Cutaneous Mast Cells Research Articles

Tumor Necrosis Factor-Alpha: Ally and Enemy in Protean Cutaneous Sceneries.

Skin is the forestage for a series of many-sided functions of tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine with staggering versatility and sizable implications for tissue homeostasis, immune responses, angiogenesis, apoptosis, local and systemic inflammation. An aberrant TNF-α-mediated crosstalk has been linked to the pathogenesis of acute and chronic skin inflammatory diseases, and indeed, TNF-α dysregulation can contribute to the development and progression of psoriasis, vitiligo, local damage following exposition to ultraviolet light radiations, cutaneous lupus erythematosus, and acne vulgaris. Therapies that target TNF-α are conspicuously used in the treatment of different skin disorders, aiming to modulate the in vivo immune functions triggered by many cutaneous cells, including keratinocytes, mast cells, or Langerhans cells, and reduce inflammation taking place within the skin. Herein, we focus on the key relationships between TNF-α and distinct skin non-neoplastic inflammatory or physiologic conditions, showing that a natural induction of TNF-α may have a protective significance but that TNF-α overproduction may be harmful or even lethal. Many questions remain unraveled in the therapeutic practice, and caution should be exercised due to eventual backlashes exerted by TNF-α in maintaining skin health or in provoking skin disease.

The calpain/ABCA1 pathway drives mast cell- initiated vascular leakage and inflammation in the skin.

Abstract Cutaneous mast cells (MCs) initiate local and systemic immune responses. To reach this end, activated MCs immediately release an arsenal of pro-inflammatory proteases. In this study, we evaluated the role of the cysteine protease, calpain in MC function. Calpain activity and protein were confirmed in the supernatants of MCs activated via either the FceR or the MrgprB2. In vivo, extracellular calpain induces vascular leakage in a MC- dependent manner. We then investigated the mechanism of calpain release. In vitro and in vivo studies suggest that the cholesterol transporter, the ATP- binding cassette A1 transporter (ABCA1) externalizes calpain. To investigate the role of the ABCA1 in MC biology, we generated mice lacking the Abca1 specifically on connective tissue MCs (Mcpt5-Cre+Abca1fl/fl mice). In vitro, Abca1-deficient MCs accumulate intracellular cholesterol, have reduced calpain release and reduced pro-inflammatory cytokines levels. In vivo, in the MC903-induced atopic dermatitis model, Mcpt5-Cre+Abca1fl/fl mice have reduced inflammation and a fewer MCs in affected skin compared to littermate controls. Corroborating this finding, global ABCA1 blockade with FDA-approved glyburide similarly reduced inflammation induced by MC903. Collectively, these data suggest that targeting the calpain/ABCA1 pathway may open new therapeutic avenues for MC -mediated inflammation in the skin.

Neurokinin A reduces the influx of inflammatory cells into the skin in a mast-cell dependent manner

Abstract Cutaneous mast cells promote immune responses but are also involved in reducing inflammation and in promoting immune resolution. Mechanisms initiating the anti-inflammatory function of mast cells are poorly defined. Mast cells reside in close proximity to neurons and their activation is modulated by neuropeptides, including the tachykinin family members. Neurokinin A (NKA) is an understudied tachykinin family member that limits cutaneous inflammation in a murine contact hypersensitivity (CHS) model but increases inflammation in colitis. In this study, the regulatory function of NKA in cutaneous inflammation is mechanistically evaluated using a robust model of DNFB-induced CHS. Administration of NKA prior to sensitization inhibited the expression of inflammatory cytokines and chemokines, including Il1b, Il6 and Ccl2. Correspondingly, NKA reduced recruitment of CCR2+ neutrophils and inflammatory monocytes to the skin. In mast cell-deficient Mcpt5Cre+ x Rosa26DTA and in mice in which mast cells do not produce IL-10 (Mcpt5Cre+ x Il10fl/fl) the capacity for NKA to reduce cytokines and chemokines was diminished. Lastly, in skin explant NKA diminished IL-1b and CCL2, genes upregulated after DNFB-treatment. Collectively, these data suggest that NKA reduces inflammation in the skin in a mast cell/IL-10 dependent manner and demonstrate a novel regulatory pathway for NKA in the skin that acts on mast cells to unleash their potential to reduce cutaneous inflammation.

