Identification of disease-associated proteins by proteomic approach in ankylosing spondylitis

Liu, Jing; Zhu, Ping; Peng, Jiarou; Li, Keqiu; Du, Jiang; Gu, Jiangying; Ou, Yuan

doi:10.1016/j.bbrc.2007.03.179

Cited by 26 publications

(22 citation statements)

References 28 publications

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“…The authors investigated the serum protein profiles of ankylosing spondylitis patients and healthy controls from a large Chinese ankylosing spondylitis family using two-dimensional electrophoresis analysis. A group of four highly expressed protein spots was observed in all ankylosing spondylitis patients' profiles and subsequently identified as isoforms of HP by ESI-Q-TOF MS/MS (95). Increased expression of HP was also observed in sera of sporadic ankylosing spondylitis patients.…”

Section: Diseases In Which Zonulin Has Been Identified As a Biomarkermentioning

confidence: 77%

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

Fasano

2011

Physiological Reviews

762

633

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The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a “leaky gut” in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.

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Section: Diseases In Which Zonulin Has Been Identified As a Biomarkermentioning

confidence: 77%

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

Fasano

2011

Physiological Reviews

762

633

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“…70 Four isoforms of prehaptoglobin were found to be highly expressed in all the study patients with active disease. The decapeptide VRYQCKNYYK was predicted to have a much higher binding affinity to HLA-B27 than conventional epitopes, and so it was concluded that prehaptoglobin is involved in the pathogenesis of AS.…”

Section: The Role Of Hla-b27 In Asmentioning

confidence: 88%

The pathogenesis of ankylosing spondylitis

Shamji

Bafaquh²,

Tsai³

2008

FOC

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✓ Ankylosing spondylitis (AS) is a chronic inflammatory disease that can cause significant functional complications by affecting the sacroiliac joints and axial skeleton. Despite a longstanding knowledge about the familial associations of this disease, particularly among patients positive for human leukocyte antigen (HLA)–B27, the fundamental pathogenetic mechanism by which this disease arises in genetically susceptible individuals remains ill defined. Furthermore, the molecular predilection for characteristic articular site involvement remains under ongoing investigation. Current theories about the HLA-B27 association range from the presentation of novel arthritogenic peptides, to abnormal autoimmune stimulation, to anomalous microbial tolerance. The immune effectors of this damage include CD4+, CD8+, and natural killer cells, with marked heterogeneity at different sites. Biomechanical stresses may trigger this disease by exposing the body to previously immune-sequestered autoantigens or by providing a route for bacterial seeding. Environmental triggers such as infection have not been definitively established but may represent a primary pathogenic step in a molecular-mimicry process. In this article, the authors review the current literature on the origin and pathophysiology of AS, focusing on genetic and molecular associations, consequent pathomechanisms, and associated triggers. An improved understanding of the sequence of molecular events that predispose and initiate the onset of this disease will allow for more specific and targeted therapy and better avoidance of the significant side effects of systemic immunomodulation.

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“…Therefore, the concentrations of zonulin used in this study are within physiological range and are most likely indicative of the signaling pathways activated when zonulin is up-regulated during pathological processes. Besides CD, increased IP has been reported in other autoimmune diseases, including T1D (11), systemic lupus erythematosus (37), and ankylosing spondylitis (38), further delineating the importance of the paracellular pathway in the pathogenesis of autoimmune diseases. These findings, together with the observation that zonulin is overexpressed during the acute phase of several immune-mediated diseases and its blockage prevents the onset of the autoimmune response, suggest that zonulin contributes to the pathogenesis of these conditions, opening previously undescribed paradigms in the pathobiology and treatment options of immune-mediated diseases.…”

Section: Discussionmentioning

confidence: 99%

Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2

Tripathi¹,

Lammers²,

Goldblum³

et al. 2009

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

350

355

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Increased intestinal permeability (IP) has emerged recently as a common underlying mechanism in the pathogenesis of allergic, inflammatory, and autoimmune diseases. The characterization of zonulin, the only physiological mediator known to regulate IP reversibly, has remained elusive. Through proteomic analysis of human sera, we have now identified human zonulin as the precursor for haptoglobin-2 (pre-HP2). Although mature HP is known to scavenge free hemoglobin (Hb) to inhibit its oxidative activity, no function has ever been ascribed to its uncleaved precursor form. We found that the single-chain zonulin contains an EGF-like motif that leads to transactivation of EGF receptor (EGFR) via proteinase-activated receptor 2 (PAR 2) activation. Activation of these 2 receptors was coupled to increased IP. The siRNA-induced silencing of PAR 2 or the use of PAR 2 ؊/؊ mice prevented loss of barrier integrity. Proteolytic cleavage of zonulin into its ␣2-and ␤-subunits neutralized its ability to both activate EGFR and increase IP. Quantitative gene expression revealed that zonulin is overexpressed in the intestinal mucosa of subjects with celiac disease. To our knowledge, this is the initial example of a molecule that exerts a biological activity in its precursor form that is distinct from the function of its mature form. Our results therefore characterize zonulin as a previously undescribed ligand that engages a key signalosome involved in the pathogenesis of human immunemediated diseases that can be targeted for therapeutic interventions.autoimmune diseases ͉ epidermal growth factor receptor ͉ gut permeability ͉ proteinase-activated receptor 2 ͉ celiac disease

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Identification of disease-associated proteins by proteomic approach in ankylosing spondylitis

Cited by 26 publications

References 28 publications

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

The pathogenesis of ankylosing spondylitis

Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2

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