later.…”

Section: Hla-b27mentioning

confidence: 85%

The genomics and genetics of ankylosing spondylitis

Kenna¹,

Davidson²,

Thomas³

2011

AGG

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Abstract:The spondyloarthropathies are a group of arthritides which specifically target the spine and pelvis with ankylosing spondylitis (AS) being the most prevalent and debilitating of these conditions. Unique to AS is the progression to excessive uncontrolled bone formation following an initial inflammatory phase that can result in joint fusion and significant disability. Spondyloarthritis is estimated to affect 1%-2% of the population, twice as many as rheumatoid arthritis and thus constitutes a significant health problem. Currently AS pathogenesis is very poorly understood but recent large-scale genetics and gene expression profiling studies have identified some of the underlying mechanisms and pathways contributing to the disease. Genome-wide association studies have identified a number of candidate genes associated with AS sharing the same pathways which are now being targeted for therapeutic intervention. However, although such approaches can identify genes contributing to the disease process and are very informative as to disease aetiopathogenesis, they cannot profile the actual changes in gene/cell activity at any point in the disease process or possibly more importantly at specific sites. Such information is generated using expression profiling. A number of expression profiling studies have been undertaken in AS, looking at both circulating cells and tissues from affected joints. Although some common genes/pathways have been identified, overall the results to date have been somewhat disappointing due to differences in experimental design and tissue source as well as the low power of the studies. More recent better powered studies have shown some potential in developing gene expression profiling as a diagnostic tool in AS. True future success will rely on larger genetic and genomic studies and the combination of these datasets in eQTL studies requiring significant collaborative efforts. Such larger-scale approaches will also generate sufficient power to target specific disease stages and sites.

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“…HLA-B27 has a propensity to form heavy chain homodimers (B27 2 ) in the ER and nonclassical forms, including B27 2 , at the cell surface as a result of limited peptide supply, impaired peptide selection, or high B27 expression (25,26). B27 2 have thus been implicated in the pathogenesis of AS through two different mechanisms: either the induction of the unfolded protein response (UPR) in the ER (27), or activation of innate and/or Th17 cells through KIR3DL2 engagement at the cell surface (28). Our data unify these mechanisms based on an understanding of ERAP1 function.…”

Section: Discussionmentioning

confidence: 99%

Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis

Reeves¹,

Colebatch-Bourn

Elliott

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

115

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For more than 40 y, expression of HLA-B27 has been strongly associated with the chronic inflammatory disease Ankylosing Spondylitis (AS); however, the mechanisms underlying this association are still unknown. Single nucleotide polymorphisms within the aminopeptidase endoplasmic reticulum aminopeptidase 1 (ERAP1), which is essential for trimming peptides before they are presented to T cells by major histocompatibility complex (MHC) class I molecules, have been linked with disease. We show that ERAP1 is a highly polymorphic molecule comprising allotypes of single nucleotide polymorphisms. The prevalence of specific ERAP1 allotypes is different between AS cases and controls. Both chromosomal copies of ERAP1 are codominantly expressed, and analysis of allotype pairs provided clear stratification of individuals with AS versus controls. Functional analyses demonstrated that ERAP1 allotype pairs seen in AS cases were poor at generating optimal peptide ligands for binding to murine H-2K b and -D b and the AS-associated HLA-B*2705. We therefore provide strong evidence that polymorphic ERAP1 alters protein function predisposing an individual to AS via its influence on the antigen processing pathway.

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Th17 Cells Expressing KIR3DL2+ and Responsive to HLA-B27 Homodimers Are Increased in Ankylosing Spondylitis

Cited by 278 publications

References 33 publications

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

The genomics and genetics of ankylosing spondylitis

Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis

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