Profile of Urticaria and Angioedema Patients at Dr. Moewardi General Hospital Surakarta, Indonesia

Background: Urticaria is a heterogeneous inflammatory skin disease that results from the activation and degranulation of cutaneous mast cells, followed by the release of histamine and other mediators that cause sensory nerve activation, vasodilation, plasma extravasation, and recruitment of immune cells. The prevalence and incidence of urticaria and angioedema have been extensively studied worldwide, but there is still limited data in Indonesia, especially regarding the profile of urticaria and angioedema patients. The purpose of this study was to determine the profile of urticaria and angioedema patients at Dr. Moewardi General Hospital for the period January 1st, 2020 - December 31st, 2022.
 Methods: This study is a cross-sectional retrospective study with secondary data derived from medical records of urticaria and angioedema patients.
 Results: There were 152 patients with urticaria, most of whom were in the age group >60 years (20.39%), female with a male to female ratio of 1:1.92, and worked as housewives (17.76%) and students (16.45%). Most cases were diagnosed with urticaria (86.84%) with some patients having angioedema (13.16%). The most common comorbidities rhinoconjunctivitis (2.63%), atopic dermatitis (1.97%) and asthma (1.32%). The dominant symptoms were itching and bumps (100%). The main treatment received by patients was single AH1 (71.71%) followed by combination therapy of AH1 and systemic corticosteroids (14.47%), combination therapy of AH1 and topical corticosteroids (10.53%), and the rest received combination therapy of AH1, topical corticosteroids, and systemic corticosteroids (3.29%). The skin prick test was positive in 16 patients (35.56%), with the most common allergens found being peanut (37.5%), egg yolk (37.5%), and tomato (37.5%).
 Conclusion: The characteristics of urticaria patients were dominated by elderly patients, female gender, and working as housewives or not working. Patients were predominantly diagnosed with urticaria with the most common comorbidities being diabetes mellitus. The main treatment received was AH1 class drugs. The most common types of allergens identified were peanuts, egg yolks, and tomatoes.

Unveiling the role of neutrophils in chronic spontaneous urticaria: Beyond mast cells.

Mast cells and eosinophils are considered pivotal contributors to the pathogenesis of chronic spontaneous urticaria (CSU). However, emerging evidence suggests that neutrophils also play a central role. Cutaneous mast cells and macrophages orchestrate the recruitment of neutrophils through the regulation and activation of diverse processes, including heightened local vascular permeability and chemokine release. Studies have demonstrated increased activation and elevated levels of neutrophil-related cytokines in CSU patients. Moreover, neutrophils have been proposed as antigen-presenting cells during the late-phase reaction of immunoglobulin E-mediated allergy and have been associated with the expression of calcitonin gene-related protein and vascular endothelial growth factor in CSU. Histopathological analysis of lesional skin in CSU patients revealed significantly higher eosinophil and neutrophil counts than unaffected skin. However, the extent of neutrophil infiltration in the skin does not appear to correlate with the number of neutrophils in peripheral blood. The utility of the neutrophil-lymphocyte ratio as a marker for disease activity or remission in CSU remains inconclusive. Neutrophil-targeted therapy may confer benefits for CSU patients who exhibit resistance to antihistamines. Omalizumab has demonstrated its ability to reduce neutrophil counts, the neutrophil-lymphocyte ratio, and the neutrophil-monocyte ratio in peripheral blood. While dapsone and colchicine are recommended as alternative treatment options for CSU, their evidential support from published studies remains limited. Inhibitors targeting interleukin-1 and neutrophil-related cytokines have been proposed as potential therapeutic interventions for patients exhibiting neutrophil predominance. Further research is warranted to gain deeper insights into the involvement of neutrophils in CSU and to explore potential therapeutic interventions.

Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers-Danlos syndrome.

