Interferon- Contributes to HLA-B27-associated Unfolded Protein Response in Spondyloarthropathies
Department of Clinical Immunology, State Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China. The Journal of Rheumatology
(Impact Factor: 3.19).
03/2012; 39(3):574-82. DOI: 10.3899/jrheum.101257
HLA-B27 positivity strongly influences the susceptibility to and phenotype of spondyloarthropathies (SpA). This study was designed to screen factors that activate the promoter of HLA-B27 in U937 cells, and to assess whether these promoter-activating factors induce the unfolded protein response (UPR) in HLA-B27-expressing cells.
Cytometric Bead Array, flow cytometry, and real-time polymerase chain reaction were used to detect the expression of cytokines and UPR-associated proteins in peripheral blood and synovial fluid of patients with SpA. The HLA-B27 promotor transfectant was incubated separately with cytokines and Toll-like receptor ligands. After interferon-γ (IFN-γ) stimulation, expressions of GRP78, CHOP, and XBP-1 were tested in HLA-B27-expressing U937 cells and peripheral blood mononuclear cell (PBMC) of patients with ankylosing spondylitis (AS). (Clinical trial registration no. ChiCTR-OCC-11001565)
Expressions of GRP78, CHOP, and XBP-1 in monocytes/macrophages of SpA peripheral blood and synovial fluid were higher than those in healthy controls and patients with osteoarthritis (OA) (p < 0.05). Tumor necrosis factor-α (TNF-α) and IFN-α, IFN-ß, and IFN-γ were found to have activated the HLA-B27 promoter in the U937 cell line (p < 0.05). Following stimulation with IFN-γ, the expressions of GRP78, CHOP and XBP-1 in HLA-B27-transfected U937 cells and PBMC of HLA-B27-positive AS patients were more intense than those in A2-U937 cells, HLA-B27-negative AS patients, or healthy controls (p < 0.05).
Expressions of GRP78, CHOP, and XBP-1 were higher in monocytes/macrophages of patients with SpA than those in both OA patients and healthy controls, suggesting that UPR may participate in the pathogenesis of SpA. TNF-α and IFN-α, IFN-ß, and IFN-γ significantly activated HLA-B27 promoter in the U937 cell line, and IFN-γ, the strongest activating factor, may induce the UPR in HLA-B27-expressing cells.
Available from: PubMed Central
- "Structurally, the molecule differs from other HLA molecules due to slow folding heavy chains, which form aberrant dimers [41, 42]. It is thought that these aberrant dimers accumulate within cells leading to increased unfolded protein response (UPR) that activates the stress response in cells [43, 44]. Markers of the UPR were associated with increased exposure to proinflammatory cytokines such as IFN-γ . "
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ABSTRACT: Inflammatory arthritis is a condition which is characterised by recurrent episodes of joint pain and swelling. It encompasses a spectrum of disorders ranging from rheumatoid arthritis to ankylosing spondylitis. In these conditions, for reasons that are poorly understood, the immune system raises an inflammatory response within the joint space. In some cases, autoantigens have been identified (e.g., anticitrullinated peptides in rheumatoid arthritis), but the absence of these, in the seronegative arthritides, for example, raises question as to the underlying pathogenesis. Interest has, therefore, turned to host-pathogen interactions and whether aberrant immune responses to these could explain the development of arthritis. This has been most widely studied in reactive arthritis (ReA), where an infectious episode precedes the development of the joint symptoms. In this review, we present the evidence for the role of host-bacterial interactions in the pathogenesis of joint inflammation with particular emphasis on ReA. We discuss a range of possible mechanisms including molecular mimicry, persistent low grade infections, and abnormal host responses to common bacterial causes of reactive arthritis as well as discussing some of the clinical challenges that we face in making the diagnosis and in treatment of persistent symptoms.
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ABSTRACT: Ankylosing spondylitis (AS) is a chronic disease characterized by inflammatory back pain and progressive stiffening of the spine. The association between AS and HLA-B27, a major histocompatibility complex class I molecule, has been known since 1973. Despite intense interest and active investigations into the role of HLA-B27 in the pathogenesis of AS, the specific role of HLA-B27 in AS is not yet known. One of the postulated hypotheses states that misfolding of the HLA-B27 heavy chains causes activation of the unfolded protein response, which sensitizes cells to proinflammatory cytokine production. The IL-23/Th17 axis may play an important role in this pathway. As AS is a multifactorial disease, not only genetic factors are of interest, but environmental factors, such as biomechanical stress, may also play an important role in the pathogenesis. None of the postulated mechanisms regarding the pathogenesis of AS have been strictly proven, but current results from studies are promising.
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ABSTRACT: Purpose of review:
Although scientists in China have generated a considerable amount of new information about spondyloarthritis (SpA) in recent years, part of it was published in Chinese. The aim of this review is to summarize all SpA articles for the benefit of English readers.
In the field of epidemiology, prevalence of SpA in China has been updated, especially with regard to psoriatic arthritis (PsA). In the field of genetics, Chinese scientists have discovered new single-nucleotide polymorphism (SNP) sites association with ankylosing spondylitis (AS) in Han Chinese. In the field of treatment, tumour necrosis factor-alpha (TNF-α) antagonists are wildly used almost as a routine. The usefulness of certain Chinese traditional medicine is undergoing vigorous testing. In the field of diagnosis, ultrasound has been incorporated into the testing tools. In the field of monitoring of disease activity, Ankylosing Spondylitis Disease Activity Scores (ASDAS) has been validated in a cohort of Chinese SpA patients.
Chinese scientists are using cutting-edge technology in the fields of research, diagnosis and management in SpA. What is needed are new approaches that can accommodate the large variations in socioeconomic status of various localities in the vast Chinese continent.
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