Photobiological response of mast cells to green and red light-emitting diodes (LEDs) in cutaneous burns.

This study assessed the effects of red and green LEDs on mast cells (MCs) in third-degree burns in 75 Wistar rats, divided into control, red LED (RED), and green LED (GREEN) groups. Animals were irradiated daily with RED (630 nm, 300 mW, 0.779 W/cm2, 9 J/cm2, 30 s) and GREEN (520 nm, 180 mW, 0.467 W/cm2, 60 J/cm2, 30 s). Histological sections stained with toluidine blue were analyzed for total and subtype MCs. Standardized MC counting was performed across the viable lesion area, considering lesion margins, through intact connective tissue and the integrity of skin appendages. No statistically significant differences in MCs 2 (with released granules and intact cell border) were found between groups. Irradiated groups showed increased total MCs at 7, 14, and 21 days (p < 0.05), with a decrease in MCs 1 (intact MCs) at all time points compared to control (p < 0.05). Significant changes in MCs 3 (with massive degranulation and partial or complete disintegration of the cell border) degranulation were noted in RED at 7, 14, and 21 days (p < 0.009) and in GREEN at 14 (p < 0.009) and 32 days (p < 0.028). Results suggest red and green LEDs modulate MC recruitment and degranulation in third-degree burns.

Mouse Models of Itch.

Murine models are vital preclinical and biological tools for studying itch. In this paper, we explore how these models have enhanced our understanding of the mechanisms underlying itch through both acute and chronic itch models. We provide detailed protocols and recommend experimental setups for specific models to guide researchers in conducting itch research. We distinguish between what constitutes a bona fide pruritogen versus a stimulus that causes pruritogen release, an acute itch model versus a chronic itch model, and how murine models can capture aspects of pruritus in human disease. Finally, we highlight how mouse models of itch have transformed our understanding and development of therapeutics for chronic pruritus in patients.

The Complement System Is Essential for Arteriogenesis by Enhancing Sterile Inflammation as a Relevant Step in Collateral Artery Growth.

Arteriogenesis is an inflammatory driven mechanism, describing the growth of a natural bypass from pre-existing collateral arteries to compensate for an occluded artery. The complement system component C3 is a potent natural inflammatory activator. Here, we investigated its impact on the process of collateral artery growth using C3-deficient (C3 -/-) and wildtype control mice in a murine hindlimb model of arteriogenesis. Induction of arteriogenesis by unilateral femoral artery ligation resulted in decreased perfusion recovery in C3 -/- mice on day 7 as shown by Laser Doppler imaging. Immunofluorescence staining revealed a reduced vascular cell proliferation in C3 -/- mice. Gene expression analysis displayed a significant reduction in monocyte chemoattractant protein-1 (MCP-1) expression in C3 -/- mice. Interestingly, 3 days after induction of arteriogenesis, the number of macrophages (CD68+) recruited to growing collaterals was not affected by C3 deficiency. However, a significant reduction in inflammatory M1-like polarized macrophages (CD68+/MRC1-) was noted. Forced mast cell activation by Compound 48/80 as well as exogenous MCP-1 application rescued the number of M1-like polarized macrophages along with perfusion recovery in C3 -/- mice. In summary, this study demonstrates that complement C3 influences arteriogenesis by mediating MCP-1 expression, which is essential for the induction and enhancement of sterile inflammation.

Prevalence and Clinical Relevance of Anti-FcεRI Autoantibody in Crohn's Disease.

Background: Mast cells can be activated in various ways and were shown to be involved in the development of Crohn's disease (CD). The diagnosis of CD is still challenging, and seeking novel biomarkers is a worthwhile endeavor. Methods: An indirect enzyme-linked immunosorbent assay (ELISA) was successfully established for semi-quantitative detection of IgG anti-FcεRI in serum using human FcεRIα coated microplates and an enzyme-labeled anti-human IgG as secondary antibodies. The optimal working conditions were explored, followed by conducting the method evaluation. The serum samples and clinical data of 117 CD patients and 75 healthy controls were collected. IgE was measured by the rate turbidity turbidimetry; IgG anti-IgE and IgG anti-FcεRI were detected by ELISA. IgG anti-pancreatic antibody (PAB) and anti-Saccharomyces cerevisiae antibody (ASCA) were determined by indirect immunofluorescence assay. Data were analyzed concerning the clinical characteristics. Results: IgG anti-FcεRI was an effective marker for CD (P < 0.001), but IgE and IgG anti-IgE (P = 0.089, 0.219, respectively) were not. There was a positive correlation between anti-IgE and anti-FcεRI (R = 0.380, P < 0.001). Anti-FcεRI positive patients behaved with higher disease activity [OR: 1.478 (1.200~1.821), P < 0.001], but were less likely to be located in L4 among Montreal classification [OR: 0.253 (0.077~0.837), P = 0.024]. Existing indicators, PAB and ASCA, behaved with high specificity (both > 95%) with low sensitivity (both < 30%). The combination of anti-FcεRI with existing markers significantly improved the diagnostic efficiency [AUC: 0.879 (0.831~0.928)]. Conclusion: An ELISA for the detection of anti-FcεRI was established and validated, which may contribute to facilitating research on Crohn's diseases. Anti-FcεRI positive CD patients were associated with higher disease activity indices, suggesting its potential value in the diagnosis and management of CD.

