T Cell/Mast Cell Crosstalk in the Skin of Patients Suffering From Immune-Mediated Diseases, Focusing on Chronic Spontaneous Urticaria.

Association of TG2 from mast cells and chronic spontaneous urticaria pathogenesis

This update on chronic urticaria (CU) focuses on the prevalence and pathogenesis of chronic spontaneous urticaria (CSU), the expanding spectrum of patient-reported outcome measures (PROMs) for assessing CU disease activity, impact, and control, as well as future treatment options for CU. This update is needed, as several recently reported findings have led to significant advances in these areas. Some of these key discoveries were first presented at past meetings of the Collegium Internationale Allergologicum (CIA). New evidence shows that the prevalence of CSU is geographically heterogeneous, high in all age groups, and increasing. Several recent reports have helped to better characterize two endotypes of CSU: type I autoimmune (or autoallergic) CSU, driven by IgE to autoallergens, and type IIb autoimmune CSU, which is due to mast cell (MC)-targeted autoantibodies. The aim of treatment in CU is complete disease control with absence of signs and symptoms as well as normalization of quality of life (QoL). This is best monitored by the use of an expanding set of PROMs, to which the Angioedema Control Test, the Cholinergic Urticaria Quality of Life Questionnaire, and the Cholinergic Urticaria Activity Score have recently been added. Current treatment approaches for CU under development include drugs that inhibit the effects of signals that drive MC activation and accumulation, drugs that inhibit intracellular pathways of MC activation and degranulation, and drugs that silence MCs by binding to inhibitory receptors. The understanding, knowledge, and management of CU are rapidly increasing. The aim of this review is to provide physicians who treat CU patients with an update on where we stand and where we will go. Many questions and unmet needs remain to be addressed, such as the development of routine diagnostic tests for type I and type IIb autoimmune CSU, the global dissemination and consistent use of PROMs to assess disease activity, impact, and control, and the development of more effective and well-tolerated long-term treatments for all forms of CU.

Decoding the Enigma of Urticaria and Angioedema

Studies establish a link between autoimmune factors and chronic spontaneous urticaria (CSU). T cells are crucial in immune-mediated diseases like CSU, and T-cell receptor (TCR) diversity could be pivotal in autoimmune responses. The clinical relevance of TCR variations in CSU is unknown, but understanding them may offer insights into CSU's pathogenesis and treatment. This cross-sectional study included 132 chronic urticaria (CU) patients versus 100 age-matched healthy donors (HD), with subgroup analyses on CU type, angioedema, allergic comorbidities, and anti-IgE therapy efficacy. Peripheral TCRβ repertoires were analyzed by high-throughput sequencing. CSU patients showed reduced TCR diversity (lower D50) and increased large clone proportions than HD. Moreover, TCR diversity in CSU patients was significantly lower than in those with Chronic Inducible Urticaria (ClndU). There were also differences in variable (V) and joining (J) gene usage between CU and HD groups as well as CSU and ClndU groups. However, in subgroup analyses regarding angioedema, allergic comorbidities, and the efficacy of anti-IgE treatment, no significant differences were found in TCR diversity or large TCRβ clones. Notably, patients with treatment relapse or poor response to anti-IgE therapy had a higher proportion of positively charged CDR3. Additionally, age affected TCR diversity, but TIgE value, EOS counts, CU duration, and UAS7 score did not associate significantly with D50. CSU patients exhibit reduced TCR diversity and increased large clone proportions, indicating abnormal T cell activation. The TCR diversity differences and distinct V and J gene usage between CSU and ClndU may indicate different mechanisms in T lymphocyte-associated immune responses for these two subtypes of CU. The higher positive charge in CDR3 of relapsed or poorly responsive patients to anti-IGE treatment may indicate more antigen charge involvement. These findings provide new insights into the pathogenesis of CSU and potential future treatments.

