scholarly journals Understanding the Pathogenesis of Spondyloarthritis

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1461
Author(s):  
Aigul Sharip ◽  
Jeannette Kunz

Spondyloarthritis comprises a group of inflammatory diseases of the joints and spine, with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B*27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B*27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B*27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.

Author(s):  
Aigul Sharip ◽  
Jeannette Kunz

Spondyloarthritis comprises of a group of inflammatory diseases of the joints and spine with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.


2013 ◽  
pp. 189-191
Author(s):  
Norma Marigliano ◽  
Domenico Galasso

Background: Seronegative spondyloarthritis is characterized by the presence of subcutaneous nodules, asymmetrical peripheral arthritis, sacroileitis with or without spondylitis, and rheumatoid-factor negativity. Other common clinical manifestations include oral ulcers, conjunctivitis, and cutaneous lesions such as psoriasis. Familial aggregation has also been described. According to the 1986 classification, corresponding clinical entities include ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome, arthritis associated with inflammatory bowel disease (IBD), and undifferentiated spondyloarthritis. The disease is also frequently associated with the HLA B27 antigen. From the clinical point of view, there are often incomplete forms of spondyloarthritis, such as reactive arthritis triggered by asymptomatic infections, psoriatic arthritis without psoriasis itself, initial phases of specific forms of spondyloarthritis or the phase of ankylosing spondylitis characterized by sacroiliac lesions, and all forms that remain undifferentiated for long periods of time. Moreover, there are close relations between arthropathy and IBDs, such as Crohn’s disease, ulcerative colitis, and Whipple’s syndrome. Recently, microscopic inflammatory bowel lesions and psoriatic arthritis have been described. Case report: A 30-year-old man (HLA B27-negative) who had been vaccinated against TBC and HBV presented with a 6-year history of recurrent episodes of predominantly left-sided sciatica. The pain was worse at night and during rest. He was suffering from bilateral sacroileitis without spondylitis. Three to five times a day, usually after eating, he passed watery feces containing mucous and small amounts of bright red blood. Colonoscopy revealed pancolitis with histological evidence of chronic inflammation interspersed with areas of acute inflammation, edema, hyperemia, and glandular distortion. One year later, the clinical manifestations and histological findings were essentially unchanged: glandular distortions, chronic and acute inflammation of the lamina propria and crypt microabscesses. There were no granulomas and no evidence of uveitis. The inflammatory index was positive; FR, ENA, ANA titers were negative. He began therapy with adalimumab (loading dose 80 mg followed by 40 mg every 15 days) and mesalazine (2.4 g per os), and the clinical manifestations of the disease improved significantly.


2019 ◽  
Vol 25 (9) ◽  
pp. 1481-1496 ◽  
Author(s):  
Kirsty M Hooper ◽  
Victor Casanova ◽  
Sadie Kemp ◽  
Katherine A Staines ◽  
Jack Satsangi ◽  
...  

Abstract Background Genetic studies have strongly linked autophagy to Crohn’s disease (CD), and stimulating autophagy in CD patients may be therapeutically beneficial. The aim of this study was to evaluate the effect of current inflammatory bowel disease (IBD) drugs on autophagy and investigate molecular mechanisms of action and functional outcomes in relation to this cellular process. Methods Autophagy marker LC3 was evaluated by confocal fluorescence microscopy and flow cytometry. Drug mechanism of action was investigated by polymerase chain reaction (PCR) array with changes in signaling pathways examined by immunoblot and quantitative reverse transcription PCR (RT-qPCR). Clearance of adherent-invasive Escherichia coli (AIEC) and levels of pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) were evaluated by gentamicin protection assays and RT-qPCR, respectively. The marker LC3 was analyzed in peripheral blood mononuclear cells (PBMCs) from pediatric patients by flow cytometry. Results Azathioprine induces autophagy via mechanisms involving modulation of mechanistic target of rapamycin (mTORC1) signaling and stimulation of the unfolded protein response (UPR) sensor PERK. Induction of autophagy with azathioprine correlated with the enhanced clearance of AIEC and dampened AIEC-induced increases in TNFα. Azathioprine induced significant increase in autophagosome bound LC3-II in PBMC populations ex vivo, supporting in vitro findings. In patients, the CD-associated ATG16L1 T300A single-nucleotide polymorphism did not attenuate azathioprine induction of autophagy. Conclusions Modulation of autophagy via mTORC1 and the UPR may contribute to the therapeutic efficacy of azathioprine in IBD.


2019 ◽  
Vol 20 (4) ◽  
pp. 857 ◽  
Author(s):  
Lorenza Sisinni ◽  
Michele Pietrafesa ◽  
Silvia Lepore ◽  
Francesca Maddalena ◽  
Valentina Condelli ◽  
...  

The unfolded protein response (UPR) is a stress response activated by the accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) and its uncontrolled activation is mechanistically responsible for several human pathologies, including metabolic, neurodegenerative, and inflammatory diseases, and cancer. Indeed, ER stress and the downstream UPR activation lead to changes in the levels and activities of key regulators of cell survival and autophagy and this is physiologically finalized to restore metabolic homeostasis with the integration of pro-death or/and pro-survival signals. By contrast, the chronic activation of UPR in cancer cells is widely considered a mechanism of tumor progression. In this review, we focus on the relationship between ER stress, apoptosis, and autophagy in human breast cancer and the interplay between the activation of UPR and resistance to anticancer therapies with the aim to disclose novel therapeutic scenarios. The hypothesis that autophagy and UPR may provide novel molecular targets in human malignancies is discussed.


2013 ◽  
Vol 144 (5) ◽  
pp. S-470 ◽  
Author(s):  
Orazio Palmieri ◽  
Teresa M. Creanza ◽  
Giuseppe Corritore ◽  
Tiziana Latiano ◽  
Nello Buccianti ◽  
...  

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