Targeting mast cell activation alleviates anti-MHC I antibody and LPS-induced TRALI in mice by pharmacologically blocking the TLR3 and MAPK pathway.

Transfusion-related lung injury (TRALI) poses a significant risk following blood transfusion and remains the primary cause of transfusion-related morbidity and mortality, primarily driven by the activation of immune cells through anti-major histocompatibility complex class I (anti-MHC I) antibody. However, it remains to be defined how immune microenvironmental cue contributes to TRALI. Here, we uncover that activated mast cells within the immune microenvironment promote lung inflammation and injury in antibody-mediated TRALI, both in vitro and in vivo. This was demonstrated by co-culturing lipopolysaccharide (LPS)-pretreated mast cell line with anti-MHC I antibody and establishing a "two-hit" TRALI mouse model through intratracheal injection of LPS followed by tail-vein injection of anti-MHC I antibody. Importantly, mast cell-deficient KitW-sh/W-sh mice exhibited markedly reduced lung inflammation and injury responses in antibody-mediated TRALI compared with wild-type mice. Mechanistically, activation of toll-like receptor 3 (TLR3)/mitogen-activated protein kinase (MAPK) signaling pathway in mast cells contributes to the enhanced production of proinflammatory factors. These excessive proinflammatory factors produced by activated mast cells contribute to lung inflammation and injury in antibody-mediated TRALI. Pharmacologically targeting the TLR3/MAPK pathway to inhibit mast cell activation normalizes the proinflammatory microenvironment and alleviates lung inflammation and injury in the preclinical TRALI mouse model. Overall, we find that activation of mast cells via the TLR3/MAPK pathway contributes to lung inflammation and injury in antibody-mediated TRALI, providing novel insights into its underlying mechanisms. Furthermore, targeting activated mast cells and the associated pathway offers potential therapeutic strategies for antibody-mediated TRALI.

Mammalian Inner Ear-Resident Immune Cells-A Scoping Review.

BACKGROUND: Several studies have demonstrated the presence of resident immune cells in the healthy inner ear. AIM: This scoping review aimed to systematize this knowledge by collecting the data on resident immune cells in the inner ear of different species under steady-state conditions. METHODS: The databases PubMed, MEDLINE (Ovid), CINAHL (EBSCO), and LIVIVO were used to identify articles. Systematic reviews, experimental studies, and clinical data in English and German were included without time limitations. RESULTS: The search yielded 49 eligible articles published between 1979 and 2022. Resident immune cells, including macrophages, lymphocytes, leukocytes, and mast cells, have been observed in various mammalian inner ear structures under steady-state conditions. However, the physiological function of these cells in the healthy cochlea remains unclear, providing an opportunity for basic research in inner ear biology. CONCLUSIONS: This review highlights the need for further investigation into the role of these cells, which is crucial for advancing the development of therapeutic methods for treating inner ear disorders, potentially transforming the field of otolaryngology and immunology.

Immunohistochemical Analysis of CD117 in the Mast Cells of Odontogenic Keratocysts.

