Expression of Tissue Factor by Eosinophils in Patients with Chronic Urticaria

Abstract

Background: Although several cases of chronic urticaria (CU) are currently regarded as autoimmune in origin, associated with histamine-releasing autoantibodies, an activation of blood coagulation via tissue factor (TF) and a strong expression of TF in lesional skin have been described. Eosinophils, which are involved in CU skin lesions, have recently been demonstrated as the major source of TF in human blood. We assessed whether eosinophils are the cellular source of TF in CU skin lesions. Methods: Twenty patients with severe CU were studied. Skin biopsy specimens were taken from wheals. The control group consisted of specimens of perilesional normal skin from different types of skin tumours (10) and various skin disorders with non-eosinophilic infiltrates, including leukocytoclastic vasculitis (7), lichen planus (8) and mastocytosis (3). TF expression was evaluated by immunohistochemical methods using an anti-TF monoclonal antibody. Co-localization of TF and eosinophil cationic protein, a classic cell marker of eosinophils, was investigated by double-staining studies using 2 specific monoclonal antibodies in the 4 specimens showing the highest TF reactivity scores. Results: All specimens from patients with CU clearly showed TF expression that was absent in all normal control specimens (p = 0.0001) and in the skin disorders with non-eosinophilic infiltrates (p = 0.001–0.0001). The double-staining experiments for TF and eosinophil cationic protein clearly showed that the TF-positive cells were eosinophils. Conclusions: Eosinophils are the main source of TF in CU lesional skin. This finding highlights the role of these cells in the pathophysiology of CU and might pave the way for new therapeutic strategies.

Chronic urticaria and coagulation: pathophysiological and clinical aspects

“…In addition to that, thrombin can cause degranulation of MC via PAR-1 and may increase vascular permeability by a direct effect on endothelial cells (34,35,41). The available data support the role of eosinophils as a source of TF and subsequent activation of the coagulation cascade in CU pathogenesis (22,38). Moreover, TF promotes transendothelial migration of eosinophils (Fig.…”

“…In contrast, the activation of coagulation in patients with other skin diseases such as BP is associated with an increased thrombotic risk (9,88). Chronic urticaria is frequently characterized by the presence of elevated levels of plasma markers of thrombin generation and fibrinolysis during severe exacerbations of the disease (37,38,47), which can be due to the expression of TF by activated eosinophils (22). The activation of coagulation and fibrinolysis decreases till complete normalization during remission (47,89).…”

“…In 2007 Moosbauer et al (21) noted the leading role of activated eosinophils as an intravascular TF source, and 2 years later Cugno et al (22) showed that eosinophils were the main cells expressing TF in CU. In vitro, the expression of TF by eosinophils can be enhanced by some cytokines, including PAF and GM-CSF (21).…”

Tissue Factor and Cardiovascular Disease: Quo Vadis?

“…50 Stimulation with granulocyte-macrophage colony-stimulating factor or platelet-activating factor, results in de novo TF transcription and translocation from the granules to the cell membrane 50 ; thus contributing to the pro-thrombotic state in hypereosinophilic syndromes. 51 Platelets Similar to granulocytes, TF expression in platelets is still controversially discussed. While some authors neither detected TF antigen nor activity in resting as well as calcium ionophore-or collagen-stimulated platelets, 52 others described functional TF in platelets.…”

Coagulation in Chronic Urticaria

“…In patients with severe urticaria, the activation of the coagulation cascade may be intense enough to lead to fibrinolysis, as shown by an increase in plasma levels of Ddimer paralleling disease severity [11]. In keeping with the findings by Moosbauer et al [12] showing that eosinophils are a major intravascular source of tissue factor, Cugno et al were able to demonstrate that eosinophils are the main cells expressing TF in chronic urticaria [13]. What initiates the activation of eosinophils is still unclear.…”