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders occurring in both human and veterinary patients. The genetics of these disorders are poorly described in small animal patients. Define the clinical manifestations and genetic cause of a suspected form of EDS in a cat. A 14-week-old male domestic medium hair cat was presented with skin hyperextensibility and fragility. The classic tragic facial expression was observed as well as chronic pruritus and mild hyperesthesia. Blood samples and a skin biopsy sample were collected from the affected cat. Clinical examinations, histology, electron microscopy and whole genome sequencing were conducted to characterize the clinical presentation and identify possible pathogenic DNA variants to support a diagnosis. Criteria defining variant pathogenicity were examined including human disease variant databases. Histology showed sparse, disorganized collagen and an increase in cutaneous mast cells. Electron microscopy identified ultrastructural defects commonly seen in collagen type V alpha 1 chain (COL5A1) variants including flower-like collagen fibrils in cross-section. Whole genome sequencing and comparison with 413 cats in the 99 Lives Cat Genome Sequencing Consortium database identified a novel splice acceptor site variant at exon 4 in COL5A1 (c.501-2A>C). Our report broadens the current understanding of EDS in veterinary patients and supports the use of precision medicine techniques in clinical veterinary practice. The classification of variants for pathogenicity should be considered in companion animals.

Fexofenadine: A review of its use in the treatment of urticaria in pediatric and adult populations

Urticaria is an inflammatory skin disorder primarily resulting from activation of cutaneous mast cells. The released inflammatory mediators and histamine are responsible for the development of wheals and/or angioedema. Current guidelines recommend non-sedating second generation H1 antihistamines such as fexofenadine hydrochloride as first-line therapy. A recent review by Ansotegui et al. provides an update on urticaria, both in adult and pediatric populations, and on the safety and efficacy of fexofenadine hydrochloride as a treatment option.

OMALIZUMAB: A POTENTIAL LONG-TERM THERAPEUTIC ALTERNATIVE FOR REFRACTORY DELAYED PRESSURE URTICARIA?

<h3>Introduction</h3> Delayed pressure urticaria (DPU) can go unrecognized due to its delayed onset. While most are antihistamine resistant, this case illustrates a complete response to omalizumab as a potential long-term therapeutic alternative. <h3>Case Description</h3> A 44 year-old man who works at a weapons disposal arsenal presents for chronic spontaneous delayed pressure urticaria. Exam reveals lesions on his trunk and extremities with redness and oozing blisters. Triggers include using his hands, wearing a respirator backpack, or leaning against an object for longer than 5 minutes. Skin biopsy reveals nonspecific eosinophilic infiltrate and labs showed mildly elevated CRP. He is treated with cephalexin for presumed cellulitis and high dose antihistamines, famotidine, and montelukast without relief. Given recurrent episodes, the patient is started on monthly omalizumab with complete resolution after the first injection. <h3>Discussion</h3> DPU is a physical urticaria that presents with erythematous, pruritic painful swellings, occasionally with blisters, after prolonged pressure on the skin. The incidence is 2% and occurs in up to 37% of patients with chronic spontaneous urticaria (CSU). Pathophysiology is due to late phase reaction from mast cell activation and upregulation of E selectin leading to an inflammatory response with cytokines and cellular infiltrates. Management is generally unsatisfactory and consists mainly of antihistamine, NSAIDs, colchicine, TNF-a blocker, IVIG, and montelukast. Oral steroids are the most effective treatment, but should not be used long-term. This case illustrates a favorable response to omalizumab, normally used in CSU. Proposed mechanism in a bullous DPU case involves inhibition of cutaneous mast cells, resulting in decreased eosinophil degranulation.

Mast Cell Tumour and Mammary Gland Carcinoma Collision Tumour. Case report and literature review.

Collision tumours are the coexistence, at the same venue, of distinct tumours not macroscopically distinguishable and consisting of two independent cell populations without histological admixture. In human medicine, collision tumours in different anatomical sites have been described. In the veterinary literature, few cases exist so far. A 12-year-old female Labrador with a mammary gland nodular lesion was presented for clinical examination. The nodule was surgically removed and underwent histological and immunohistochemical analysis. Histopathological examination revealed two distinct malignant tumours: a mammary gland carcinoma and a cutaneous mast cells tumour. To the author's knowledge, the paper reports the first case of a collision tumour composed of mammary gland neoplasia and mast cell tumour. The rising interest in collision tumours suggests widening their knowledge and setting up a multimodal approach that includes surgery and targeted therapy.

GRK2 inhibitors, paroxetine and CCG258747, attenuate IgE-mediated anaphylaxis but activate mast cells via MRGPRX2 and MRGPRB2.

