E in the sera of patients with chronic

E in the sera of patients with chronic PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/12711626 urticaria. They measured INF as a representative of a Th1 profile, and then measured IL4 and IL5 as representatives of a Th2 subtype. They found that IL4 was higher in the sera of patients with chronic urticaria (as well as in atopic subjects) compared to controls while IL5 and IFN levels were normal. Significant differences were found in the ability of CD4+ lymphocytes to produce IL4 and INF upon PMA-Ionomycin stimulus when healthy controls were compared to chronic urticaria patients. There was no difference in IL4 or INF production by CD8+ lymphocytes of patients vs. the control group. Likewise, no significant differences were found when comparing the ratio of INF/IL4 production by CD4+ or CD8+ lymphocytes of controls and urticaria patients. The cytokine profile found in our study does not reflect either a Th1 or Th2 predominance. These data again strengthen an immune basis for chronic urticaria, once demonstrated that the CD4+ lymphocytes of patients with this disease are activated and they release greater amounts of n-Phenylpiperazine-1-carboxamide cytokine with a non-specific stimulus. On the other hand, this finding is similar to a study in which the cellular infiltrate associated with chronic urticaria had a Th0 profile [52]. These authors analyzed skin biopsies from chronic urticaria patients by in situ hybridization. IL4, IL5 and INFgamma revealed higher cytokine m-RNA expression in chronic urticaria patients than in healthy controls, without a predominance of either a Th1 or Th2 representative cytokine. In a study composed by eight patients analyzed with immunohistochemistry, Kay reported a predominanceFerrer Clin Transl Allergy (2015) 5:Page 5 ofof Th2 initiating cytokines (IL33, IL25 and TSLP) in skin lesions among patients with CSU [68]. However, it should be noted that IL33 in some PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/9638577 instances could also promote a Th1 response [69].Coagulation pathway Recently Asero has reported the activation of the extrinsic coagulation pathway in patients with CSU suggesting that the coagulation cascade might be involved. It was first shown that several markers such as the prothrombin fragment oncotarget.13387 F1+2 [70] and activated factor VII [71] were increased. This could be explained because in cases of severe CSU, the activation of the coagulation cascade could lead to fibrinolysis leading to an increase in D-dimer levels [72]. Interestingly, D-dimer levels correlate with the severity and could predict the lack of response to antihistamines [73]. However, increased D-dimer levelwith disease activity is not specific to CSU since it is also seen in bullous pemphigoid [74] and hereditary angioedema [75]. Thus, it is not specific for mast cell mediated disease. Moreover, other coagulation cascade proteins are able to directly activate mast cells, as it is in the case ofthrombin that cleaves protease-activated receptors [76] 4,4,5,5-Tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane 1 (PAR-1) and Tissue Factor plus factor VIIa through PAR-2 [77]. The real significance of these facts in the pathogenesis of CSU is not well understood. However, they could amplify the inflammation inducing vascular permeability. Furthermore, some cascade proteins are able to induce mast cell degranulation (we include a summary of these pathways and cell cross-talk in Fig. 1).Conclusion Chronic spontaneous urticaria is an inflammatory disease. There is no single cell type that is uniquely responsible for CSU. Rather, there are several cells involved and each has its own unique role. So far, we have been able to describe differ.