scholarly journals A review of the pathogenesis of ankylosing spondylitis

2008 ◽  
Vol 24 (1) ◽  
pp. E2 ◽  
Author(s):  
Elias Dakwar ◽  
Jaypal Reddy ◽  
Fernando L. Vale ◽  
Juan S. Uribe

✓ Ankylosing spondylitis (AS) is a chronic, progressive inflammatory rheumatic disease involving primarily the sacroiliac joints and the axial skeleton. The main clinical features are back pain and progressive stiffness of the spine. Oligoarthritis of the hips and shoulders, enthesopathy, and anterior uveitis are common, and involvement of the heart and lungs is rare. The current understanding of the pathogenesis of this disorder is limited. Despite the strong association between human leukocyte antigen B27 (HLA-B27) and susceptibility to AS reported over the past 30 years, the exact pathogenic role of HLA-B27 in AS and other spondyloarthropathies has yet to be determined. The authors present a review of the literature pertaining to the pathogenesis of AS over the past several decades. Ankylosing spondylitis is a polygenic disorder, with HLA-B27 playing a critical causative role in its pathogenesis. Animal studies of the immunobiology of HLA-B27 have provided significant insight into the pathogenic role of HLA-B27. The search for the antigenic peptide to support the “arthritogenic peptide” hypothesis has been disappointing. Over the past decade there has been increasing interest in the critical role of the misfolding and unfolded protein response of the heavy chain HLA-B27 in the modulation of the inflammatory response. Although there have been significant new findings in the understanding of the pathogenesis of AS, the exact mechanisms have yet to be identified. There is considerable optimism that additional susceptibility genes, predisposing factors, and regulators of the inflammatory process will be identified that will provide avenues for future treatment.

Author(s):  
Nazanin Ebrahimiadib ◽  
Sahar Berijani ◽  
Mohammadreza Ghahari ◽  
Fatemeh Golsoorat Pahlaviani

The seronegative spondyloarthropathies are a group of autoimmune inflammatory diseases lacking rheumatoid factor or antinuclear antibody in their serum. They include ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis, spondylitis associated with Crohn’s disease and ulcerative colitis, and undifferentiated spondyloarthropathies. Inflammation mostly affects the axial joints, entheses, and extra-articular structures such as uveal tract, gastrointestinal tract, mucocutaneous tissue, and heart. Uveitis is the most common extra-articular manifestation. Spondyloarthropathies, especially AS, have a strong association with the presence of Human Leukocyte Antigen (HLA)-B27 gene. AS happens earlier in HLA-B27 patients and men are more prone to the disease. Uveitis, typically unilateral nongranulomatous acute anterior uveitis, occurs in up to 50% of the patients with AS. HLA-B27 positivity correlates with more frequent flare-ups. Conjunctivitis and scleritis are rare ocular manifestations of AS. To establish the diagnosis of AS, at least one clinical and one radiologic parameter are required for definitive diagnosis. Magnetic resonance imaging (MRI) or bone scan can help early detection of the axial skeleton inflammation. The course of eye and joint involvement are not correlated. Short-term treatment with topical corticosteroids and cycloplegic agents control the uveitis attack. In resistant cases, local or systemic therapy with corticosteroids are recommended. NSAIDs, disease-modifying anti-rheumatic drugs (DMARDs), methotrexate, azathioprine, anti-IL-17A monoclonal antibodies, and TNF- α antagonists are effective treatments for ocular and systemic manifestations of AS. If not treated adequately, uveitis may become recalcitrant and extend posteriorly. Functional impairment due to joint destruction can also occur as a result of undertreatment.


2020 ◽  
Vol 21 (17) ◽  
pp. 6401 ◽  
Author(s):  
Hiroyuki Tsukazaki ◽  
Takashi Kaito

Spondyloarthritis (SpA) is a subset of seronegative rheumatic-related autoimmune diseases that consist of ankylosing spondylitis (AS), psoriatic spondylitis (PsA), reactive spondylitis (re-SpA), inflammatory bowel disease (IBD)-associated spondylitis, and unclassifiable spondylitis. These subsets share clinical phenotypes such as joint inflammation and extra-articular manifestations (uveitis, IBD, and psoriasis [Ps]). Inflammation at the enthesis, where ligaments and tendons attach to bones, characterizes and distinguishes SpA from other types of arthritis. Over the past several years, genetic, experimental, and clinical studies have accumulated evidence showing that the IL-23/IL-17 axis plays a critical role in the pathogenesis of SpA. These discoveries include genetic association and the identification of IL-23- and IL-17-producing cells in the tissue of mouse models and human patients. In this review, we summarize the current knowledge of the pathomechanism by focusing on the IL-23/IL-17 pathway and examine the recent clinical studies of biological agents targeting IL-23 and IL-17 in the treatment of SpA.