G protein-coupled receptor (GPCR) kinase 2 (GRK2), which phosphorylates agonist-occupied GPCRs to promote their desensitization, has been investigated as an attractive therapeutic target for cardiovascular and metabolic diseases. Several GRK2-targeted inhibition strategies have been reported including the use of direct pharmacological inhibitors such as paroxetine (a widely prescribed antidepressant) and its analogs such as compound CCG258747. Cross-linking of high affinity IgE receptor (FcϵRI) on mast cells (MCs) and the resulting degranulation causes anaphylaxis and allergic asthma. Using gene silencing strategy, we recently showed that GRK2 contributes to FcεRI signaling and MC degranulation. The purpose of this study was to determine if the GRK2 inhibitors paroxetine and CCG258747 modulate FcεRI-mediated MC responses in vitro and in vivo. Utilizing rat basophilic leukemia (RBL-2H3) cells and primary mouse lung MCs (LMCs), we found that paroxetine and CCG258747 inhibit FcϵRI-mediated calcium mobilization and degranulation. Furthermore, intravenous administration of paroxetine and CCG258747 in mice resulted in substantial reduction of IgE-mediated passive cutaneous anaphylaxis. Unlike LMCs, human cutaneous MCs abundantly express a novel GPCR known as MRGPRX2 (mouse; MRGPRB2). We found that in contrast to their inhibitory effects on FcεRI-mediated MC responses, both paroxetine and CCG258747 induce calcium mobilization and degranulation in RBL-2H3 cells stably expressing MRGPRX2 but not in untransfected cells. Furthermore, paroxetine and CCG258747 induced degranulation in peritoneal MCs from Wild-type (WT) mice in vitro and caused increased cutaneous vascular permeability in vivo, but these responses were substantially reduced in Mrgprb2−/− mice. Additionally, upon intradermal injection, paroxetine also induced neutrophil recruitment in WT but not Mrgprb2−/− mice. These findings suggest that in addition to their potential therapeutic utility against cardiovascular and metabolic disorders, paroxetine-based GRK2-inhibitors may serve to modulate IgE-mediated anaphylaxis and to enhance cutaneous host defense by harnessing MC’s immunomodulatory property through the activation of MRGPRX2/MRGPRB2.

Song's Mast Cell Theory of Acupuncture.

Professor. Jimei Song (1924–1987), from the Liaoning College of Traditional Medicine, first proposed the hypothesis that cutaneous mast cells (MCs) may be responsible for some of the phenomena associated with activation of meridians, acupoints, and De Qi in acupuncture. This was in 1977 and she subsequently published the first investigative report on human subjects. Supported by hundreds of extensive research reports later on, now Song's Mast Cell Theory of Acupuncture is one of the leading theories in acupuncture research. As a scientist and mother, Professor Song belonged to a special generation of female professionals in China. These women were living in a very unique and challenging era. Called “half of the sky” or “bourgeoisie intellectuals,” they faced unbearable difficulties in their lives and their work. The contribution of Professor Song to acupuncture is as significant as the contribution of Ms. Youyou Tu to Chinese herbal medicine. The difference is that Professor Song did not receive any award or significant recognition before she died in 1987. This review provides some background about her life, her contributions, and related publications, as well as a brief review of recent advances on MC mapping and acupuncture based on her MC theory.

Mefloquine causes selective mast cell apoptosis in cutaneous mastocytosis lesions by a secretory granule-mediated pathway.

Mastocytosis is a KIT-related myeloproliferative disease characterised by abnormal expansion of neoplastic mast cells (MC) in the skin or virtually any other organ system. The cutaneous form of adult-onset mastocytosis is almost invariably combined with indolent systemic involvement for which curative therapy is yet not available. Here we evaluated a concept of depleting cutaneous MCs in mastocytosis lesions ex vivo by targeting their secretory granules. Skin biopsies from mastocytosis patients were incubated with or without mefloquine, an antimalarial drug known to penetrate into acidic organelles such as MC secretory granules. Mefloquine reduced the number of dermal MCs without affecting keratinocyte proliferation or epidermal gross morphology at drug concentrations up to 40 μM. Flow cytometric analysis of purified dermal MCs showed that mefloquine-induced cell death was mainly due to apoptosis and accompanied by caspase-3 activation. However, caspase inhibition provided only partial protection against mefloquine-induced cell death, indicating predominantly caspase-independent apoptosis. Further assessments revealed that mefloquine caused an elevation of granule pH and a corresponding decrease in cytosolic pH, suggesting drug-induced granule permeabilisation. Extensive damage to the MC secretory granules was confirmed by transmission electron microscopy analysis. Further, blockade of granule acidification or serine protease activity prior to mefloquine treatment protected MCs from apoptosis, indicating that granule acidity and granule-localised serine proteases play major roles in the execution of mefloquine-induced cell death. Altogether, these findings reveal that mefloquine induces selective apoptosis of MCs by targeting their secretory granules and suggest that the drug may potentially extend its range of medical applications.

