**2. Pathophysiology**

At the very beginning (four decades ago), CSU was considered to be a T-cell mediated disorder, supported by the finding of rich CD4+ T-cell infiltration in the skin of CSU patients [11]. The involvement of activated T-cells in peripheral blood of CSU patients, namely the increased expression of CD40 ligand on T-cells similarly to what we find on activated T-cells from patients suffering from active systemic lupus erythematosus and other autoimmune diseases was also reported [12]. In concert with this, there are studies showing an increased switch of Th1 to Th17 in the peripheral blood of CSU patients in correlation with CSU disease severity, and IL-17 levels are significantly higher in the autologous serum skin test (ASST) positive than ASST negative CSU patients. Plasma levels of interferon-γ (IFN-γ), IL-2 and IL-21 were also found to be significantly higher in ASST-positive CSU subgroups, known to involve the positive regulation of the Janus-kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway [13]. In a recent study using Kunming mice (a model of CSU), a longer duration and higher intensity of pruritus was demonstrated to be in association with enhanced levels of eosinophils, inflammatory cytokine expression and activated the JAK/STAT signaling pathway. This was found to be in mice overexpressing IL-9 and IL-10, contributing to the development of CSU by signaling the JAK/STAT pathway [14]. Commensurate with this, is the later finding of antigen/disease-specific autoreactive CD4 + T cells that target FcεRIα in most patients with CSU, with a cytokine secretion profile typical of aTh1 immune response. This is compatible with the earlier finding of IgG autoantibodies to FcεRIα on dermal mast cells and basophils, supporting the concept that CSU is an autoimmune disorder probably mediated by auto-reactive T cells. IFN-γ and autoantibody responses to FcεRIα were found to be inversely related, with IFN-γ responses being detected earlier than autoantibodies in the course of CSU. This finding of inverse relationship between auto-reactive T-cell responses and autoimmunity suggests these responses to be different stages in the pathogenesis of CSU [15]. In a very recent study we found that increased numbers of CD4 + T cells and mast cells were present in both lesional and nonlesional skin of CSU patients when compared with the healthy controls. Both types of cells were strongly positive for IL-17A and found to be in close proximity to each other [16]. With respect to the aforementioned, autoimmunity in CSU patients is reported to be found in at least 50% of cases. Two types of autoimmunity have been documented and supported by numerous reports. The first (type I) is driven by

#### *New Biological Treatment Options in CSU DOI: http://dx.doi.org/10.5772/intechopen.97647*

IgE auto-antibodies against thyroid antigens and/or auto-allergens, defined by the presence of anti-TPO antibodies. In parallel to this, is the finding of type IIb autoimmunity characterized by the binding of IgG auto-antibodies (recently also IgA and Ig M) to IgE and/or FcɛRIα on mast cells [17–19]. Both types are followed by the intense activation and degranulation of mast cells and the release of inflammatory mediators in the skin that are able to induce itchy wheals and angioedema. Among the many mediated agents, histamine, pro-inflammatory cytokines and chemokines are the most frequent [20]. Basophils and Eosinophils have recently been included among other cells actively involved in the pathogenesis of CSU. In this respect, peripheral blood basopenia is frequently reported in association with CSU disease severity. It has been postulated that this is a result of the migration of basophils from blood to the skin of active CSU patients. Basopenia resolves in parallel with CSU remission and therefore may become a suitable marker for follow-up [21]. Recent evidence suggests that eosinophils may also play role in the pathogenesis of CSU. Both eosinophils and eosinophil granules were displayed in lesional skin of CSU patients. This is in contrast to allergic rhinitis and asthma where peripheral blood eosinophilia is a characteristic finding, while in CSU, peripheral blood eosinopenia is observed in association with disease severity. As in the case of basopenia, depletion of active eosinophils and their shift to the skin of CSU patients is the most accepted mechanism of this phenomenon [22]. The issue of how all these cells, and mechanisms, are linked, and how they act at onset or during the persistence of CSU is extremely complex. However, current therapies, targeting free IgE, mast cells and T cells are reported to be tremendously efficient in inducing CSU remission.