BACKGROUND: Odontogenic lesions contain mast cells (MCs), particularly those with a cystic appearance. Because of their high recurrence rates and aggressive clinical behaviour, odontogenic keratocysts (OKCs) require special treatment. A particular kind of protein called cluster of differentiation (CD) 117/ receptor tyrosine kinase (c-KIT) is present on the surface of many cells. Most hematopoietic cells lose their expression of KIT during the differentiation process, with the exception of MCs, which continue to express KIT throughout their lifetime. AIM: Using the CD117 immunomarker, this immunohistochemical investigation sought to assess the presence and location of MCs in OKCs and examine the relationship between MC numbers in sporadic, syndromic, and recurrent OKCs. METHODS: The study comprised 30 paraffin-embedded tissue specimens, and a histopathological diagnosis was made from hematoxylin and eosin-stained sections with a thickness of 4-5 µ. Out of 30 specimens, 21 were sporadic, six were recurrent OKCs, and three were syndrome-associated OKCs. CD-117/c-kit rabbit polyclonal primary antibody was used to stain the sections for observing MCs, which were then viewed under a light microscope with a digital camera and a desktop computer with MICAPS software for viewing images. RESULT: To compare the number of MCs among OKCs, a one-way ANOVA test was used. Our study revealed that a statistically significant increase in MCs has been observed in the subepithelial and deep connective tissue of recurrent OKC (p < 0.05). However, a comparison of the mean MC value among three OKC subtypes did not reveal any statistically significant differences. An increased mast count was observed in the deep connective tissue layer of syndromic OKC under multiple comparisons. CONCLUSION: Our study concluded that MCs were present in increased numbers both in the superficial and deep connective tissue of recurrent OKCs, indicative of their aggressive clinical behaviour. Increased mean MC counts observed in some of the sporadic cases may be an indicator of their chances of recurrence in the future.

Renal Mast Cell-Specific Proteases in the Pathogenesis of Tubulointerstitial Fibrosis.

Chronic kidney disease is detected in 8-15% of the world's population. Along with fibrotic changes, it can lead to a complete loss of organ function. Therefore, a better understanding of the onset of the pathological process is required. To address this issue, we examined the interaction between mast cells (MCs) and cells in fibrous and intact regions, focusing on the role of MC proteases such as tryptase, chymase, and carboxypeptidase A3 (CPA3). MCs appear to be involved in the development of inflammatory and fibrotic changes through the targeted secretion of tryptase, chymase, and CPA3 to the vascular endothelium, nephron epithelium, interstitial cells, and components of intercellular substances. Protease-based phenotyping of renal MCs showed that tryptase-positive MCs were the most common phenotype at all anatomic sites. The infiltration of MC in different anatomic sites of the kidney with an associated release of protease content was accompanied by a loss of contact between the epithelium and the basement membrane, indicating the active participation of MCs in the formation and development of fibrogenic niches in the kidney. These findings may contribute to the development of novel strategies for the treatment of tubulointerstitial fibrosis.

Maternal High-Fat Diet Exacerbates Epicutaneous Sensitization and Oral Challenge-Induced Food Allergy to Ovalbumin in Offspring Mice.

Dietary factors have been associated with an increased prevalence of food allergy (FA). However, little is known about how an unhealthy diet in early life affects FA reactions in offspring. The objective of this study is to provide a scientific foundation for developing and promoting healthy dietary patterns in early life. In this study, we found that maternal high-fat diet (HFD) during pregnancy and lactation exacerbates FA (HFD-FA) in offspring mice, leading to increased serum levels of mast cell protease 1. First, we studied the systemic immunity of the HFD-FA mice and observed elevated levels of proinflammatory cytokines (IL-4, IL-6, and IL-1ß) and a reduced frequency of Treg cells in splenocytes. Additionally, the HFD-FA mice showed increased gut permeability, accumulation of intestinal mast cells, and a decrease in the Treg cell frequency in the mesenteric lymph nodes. Furthermore, our findings also indicated a reduction in gut microbial diversity and abundance in HFD-FA mice. Importantly, lipid metabolism profiling revealed unique lipid profiles in the HFD-FA mice, with significant upregulation of triglycerides and downregulation of sphingolipids. Taken together, our results suggest that maternal HFD alters intestinal homeostasis and increases FA susceptibility in offspring mice.

Emerging trends and research hotspots in the relationship between mast cells and atopic dermatitis based on the literature from 2001 to 2024: A bibliometric and visualized analysis.

