Auto-antibodies to vascular endothelial cadherin in humans: association with autoimmune diseases

Bouillet, Laurence; Baudet, A.; Deroux, Alban; Sidibé, Adama; Dumestre-Pérard, Chantal; Mannic, Tiphaine; Treillard, Bertrand; Arboléas, Mélanie; Chiquet, Christophe; Gulino-Debrac, Danièle; Vilgrain, Isabelle

doi:10.1038/labinvest.2013.106

Cited by 18 publications

(11 citation statements)

References 33 publications

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“…It belongs to the cadherin superfamily and is expressed in the kidney and the thyroid gland. Although CDH16 has not been described as an autoantigen, autoantibodies to vascular endothelial cadherin are reported to be a marker of endothelial dysfunction in autoimmune diseases [59].…”

Section: Resultsmentioning

confidence: 99%

A repertoire of 124 potential autoantigens for autoimmune kidney diseases identified by dermatan sulfate affinity enrichment of kidney tissue proteins

Zhang

Rho²,

Roehrl³

et al. 2019

PLoS ONE

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Autoantigens are the molecular targets in autoimmune diseases. They are a cohort of seemingly unrelated self-molecules present in different parts of the body, yet they can trigger a similar chain of autoimmune responses such as autoantibody production. We previously reported that dermatan sulfate (DS) can bind self-molecules of dying cells to stimulate autoreactive CD5+ B cells to produce autoantibodies. The formation of autoantigen-DS complexes converts the normally non-antigenic self-molecules to none-self antigens, and thus DS-affinity represents a common underlying biochemical property for autoantigens. This study sought to apply this property to identify potential autoantigens in the kidney. Total proteins were extracted from mouse kidney tissues and loaded onto DS-Sepharose resins. Proteins without affinity were washed off the resins, whereas those with increasing DS-affinity were eluted with step gradients of increasing salt strength. Fractions with strong and moderate DS-affinity were sequenced by mass spectrometry and yielded 25 and 99 proteins, respectively. An extensive literature search was conducted to validate whether these had been previously reported as autoantigens. Of the 124 proteins, 79 were reported autoantigens, and 19 out of 25 of the strong-DS-binding ones were well-known autoantigens. Moreover, these proteins largely fell into the two most common autoantibody categories in autoimmune kidney diseases, including 40 ANA (anti-nuclear autoantibodies) and 25 GBM (glomerular basement membrane) autoantigens. In summary, this study compiles a large repertoire of potential autoantigens for autoimmune kidney diseases. This autoantigen-ome sheds light on the molecular etiology of autoimmunity and further supports our hypothesis DS-autoantigen complexes as a unifying principle of autoantigenicity.

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Section: Resultsmentioning

confidence: 99%

A repertoire of 124 potential autoantigens for autoimmune kidney diseases identified by dermatan sulfate affinity enrichment of kidney tissue proteins

Zhang

Rho²,

Roehrl³

et al. 2019

PLoS ONE

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“…VE-cadherin is a transmembrane protein which plays an essential role in stabilizing adherens junctions between endothelial cells [18]. A recent publication [11] reported an increase in serum levels of this protein during an episode of bradykinin-mediated AE and an increased release of VE-cadherin upon exposure of an endothelial cell monolayer to bradykinin and kallikrein.…”

Section: Discussionmentioning

confidence: 99%

BIOBRAD Study: The Search for Biomarkers of Bradykinin-Mediated Angio-Oedema Attacks

