High Association of an HL-A Antigen, W27, with Ankylosing Spondylitis

Schlosstein, Lee; Terasaki, Paul I.; Bluestone, Rodney; Pearson, Carl M.

doi:10.1056/nejm197304052881403

Cited by 1,284 publications

(474 citation statements)

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“…The high frequency of idiopathic ankylosing spondylitis and Reiter's syndrome in these HLA-B27 patients (81%) was not unexpected since this association has been extensively documented (1,2,(4)(5)(6)(7)(8)(9)(10)(11)(12). Recent studies have emphasized the clinical diversity of these and related spondylarthritic syndromes and the potential importance of HLA typing in the diagnosis of early, ill defined, or atypical seronegative arthritides (25-29).…”

Section: Discussionmentioning

confidence: 65%

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High prevalence of hla‐cw1 and cw2 antigens in spondylarthritis

Kozin

Duquesnoy

Rodey

et al. 1978

Arthritis & Rheumatism

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HLA‐B27 is frequently, but not invariably, found in patients with spondylarthritic diseases. Recently it has been shown that HLA‐C‐locus antigens w1 and w2 (w1/2) are in linkage disequilibrium with B27. A group of 139 patients with seronegative arthritis or spondylitis has been studied to determine the clinical and radiographic features associated with these antigens. An increased frequency of spondylarthritis was present in HLA‐B27‐negative, Cw1/2‐positive patients when compared with B27‐ and Cw1/2‐negative patients (P < 0.01). In addition, a large group of patients who did not fulfill accepted criteria for a specific spondylarthritic syndrome were identified; the frequency of both HLA‐B27 and Cw1/2 was greater in these individuals than in healthy blood donors. Thus HLA‐Cw1/2 are spondylitis‐associated antigens. These findings suggest that the critical genetic locus is neither B27 nor Cw1/2 but is a closely linked gene.

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Section: Discussionmentioning

confidence: 65%

“…The high prevalence of transplantation antigen HLA-B27 in spondylarthritis is well established (1)(2)(3)(4)(5)(6)(7)(8)(9). This association is particularly strong in idiopathic ankylosing spondylitis and Reiter's syndrome where B27 is present in 88-96% (1, 2) and 63-96% (4-9) of cases, respectively.…”

mentioning

confidence: 99%

High prevalence of hla‐cw1 and cw2 antigens in spondylarthritis

Kozin

Duquesnoy

Rodey

et al. 1978

Arthritis & Rheumatism

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“…HLA-B27 is an MHC-encoded class I protein that is linked to the development of spondyloarthritis (SpA) including ankylosing spondylitis [22,23], and when expressed in rats along with human b 2 m (HLA-B27-Tg) results in the development of an inflammatory disease that recapitulates many features of human SpA [24]. A proportion of HLA-B27 misfolds in the ER, resulting in increased degradation by ERAD [25], and formation of disulfide-linked and BiP-bound complexes [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

et al. 2008

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Type I IFN are strongly induced upon engagement of certain pattern recognition receptors by microbial products, and play key roles in regulating innate and adaptive immunity. It has become apparent that the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), in addition to restoring ER homeostasis, also influences the expression of certain inflammatory cytokines. However, the extent to which UPR signaling regulates type I IFN remains unclear. Here we show that cells undergoing a UPR respond to TLR4 and TLR3 ligands, and intracellular dsRNA, with log-fold greater IFN-b induction. This synergy is not dependent on autocrine type I IFN signaling, but unexpectedly requires the UPR transcription factor X-box binding protein 1 (XBP-1). Synergistic IFN-b induction also occurs in HLA-B27/human b 2 m-transgenic rat macrophages exhibiting a UPR as a consequence of HLA-B27 up-regulation, where it correlates with activation of XBP-1 splicing. Together these findings indicate that the cellular response to endogenous 'danger' that disrupts ER homeostasis is coupled to IFN-b induction by XBP-1, which has implications for the immune response and the pathogenesis of diseases involving the UPR.Key words: HLA-B27 Á Interferons Á Protein misfolding Á Unfolded protein response IntroductionInitially identified as antiviral cytokines, type I IFN (IFN-a/b) are now recognized to have diverse immunoregulatory effects activating macrophages and NK cells, promoting T cell survival and dendritic cell (DC) maturation, and increasing the production of Th1-polarizing cytokines to mediate innate and adaptive immune responses [1]. Type I IFN also exert biological effects at low and even constitutive levels of expression [2]. For example, weak IFN-b-mediated signaling augments IFN-a/b induction in response to LPS through positive feedback involving autocrine/ paracrine up-regulation of IFN regulatory factor (IRF)7. In addition, low levels of IFN-a/b prime cells to respond to IFN-c and IL-6 by providing a phosphorylated type I IFN receptor 'niche' for commonly used signaling molecules in proximity to other cytokine receptor complexes [3,4]. Mice deficient in IFN-b are more susceptible to viral infection, have lower numbers of macrophages and mature B cells, and exhibit reduced bone mass [5], as IFN-b is a positive regulator of bone formation through inhibition of osteoclast differentiation [6]. Thus, even constitutive levels of this cytokine are important in osteo-immune homeostasis.IFN-b is produced by most cell types upon viral infection, and in large amounts by macrophages and DC, following engagement of pattern recognition receptors (PRR) by conserved molecular structures referred to as pathogen-associated molecular patterns [7, 8]. PRR that mediate IFN-b induction include cell surface TLR4 and endosomal TLR3 for LPS and dsRNA, respectively [9]. In both instances increased IFN-b gene transcription occurs via TLR/IL-1R domain-containing adapter inducing IFN-b (TRIF)-dependent IRF3 and NF-jB activation. PRR in the retinoic ...

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“…The significance of this lies in the undisputed association of AS with HLA-B27 Brewerton et al 1973;Schlosstein et al 1973), and strongly suggests that molecular mimicry could play a role in the pathogenesis of AS. Welsh et al (1980) demonstrated cross-reactions between rabbit anti-human B27 lymphocyte sera and some gram-negative bacteria including klebsiella and Avakian et al (1980) showed cross-reactions between mono-specific HLA-B27 typing sera and klebsiella antigens.…”

Section: Introductionmentioning

confidence: 90%