Translationally controlled tumor protein (TCTP) is also known as histamine releasing factor as it has the ability to activate mast cells. To investigate the role of TCTP in the pathogenesis of chronic spontaneous urticaria (CSU), we evaluated serum level of TCTP and effect of TCTP on basophil and mast cell degranulation. TCTP levels in the sera from 116 CSU patients and 70 normal healthy controls (NCs) were measured by ELISA. CD203c expression on basophils from CSU patients and β-hexosaminidase release from Laboratory of Allergic Disease 2 mast cells were measured upon stimulation monomeric and dimeric TCTP. Non-reducing Western blot analysis was used for detecting dimeric TCTP. No difference was observed in serum TCTP levels between CSU patients and NCs (p=0.676). However, dimeric TCTP intensity on Western blot was stronger in CSU patients than in NCs. TCTP levels were higher in patients with severe CSU (p=0.049) and with IgG positivity to FcɛRIα (p=0.038). A significant positive correlation was observed between TCTP and eosinophil cationic protein levels (Spearman's rho=0.341; p=0.001). Both basophil and mast cell degranulation were significantly increased after stimulation with dimeric TCTP, but not with monomic TCTP. The ability of TCTP to activate basophil and mast cells is dependent on dimerization, suggesting that the inhibition of TCTP dimerization can be a therapeutic option for CSU. Association between TCTP levels and the presence of IgG to high affinity Fc epsilon receptor I alpha subunit in CSU patients indicates that autoimmune mechanisms may be involved in the dimerization of TCTP.

Chronic spontaneous urticaria (CSU) is defined as recurrent episodes of spontaneous wheal development and/or angioedema for more than six weeks and at least twice a week. The core link in the pathogenesis of CSU is the activation of mast cells, T cells, eosinophils, and other immune cells infiltrating around the small venules of the lesion. Increased vascular permeability, vasodilatation, and recruitment of inflammatory cells directly depend on mast cell mediators’ release. Complex regulatory systems tightly influence the critical roles of mast cells in the local microenvironment. The bias toward Th2 inflammation and autoantibodies derived from B cells, histamine expressed by basophils, and initiation of the extrinsic coagulation pathway by eosinophils or monocytes exerts powerful modulatory influences on mast cells. Cell-to-cell interactions between mast cells and eosinophils/T cells also are regulators of their function and may involve CSU’s pathomechanism. This review summarizes up-to-date knowledge regarding the crosstalk between mast cells and other immune cells, providing the impetus to develop new research concepts and treatment strategies for CSU.

Chronic spontaneous urticaria (CSU) is a debilitating condition characterized by mast cell activation. Platelet-activating factor (PAF) is produced by various immune cells, including mast cells, basophils, lymphocytes, and eosinophils, which play crucial roles in CSU pathogenesis. It induces mast cell degranulation, increases vascular permeability, and promotes the chemotaxis of inflammatory cells. These effects result in the release of inflammatory mediators, the development of edema, and the persistence of inflammation, which are key features of CSU. Notably, elevated PAF levels have been linked to heightened disease activity and resistance to antihistamine treatment in CSU patients. Despite these findings, the precise role of PAF in CSU pathogenesis remains unclear. Rupatadine, an antihistamine, and heat shock protein 10, a natural anti-inflammatory peptide that selectively inhibits PAF-induced mast cell degranulation, have demonstrated anti-PAF activity. Furthermore, with the molecular structure of the PAF receptor now identified, several experimental PAF receptor antagonists have been synthesized. However, there remains a significant need for the development of therapeutic options targeting PAF in CSU management.

Chronic urticaria (CU) is a common disease characterized by recurrent itchy wheals and/or angioedema for more than 6 weeks. Increased levels of the pro-angiogenic mediator vascular endothelial growth factor (VEGF) have been described in skin disorders, such as chronic urticaria (CU), psoriasis and atopic dermatitis. Up to now, no data on the role of VEGF endogenous inhibitors Endostatin (ES) and Thrombospondin-1 (TSP-1) in CU are available. The aim of our study is to investigate the potential involvement of ES and TSP-1 in patients with chronic spontaneous urticaria (CSU). The levels of ES and TSP-1 were measured in the sera of 106 adult patients with CSU and 98 healthy subjects by enzyme immunoassays. The serum levels of the anti-angiogenic mediators ES and TSP-1 resulted significantly higher in CSU than in control subjects. Analysis of these mediators in CSU sub-groups, defined by the results of the autologous serum skin test (ASST), identified a significant increase of ES and TSP-1 in both ASST-positive and ASST-negative sub-groups as compared to the controls. Levels of ES and TSP-1 do not parallel the disease severity in CSU. Our study suggests that the extracellular matrix (ECM) fragments ES and TSP-1 with anti-angiogenic activity play a potential role in the pathogenesis of CSU but do not parallel disease activity.