Deroux¹,

Dumestre-Pérard²,

Khalil-Mgharbel³

et al. 2016

Int Arch Allergy Immunol

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Background: The aetiology of angio-oedema (AE) is difficult to determine; however, it is essential in emergency situations when two major contexts may be present: mast cell-mediated AE and bradykinin-mediated AE. Different forms of AE are currently distinguished based on clinical criteria (spontaneous duration of the attack, presence of concomitant or late-appearing superficial urticaria, history of atopy, and others), but specific biomarkers could improve patient management. Objective: In this prospective study, potential biomarkers have been identified, and their statistical characteristics were examined. Methods: Samples were taken on day 0 (D0) and D7 for 3 patient groups (n = 11 each): bradykinin-mediated AE [peripheral site of attack, ear, nose, throat (ENT), and abdominal involvement], mast cell-mediated AE, and non-bradykinin-mediated abdominal pain. Results: Assay of the potential biomarkers revealed no significant differences in C1 inhibitor and C4 levels. In contrast, D-dimer levels peaked during bradykinin-mediated AE attacks (median 2.2 mg/l at D0 vs. 0.52 mg/l at D7; p < 10^-3) as well as during mast cell-mediated AE attacks (1.97 vs. 0.65 mg/l; p = 0.04) and were high in bradykinin-mediated AE compared to the control group (0.69 mg/l; p = 0.01). A threshold value of 0.62 mg/l was found to have a negative predictive value of 100% for bradykinin-mediated AE compared to other causes of abdominal pain (group 3). Circulating VE-cadherin levels were also increased during an attack (1,990 at D0 vs. 1,566 ng/ml at D7; p = 0.01), but could not distinguish between bradykinin-mediated and mast cell-mediated AE, like D-dimers. Conclusions: Exploration of changes in fibrinolysis-related markers (particularly D-dimers) is thus promising for the diagnosis of AE attacks in difficult-to-diagnose abdominal forms, although it was not able to differentiate between bradykinin and mast cell-mediated AE.

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“…34 Thus, exposure of an endothelial cell monolayer to these antibodies in vitro decreases the adhesive function of VEC resulting in the monolayer dissociation and enhanced vascular permeability. 35 And, in vivo, the effect of these antibodies appeared to be much stronger than the effect of other antibodies against several other adhesion molecules located at the endothelial cell interfaces. 4 Antibodies directed against the extracellular domain of VEC were shown to increase vascular permeability, while decreasing tumor growth and metastasis were observed.…”

Section: Auto-antibodies To Human Vec (Aaves) Are Associated With Autmentioning

confidence: 97%

Soluble vascular endothelial-cadherin and auto-antibodies to human vascular endothelial-cadherin in human diseases: Two new biomarkers of endothelial dysfunction

2015

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Vascular endothelial-cadherin is the most important transmembrane component of endothelial adherens junctions, exclusively expressed by endothelial cells in all types of vessels. Targeting either the extracellular domain or the cytoplasmic tail deleteriously affects the junctional strength and leads to vascular permeability. Recently, cytokineinduced phosphorylation of the vascular endothelial-cadherin cytoplasmic domain was reported to trigger cleavage of its extracellular domain, producing the soluble form of the protein -soluble vascular endothelial-cadherin. Hence, the presence of soluble vascular endothelial-cadherin or auto-antibodies to human vascular endothelial-cadherin in human serum could signalize the presence of vascular abnormalities. This systematic review covers many human studies reporting increased levels of soluble vascular endothelial-cadherin, as well as auto-antibodies to human vascular endothelial-cadherin, which could be promising biomarkers of endothelial dysfunction in a large panel of diseases.

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Auto-antibodies to vascular endothelial cadherin in humans: association with autoimmune diseases

Cited by 18 publications

References 33 publications

A repertoire of 124 potential autoantigens for autoimmune kidney diseases identified by dermatan sulfate affinity enrichment of kidney tissue proteins

A repertoire of 124 potential autoantigens for autoimmune kidney diseases identified by dermatan sulfate affinity enrichment of kidney tissue proteins

BIOBRAD Study: The Search for Biomarkers of Bradykinin-Mediated Angio-Oedema Attacks

Soluble vascular endothelial-cadherin and auto-antibodies to human vascular endothelial-cadherin in human diseases: Two new biomarkers of endothelial dysfunction

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