Candidalysin, a Virulence Factor of Candida albicans, Stimulates Mast Cells by Mediating Cross-Talk Between Signaling Pathways Activated by the Dectin-1 Receptor and MAPKs.

Although mast cells (MCs) modulate the activity of effector cells during Candida albicans infection, their role in the pathogenesis of candidiasis remains unclear. Candidalysin, a C. albicans-derived peptide toxin, is a crucial factor in fungal infections. We aimed to investigate the effect of candidalysin on MC activation and the underlying molecular mechanism. Serum from candidalysin-immunized mice was used to measure candidalysin expression in patients infected with C. albicans. MC degranulation and migration were evaluated by β-hexosaminidase release assay and chemotaxis assay, respectively. EIA and ELISA were used to evaluate the production of eicosanoids and cytokines/chemokines, respectively. The production of nitric oxide (NO) was measured with a DAF-FM diacetate kit, while reactive oxygen species (ROS) production was analyzed by flow cytometry. MAPK activation was evaluated by Western blotting. We detected high candidalysin expression in the lesions of patients infected with C. albicans, and the MC number was increased in these lesions. LL-37 colocalized with MCs in the lesions of candidiasis patients. Candidalysin-enhanced MC accumulation in mice and treating LAD2 and HMC-1 cells with candidalysin induced their degranulation, migration, and production of pro- and anti-inflammatory cytokines/chemokines, eicosanoids, ROS, NO, and LL-37. Interestingly, C. albicans strains lacking candidalysin failed to induce MC activation. Moreover, candidalysin increased dectin-1 expression, and the inhibition of dectin-1 decreased MC activation. Downstream dectin-1 signaling involved the MAPK pathways. The finding that candidalysin causes cutaneous MC activation may improve our understanding of the role of MCs in the pathology of cutaneous C. albicans infection.

Inhibition of Orai Channel Function Regulates Mas-Related G Protein-Coupled Receptor-Mediated Responses in Mast Cells.

Mast cells (MCs) are tissue resident immune cells that play important roles in the pathogenesis of allergic disorders. These responses are mediated via the cross-linking of cell surface high affinity IgE receptor (FcϵRI) by antigen resulting in calcium (Ca2+) mobilization, followed by degranulation and release of proinflammatory mediators. In addition to FcϵRI, cutaneous MCs express Mas-related G protein-coupled receptor X2 (MRGPRX2; mouse ortholog MrgprB2). Activation of MRGPRX2/B2 by the neuropeptide substance P (SP) is implicated in neurogenic inflammation, chronic urticaria, mastocytosis and atopic dermatitis. Although Ca2+ entry is required for MRGPRX2/B2-mediated MC responses, the possibility that calcium release-activated calcium (CRAC/Orai) channels participate in these responses has not been tested. Lentiviral shRNA-mediated silencing of Orai1, Orai2 or Orai3 in a human MC line (LAD2 cells) resulted in partial inhibition of SP-induced Ca2+ mobilization, degranulation and cytokine/chemokine generation (TNF-α, IL-8, and CCL-3). Synta66, which blocks homo and hetero-dimerization of Orai channels, caused a more robust inhibition of SP-induced responses than knockdown of individual Orai channels. Synta66 also blocked SP-induced extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation and abrogated cytokine/chemokine production. It also inhibited SP-induced Ca2+ mobilization and degranulation in primary human skin MCs and mouse peritoneal MCs. Furthermore, Synta66 attenuated both SP-induced cutaneous vascular permeability and leukocyte recruitment in mouse peritoneum. These findings demonstrate that Orai channels contribute to MRGPRX2/B2-mediated MC activation and suggest that their inhibition could provide a novel approach for the modulation of SP-induced MC/MRGPRX2-mediated disorders.