BACKGROUND: Atopic dermatitis (AD) is a prevalent chronic inflammatory and highly pruritic skin condition characterized by the infiltration of immune cells, notably eosinophils and mast cells. Mast cells (MCs) critically participate in the complex pathogenesis of AD through multiple pathways and have recently garnered growing attention in research. Despite the abundance of related studies published over the years, a comprehensive bibliometric analysis on this topic remains lacking. OBJECTIVE: Our objective was to perform an up-to-date bibliometric analysis of the literature focusing on the relationship between MCs and AD. This analysis would provide valuable insights through a thorough bibliometric review, enabling a clearer understanding of the current research landscape, pinpointing key studies, and detecting emerging trends within this field. METHODS: We searched the Web of Science Core Collection (WoSCC) database on 15 July 2024. The data retrieval strategy was structured as follows: #1: TS = ("mast cells") OR TS = ("mast cell") OR TS = ("mastocyte"); #2: TS = ("atopic dermatitis") OR TS = ("atopic eczema") Final data: (#1 AND #2). A total of 2272 items published between 2001 and 2024 were included. Several scientometric visualization tools, including VOSviewer, R-bibliometrix, CiteSpace and an online analytical platform, were utilized to conduct text mining and to visualize the bibliometric data, facilitating a comprehensive analysis of research trends and patterns. RESULTS: Out of the initial 2272 articles retrieved, 2168 were selected for analysis after applying inclusion and exclusion criteria based on publication type. The findings indicate a steady and substantial exponential growth in the annual number of publications focused on the relationship between over the years. The South Korea (547/2168), USA (465/2168) and Japan (436/2168) were the major contributors within this field, collectively constituting more than half of the total publications. To clarify the underlying mechanisms and role of MCs in the pathogenesis of AD and to make MCs prime targets for therapeutic intervention have garnered the most attention in this field. According to references analysis, the research emphasis has shifted to developing MC-related therapeutics and intervention and regulating the immune system of AD patients through modulating the activity of various immune cells. On the basis of keywords analysis, we outlined the following research frontiers and hotpots in the future: the role of oxidative stress in the pathogenesis; imbalance in the different types of T helper (Th) cells during immune response; skin barrier and barrier dysfunction; improving quality of life; sensory neurons; biological agents and small-molecule drugs. Furthermore, IL-13, IL-4, NFKB1, BCGF-1 and CD4 ranked as the top five genes that have received the most investigative attention in the intersection of MCs and AD. CONCLUSION: In a word, this analysis would greatly benefit from a thorough bibliometric review to gain a deeper understanding of the current research landscape, identify pivotal studies and pinpoint emerging trends in the field of MCs and AD. Meanwhile, our findings offered researchers a holistic perspective of ongoing developments, serving as a valuable resource for guiding future research and informing decision-making for both researchers and policymakers in this area.

Amphotericin B for injection triggers degranulation of human LAD2 mast cells by MRGPRX2 and pseudo-allergic reactions in mice via MRGPRB2 activation.

Amphotericin B, a polyene macrolide antifungal agent, still plays an important role in the management of serious systemic fungal infections. Amphotericin B deoxycholate (AmBd) has been used to treat invasive fungal infections for over 60 years and remains the primary clinical formulation currently available. Anaphylactoid reactions triggered by AmBd in the clinic have been documented. However, the molecular and cellular events contributing to these reactions have not been clearly elucidated to date. This study demonstrates that the human Mas-related G protein-coupled receptor X2 (MRGPRX2) is the receptor that mediates these anaphylactoid responses. Molecular docking and cellular thermal shift assay (CETSA) indicate that AmBd exhibits potential affinity with MRGPRX2. In vitro, exposure to AmBd results in significant release of LAD2 mast cell granules and induces intracellular Ca2+ mobilization as well as activation of PLC-γ/IP3R and PI3K/AKT signaling pathways. However, these phenomena are reduced in MRGPRX2-knockdown LAD2 cells. In vivo, AmBd triggers paw swelling and a rapid drop in core body temperature in wild-type (WT) mice. However, these reactions are almost absent in MRGPRB2 (the mouse homolog of MRGPRX2) knockout mice (MRGPRB2MUT, MUT). The above results suggest that AmBd activates PLC-γ/IP3R and PI3K/AKT signaling via MRGPRX2 (in human LAD2 mast cells) or MRGPRB2 (in mice), leading to the release of mast cell granules and subsequent triggering of pseudo-allergic reactions. Taken together, this study clarifies the role of MRGPRX2 in triggering pseudo-allergic reactions to AmBd and suggests that MRGPRX2 could be a potential therapeutic target for controlling these reactions.

Dynamin 2-mediated endocytosis of BLT1 is required for IL-8 production in HMC-1 cells induced by Trichomonas vaginalis-derived secretory products.