1985 ◽  
Vol 48 (6) ◽  
pp. 538-545 ◽  
Author(s):  
DOUGLAS L. ARCHER

The role of foodborne enteric pathogens in the development of three seronegative spondarthropathies (ankylosing spondylitis, Reiter's disease and reactive arthritis) is discussed. Although the prevalence of the HLA-B27 antigen in blood-related individuals suggests a genetic predisposition to these diseases, exogenous environmental factors are also indicated. A clinical profile is given to clarify certain relationships of the seronegative arthropathies. Evidence of the involvement of enteric pathogens in the onset of these conditions following gastrointestinal illness is considered along with the interactions of general and molecular mechanisms of the disease processes and the immune response.


Open Biology ◽  
2014 ◽  
Vol 4 (2) ◽  
pp. 130217 ◽  
Author(s):  
Puneet Sharma ◽  
Alo Nag

The ability of cullin 4A (CUL4A), a scaffold protein, to recruit a repertoire of substrate adaptors allows it to assemble into distinct E3 ligase complexes to mediate turnover of key regulatory proteins. In the past decade, a considerable wealth of information has been generated regarding its biology, regulation, assembly, molecular architecture and novel functions. Importantly, unravelling of its association with multiple tumours and modulation by viral proteins establishes it as one of the key proteins that may play an important role in cellular transformation. Considering the role of its substrate in regulating the cell cycle and maintenance of genomic stability, understanding the detailed aspects of these processes will have significant consequences for the treatment of cancer and related diseases. This review is an effort to provide a broad overview of this multifaceted ubiquitin ligase and addresses its critical role in regulation of important biological processes. More importantly, its tremendous potential to be exploited for therapeutic purposes has been discussed.


2014 ◽  
Vol 66 (2) ◽  
pp. 284-294 ◽  
Author(s):  
Liye Chen ◽  
Roman Fischer ◽  
Yanchun Peng ◽  
Emma Reeves ◽  
Kirsty McHugh ◽  
...  

Author(s):  
Marjatta Leirisalo-Repo ◽  
John D. Carter

Spondyloarthritis (SpA) is the designation encompassing a group of inflammatory diseases with several features in common. The patients have mono- or oligoarthritis with or without inflammatory back symptoms. Distinctive extra-articular inflammatory symptoms also characterize the diseases. The diagnostic subgroups in the SpA family include reactive arthritis (ReA), ankylosing spondylitis (AS), arthritis associated with inflammatory bowel disease (IBD), psoriasis arthritis (PsA), and some forms of juvenile-onset arthritis. These diseases share a strong association with a genetic marker, HLA-B27, absence of rheumatoid factor, tendency to family aggregation, and frequently occurring extra-articular manifestations. This chapter discusses the role of infections, either as triggering of the disease, most evident in the case of ReA, or as possibly contributing factors in the development of chronic forms of SpA and AS.


2004 ◽  
Vol 65 (12) ◽  
pp. 1451-1454 ◽  
Author(s):  
Agathi Varnavidou-Nicolaidou ◽  
Katerina Karpasitou ◽  
Dora Georgiou ◽  
Galatia Stylianou ◽  
Avgousta Kokkofitou ◽  
...  

2017 ◽  
Vol 15 (4) ◽  
pp. 1943-1951 ◽  
Author(s):  
Bin Chen ◽  
Jia Li ◽  
Chongru He ◽  
Dahe Li ◽  
Wenwen Tong ◽  
...  

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12123-e12123
Author(s):  
Antonino Bonaventura D'Assoro

e12123 Background: Onset of metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which include dissemination of cancer cells from the primary tumor to secondary organs. NOTCH signaling plays a critical role in promoting Triple Negative Breast Cancer (TNBC) metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We established unique TNBC cells (TNBC-M14, -M25 and –M40), isolated from patient-derived brain metastasis xenografts (PD-BMXs). NOTCH3 genetic targeting was achieved using Lenti-vector shRNAs. Immunoblot analysis was used to assess NOTCH3 expression. ALDH1 activity was measured using the ALDEFLUOR Kit. To assess self-renewal capacity and resistance to docetaxel-based chemotherapy, TNBC cells were cultured under non-adherent conditions to form mammospheres (MPS). A publicly clinical database ( http://kmplot.com ) was employed to analyze NOTCH3 expression in a selected cohort of 107 lymph- node+ TNBC patients. Results: TNBC-M14, -M25 and -M40 MPS showed NOTCH3 overexpression and higher ALDH1 activity compared to MDA-MB 231 MPS used as control. To investigate the causative role of NOTCH3 in inducing ALDH1 activity, self-renewal capacity and chemoresistance, we infected TNBC MPS with Lenti-vector shRNAs targeting NOTCH3. NOTCH3 geneting targeting induced a significant reduction of ALDH1 activity compared to TNBC MPS infected with scrambled Lenti-shRNAs. NOTCH3 geneting targeting significantly impaired MPS formation and restored sensitivity to docetaxel. The correlation between aberrant NOTCH3 expression and poor outcome in patients with advanced TNBC was validated in a publicly clinical database. Conclusions: These findings provide a compelling preclinical rationale for the design of novel clinical trials that will selectively target NOTCH3 to restore chemosensitivity and to improve the progression-free survival of TNBC patients that lack FDA-approved targeted therapies.


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