Features of the clinical manifestation of the cutaneous form of mastocytoma in dogs

According to foreign researchers, mastocytoma is one of the most common (7–12 %) skin tumors in dogs. The study aimed to study the features of the clinical manifestation of cutaneous mast cells according to the criteria of the clinical TNM classification. We analyzed 24 cases of cutaneous mastocytoma in dogs during 2016–2020, of diagnostic and therapeutic measures in the Department of Surgery and Clinic of the Small Pets Stepan Gzhytskyi National University of Veterinary Medicine and Biotechnologies Lviv. According to the criteria of the international clinical TNM classification at the time of admission to the clinic in 7 (29.2 %) dogs established stage I of the tumor, 10 (41.7 %) – II, 6 (25 %) – III, and 1 4.1 %) animals – stage IV. Based on cytological evaluation of biopsy material selected from tumors and regional lymph nodes of low-grade mastocytes, 17 (70.8 %) animals were found, and in 7 (29.2 %) cases, neoplasia was characterized as high-grade.

Clinical and pathomorphological characteristics of cutaneous mastocytoma of dogs

According to foreign researchers, mastocytoma is one of dogs' most common (7–12 %). The study aimed to study the features of clinical manifestations of cutaneous mast cells according to the criteria of clinical TNM classification and pathomorphological (cytological and histological) verification of neoplasia according to the two-stage Kiupel classification. We analyzed 24 cases of cutaneous mastocytoma in dogs. During 2016–2020 underwent an entire course of diagnostic and therapeutic measures in the Department of Surgery and Clinic of Small Pets of Stepan Gzhytskyi National University of Veterinary Medicine and Biotechnologies Lviv. According to the criteria of the international clinical TNM classification at the time of admission to the clinic in 7 (29.2 %) dogs established stage I of the tumor, 10 (41.7 %) – II, 6 (25 %) – III, and 14.1 %) animals – stage IV. Based on cytological evaluation of biopsy material selected from tumors and regional lymph nodes, low-grade mastocyte was found in 17 (70.8 %) animals, and in 7 (29.2 %) cases, neoplasia was characterized as high-grade. Histological examination of excisive material selected during surgery in 16 (66.7 %) dogs verified mastitis of low malignancy and, accordingly, in 8 (33.3 %) animals MCTs of high malignancy. The sensitivity of the pathomorphological study was 87.5 % and the specificity of 95.8 %. It has been proven that cutaneous mastocytoma belongs to neoplasms with specific clinical manifestations. Therefore, targeted biopsy should be performed under ultrasound control, fine-needle biopsy (FNA), and material selection for the cytological examination. A comparative analysis of clinical TNM classification data and the results of two-stage histological classification (Kiupel) showed that the size of the tumor and the degree of its malignancy are interrelated, as there is a trend in which, along with increasing T, the clinical TNM classification of cancer, the number of cases of verification of malignant neoplasms is also growing. It was also found that the malignant course of the disease is characteristic of mast cells localized in dogs in areas of the body freely available for permanent injury (limbs, groin, perineum, neck). The obtained data will supplement the evidence of researchers from other countries on the histological structure of tumors and expand knowledge about the pathogenesis of mastocytoma in dogs.

Mast cell-deficient mice Mcpt5Cre/Dicer fl/fl redefine the role of mast cells in experimental bullous pemphigoid.

BackgroundBullous pemphigoid (BP) is the most frequent autoimmune blistering disease of the skin affecting the elderly. BP is immunopathologically characterized by autoantibodies against BP180 and BP230. With the growing evidence of cell‐mediated autoimmunity in the pathogenesis of BP, it still remains unclear whether mast cells (MCs) are involved, due to conflicting data obtained from Kit‐dependent MC‐deficient mouse models.ObjectivesTo clarify the role of MCs in experimental BP; the dynamics in cutaneous MC numbers, associated immune cells and the development of disease in Kit‐independent MC‐deficient mouse model.MethodsEmploying a recently established murine adult passive transfer model of BP induced by the transfer of pathogenic immunoglobulin G (IgG), lesional skin biopsies were investigated histologically and immunohistochemically for the time‐dependent MC accumulation and dermal infiltration.ResultsThe numbers of cutaneous MCs increased following the induction of BP, in part, maintained by MC proliferation. Numbers of T cells, neutrophils and eosinophils in the skin also increased after BP induction, with eosinophils showing a preferential co‐localization with MCs. Furthermore, clinical disease manifestation in MC‐deficient Mcpt5Cre/Dicer fl/fl mice remained unchanged compared to MC‐sufficient Dicer fl/fl mice. The composition of the immune cell infiltration including as T cells, neutrophils and eosinophils was largely unaffected by the absence of MCs.ConclusionMCs do not play a pivotal role in the pathogenesis of passive IgG‐transfer mediated BP model. Their increase in number may be a bystander effect following tissue injury. We therefore suggest caution regarding the selection of MCs as sole targets for the development of novel drugs for BP.