Myeloid and Mast Cell Progenitors Are Elevated in Atopic Dermatitis.

Chronic spontaneous urticaria (CSU) in children is mostly spontaneous in onset (57%). Treatment comprises long-term antihistaminic therapy without need for elaborate investigations. A subset of such patients don't respond to conventional treatment and novel therapies to help reduce pill burden is the need of the hour. To determine the efficacy and safety of autologous serum therapy (AST) in pediatric patients with chronic spontaneous urticaria. All pediatric patients, aged between 6-16 years, attended to our OPD from March 2019 to March 2020 were recruited. Clinico-demographic data and baseline investigations of all patients were performed. Two-weekly AST therapy was given for 8 visits with levocetrizine tablet 5mg on an on-demand basis. Urticaria activity score (UAS) sheet was provided to record and return every 2 weeks. Statistical analysis was done using the IBM SPSS 26 software package. Autologous serum skin test (ASST) was positive in 63% patients. Both the ASST positive and ASST negative group showed significant reduction in UAS7 score at week 14 compared to baseline. The reduction in mean UAS7 score was associated with a decreased pill burden and positive response in the patient and physician global assessment scale. No statistically significant difference between the two groups in terms of mean UAS7 reduction was found. This study has explored the efficacy and safety of autologous serum therapy in the pediatric CSU patients. Both ASST positive and ASST negative group respond to AST therapy.

Chronic spontaneous urticaria: update on pathogenesis and therapeutic implications.

The Editors' Choice

BACKGROUND: Chronic urticaria is a skin disease characterized by the appearance of itchy weals and/or angioedema for 6 or more weeks. Chronic urticaria is subdivided into chronic spontaneous urticaria, which occurs due to an unknown cause, and chronic inducible urticaria, which occurs as a result of exposure to various physical factors (water, cold, heat, pressure, mechanical irritation), can occur simultaneously or independently of each other. Omalizumab, anti-IgE monoclonal antibody, is approved for the treatment of patients with chronic spontaneous urticaria and is the second choice in cases of resistance to antihistamine treatment. In patients with a combination of chronic spontaneous urticaria and chronic inducible urticaria, the effectiveness of treatment with omalizumab has been little studied.
 AIM: compare the effectiveness of omalizumab treatment in patients with chronic spontaneous urticaria and patients with a combination of chronic spontaneous and chronic induced urticaria.
 MATERIALS AND METHODS: Under supervision there were 30 patients with chronic spontaneous urticaria and combined chronic spontaneous and inducible urticaria (15 patients in each group). Evaluation of the effectiveness of treatment was carried out according to the results of the questionnaires DLQI (dermatological index of quality of life), CU-Q2oL (questionnaire for quality of life in chronic urticaria), UCT (urticaria control test), UAS (urticaria activity scale), HADS (Hospital Anxiety and Depression Scale) and provocation tests in dynamics before and during treatment.
 RESULTS: All patients received omalizumab 300 mg subcutaneously once a month for 6 to 12 months. After the first injection of omalizumab, we noted a decrease in the severity of urticaria, an increase in the level of disease control and quality of life when comparing parameters before and during treatment in more than 90% of patients. Improved performance remained at this level throughout all subsequent months of treatment.
 CONCLUSION: Omalizumab is equally effective in patients with an isolated form of chronic spontaneous urticaria and in patients with a combined form of chronic spontaneous and inducible urticaria. The use of omalizumab allows you to control the symptoms of chronic spontaneous and inducible urticaria, even with prolonged use.

Pathogenesis of Chronic Spontaneous Urticaria With or Without Angioedema.

MRGPRX2 gain-of-function mutation drives enhanced mast cell reactivity in chronic spontaneous urticaria.