We previously reported that leukotriene B4 (LTB4) contained in Trichomonas vaginalis-derived secretory products (TvSP) play an essential role in interleukin-8 (IL-8) production in human mast cell line (HMC-1 cells) via LTB4 receptor (BLT)-mediated Nuclear Factor-kappa B (NF-кB) activation. Dynamin, a GTPase, has been known to be involved in endocytosis of receptors for signaling of production of cytokine or chemokines. In the present study, we investigated the role of dynamin-mediated BLT1 endocytosis in TvSP-induced IL-8 production. When HMC-1 cells were transfected with BLT1 or BLT2 siRNA, TvSP-induced IL-8 production was significantly inhibited compared with that in cells transfected with control siRNA. In addition, pretreatment of HMC-1 cells with a dynamin inhibitor (Dynasore) reduced IL-8 production induced by TvSP or LTB4. TvSP- or LTB4- induced phosphorylation of NF-кB was also attenuated by pretreatment with Dynasore. After exposing HMC-1 cells to TvSP or LTB4, BLT1 was translocated from the intracellular compartments to the plasma membrane within 30 min. At 60 min after stimulation with TvSP or LTB4, BLT1 remigrated from the cell surface to intracellular areas. Pretreatment of HMC-1 cells with dynamin-2 siRNA blocked internalization of BLT1 induced by TvSP or LTB4. Co-immunoprecipitation experiments revealed that dynamin-2 strongly interacted with BLT1 60 min after stimulation with TvSP or LTB4. These results suggest that T. vaginalis-secreted LTB4 induces IL-8 production in HMC-1 cells via dynamin 2-mediated endocytosis of BLT1 and phosphorylation of NF-кB.

Solitary Cutaneous Mastocytoma in an Adult Diagnosed on Cytology: A Rare Case Report.

Mastocytosis is characterized by the proliferation of neoplastic mast cells in various organs, which can have either cutaneous or systemic presentation. Solitary cutaneous mastocytomas are most commonly seen in the pediatric age group but rarely present in adults. Histopathology of cutaneous mastocytoma is well described in the literature but only a few studies are available describing the cytomorphological features. We present a case of a 19-year-old female who presented with a 6-month history of a right supraclavicular single, 0.5 × 0.5 cm, well-defined, reddish-brown round nodule. The fine needle aspiration cytology (FNAC) smears were highly cellular showing monomorphic cells, predominantly dispersed singly and occasionally in small clusters. The cells were round to oval, with moderate cytoplasm containing coarse metachromatic granules. Toluidine blue stain and CD117 immunocytochemical stain confirmed the presence of mast cell granules. Based on the cytomorphology, staining, clinical history, and examination, a diagnosis of solitary cutaneous mastocytoma was rendered. FNAC plays a pivotal role in diagnosing mast cell tumors and even obviates the need for tissue biopsy in selected cases.

No signs of mast cell involvement in long-COVID: A case-control study.

Long-COVID caused by SARS-CoV-2 infection has significant and increasing effects on human health worldwide. Although a unifying molecular or biological explanation is lacking, several pathophysiological mechanisms have been proposed. Involvement of mast cells-evolutionary old "multipurpose" innate immune cells-was reported recently in studies of acute infection and post-acute-COVID-19 syndrome. Mast cell activity has been suggested in long-COVID. In this case-control study, we compared data from 24 individuals with long-COVID (according to the NICE criteria) and 24 age- and sex-matched healthy individuals with a history of SARS-CoV-2 infection without developing sequelae. Serum levels of the proteases beta-tryptase (TPSB2) and carboxypeptidase (CPA3), which are mast cell specific, were measured using immunoassays. The values were compared between the two groups and correlated to measures of physical exertional intolerance. TPSB2 and CPA3 levels were median (range) 26.9 (2.0-1000) and 5.8 (1.5-14.0) ng/mL, respectively, in the long-COVID group. The corresponding values in the control group were 10.9 (2.0-1000) (p = 0.93) and 5.3 (3.5-12.9) ng/mL (p = 0.82). No significant correlations between TPSB2 or CPA3 levels and scores on the ten physical subscales of SF-36, 3.1-3.10 were revealed. We found no significant differences in the levels of mast cell activation markers TPSB2 and CPA3 between the long-COVID and control groups and no correlations with proxy markers of exercise intolerance. Mast cell activation does not appear to be part of long-term pathogenesis of long-COVID, at least in the majority of patients.

Nebivolol hydrochloride and its impurities induce pseudo-allergic reactions via mast cell activation.