Pathogenesis of solar urticaria: Classic perspectives and emerging concepts.

Solar urticaria is a rare, immunologically mediated photodermatosis in which activation of cutaneous mast cells is triggered by specific wavelengths of solar electromagnetic radiation. This manifests clinically as the rapid development of cutaneous itch, erythema and wheal formation after several minutes of sun exposure. Disease mechanisms in solar urticaria remain incompletely elucidated and there have been few recent investigations of its pathobiology. Historic passive transfer experiments performed during the twentieth century provide support for a 'photoallergy' model of disease pathogenesis, wherein molecular alteration of a putative chromophore by solar electromagnetic radiation produces mast cell activation via an IgE-dependent mechanism. However, this model does not account for several observations made during passive transfer experiments nor does it explain a range of subsequent clinical and photobiological observations made in solar urticaria patients. Furthermore, increased understanding of the molecular dynamics underpinning cutaneous mast cell responses highlights the need to reformulate our understanding of solar urticaria pathogenesis in the context of this contemporary scientific landscape. In this review, we discuss the current understanding of solar urticaria pathogenesis and, by incorporating recent scientific and clinical observations, develop new hypotheses to drive future investigation into this intriguing disorder.

Iodixanol activation of mast cells: Implications in the pathogenesis of iodixanol-induced delayed cutaneous adverse reactions

Iodinated contrast media (ICM) is widely used in radiological examination and interventional therapy. In the commonly used ICM, iodixanol is considered to be the safer one. However, compared with other ICMs, it has a higher incidence of delayed cutaneous adverse reactions. The underlying mechanisms are unclear. In this study, mice with positive allergic reactions were selected based on the mouse clinical allergy symptom score and skin and blood samples taken 1, 6, 24, 48, and 72 h after ICMs (6 g iodine/kg) injection for histological and blood analyses. ICMs-induced pseudo-allergic reactions were investigated through in vivo intravital vascular imaging and passive cutaneous anaphylaxis (PCA) not mediated by IgE and through, calcium imaging degranulation of mast cells (MCs), and western blot assays in vitro. Results shows iodixanol-induced systemic anaphylaxis caused severe extravasation of plasma proteins and degranulation of skin MCs, and increased levels of plasma histamine, cytokines and inflammatory chemokines. Mechanistically, iodixanol increases degranulation of MCs and promotes the synthesis of inflammatory factors by activating PLC-γ and PI3K-related pathways. Trigonelline inhibit iodixanol-induced MC-related pseudo-allergic reactions in vitro and in vivo. These results suggest that mice in the iodixanol group had a higher incidence of delayed cutaneous reactions, characterized by cytokine release over time and delayed cutaneous MC degranulation. Iodixanol’s delayed cutaneous adverse reactions may be due to a delayed phase of MC-related pseudo-allergic reactions. Trigonelline revealed anti-allergic activity in iodixanol-induced MC-related pseudo-allergic reactions.

In the search of mobile target for acupuncture: why is mast cell?

Both clinical practice and basic research of acupuncture have pointed out that acupuncture treatment has specific tissue and cellular targets. In addition to the known fixed tissue targets such as nerves and blood vessels, the author analyzes the biological characteristics of other skin resident cells in the skin and concludes that cutaneous mast cells are the most suitable candidate for the cellular target of acupuncture. A hypothesis of the bionic acupuncture is proposed to explain the biological principles by which the innate immunity and healing system respond to acupuncture. The distribution of mast cells in the human skin is characterized by "approaching to the terminals and gathering at the orifices", and the cell density is highly correlated with the density of acupoints and the micro-acupuncture systems. These evidences all support that mast cells are the mobile target cells for acupuncture, which can explain some clinical phenomena and principles of acupuncture, and suggest mast cells as one of the tissue markers for acupoints.