Nebivolol hydrochloride is a third-generation ß-blocker commonly used to treat cardiovascular diseases. However, it has been reported to induce allergic reactions in clinical use which deserves much attention. Therefore, this study focused on the ability of two isomers of nebivolol and chiral isomer impurities to induce allergic reactions. Our findings demonstrate that both nebivolol and two isomeric impurities can activate mast cell degranulation in vitro and show significant retention on Mas-related G-protein-coupled receptor X2 (MRGPRX2)-HEK293 cell membrane chromatography. These effects were further validated in vivo, where nebivolol and impurity IP-3 were observed to cause toe swelling and mast cell degranulation in mice. Molecular docking studies revealed interactions between these compounds and key amino acids of MRGPRX2, suggesting a mechanism for the induced allergic reactions. This work lays the foundation for improving the clinical safety of nebivolol.

The effect of aging on mast cell density in human skin: a comparative analysis of photoexposed and photoprotected regions.

BACKGROUND: Mast cells are mononuclear cells originating from bone marrow. They produce various biologically active substances, which allow them to actively participate in immune and inflammatory processes associated with intrinsic and extrinsic skin aging. This research focused on distribution and density of mast cells in healthy skin in different stages of skin aging. MATERIAL AND METHODS: This project included samples of photoexposed and photoprotected skin, obtained from 90 cadavers aged 0-82 years. The samples were classified into five age groups: newborns, young age, middle age, senior age and the oldest age. In order to visualize the mast cells, we have employed several histochemical staining protocols. RESULTS: The number of mast cells of the photoexposed skin significantly correlated to the individual's age. The number of mast cells of the photoprotected skin was in general statistically significantly lower in younger compared to older groups; however, the correlation of the mast cell density in photoprotected skin and the age did not reach statistical significance. In middle age, senior age and the oldest age groups, a significantly higher number of mast cells was recorded in the skin of the photoexposed compared to photoprotected region. CONCLUSIONS: The increase in mast cell density correlated with age only in photoexposed skin. Age-related higher accumulation of dermal mast cells in photoexposed skin can be an important factor in the photoaging process, as well as the contributing factor in the occurrence of skin cancer.

Airway tryptase levels inform the lack of clinical efficacy of the tryptase inhibitor MTPS9579A in asthma.

BACKGROUND: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract. METHODS: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid. RESULTS: MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline. CONCLUSIONS: The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.

Peanut-specific IgG subclasses as biomarkers of peanut allergy in LEAP study participants.

Antigen-specific IgG2 and IgG3 are rarely measured in food allergy clinical trials despite known function in preventing mast cell and basophil activation. Our objective was to determine whether measuring peanut-specific IgG2 and IgG3 levels would correlate with peanut allergy status. Peanut-specific IgG subclasses were measured via ELISA assays in Learning Early About Peanut allergy (LEAP) trial participants at 5 years of age and were correlated with peanut allergy vs peanut sensitization vs non-peanut allergic and peanut consumption vs peanut avoidance. Peanut-specific IgG1, IgG2, IgG3, and IgG4 levels were significantly different between participants with peanut allergy vs peanut sensitization vs non-peanut allergic, and a multivariate logistic regression model and stepwise selection found that IgG1 most closely associated with peanut allergy status. Similarly, all subclasses differentiated those consuming vs those avoiding peanut, but subsequent modeling found that IgG4 most closely associated with consumption status. Amongst the peanut-specific IgG subclasses, IgG1 was the best biomarker for peanut allergy, while IgG4 was the best biomarker for peanut antigen exposure in this highly atopic cohort. Our study did not find added value from evaluating peanut-specific IgG 2 and 3 as biomarkers of peanut allergy, although they did correlate with peanut allergy. Subsequent studies should assess the value of adding IgG subclasses to multivariate models predicting peanut allergy status.

The Contribution of Mast Cells to the Regulation of Elastic Fiber Tensometry in the Skin Dermis of Children with Marfan Syndrome.

Marfan syndrome (MFS) is a hereditary condition accompanied by disorders in the structural and regulatory properties of connective tissue, including elastic fibers, due to a mutation in the gene encodes for fibrillin-1 protein (FBN1 gene) and the synthesis of abnormal fibrillin-1 glycoprotein. Despite the high potential of mast cells (MCs) to remodel the extracellular matrix (ECM), their pathogenetic significance in MFS has not been considered yet. The group of patients with Marfan syndrome included two mothers and five children (three girls aged 4, 11, and 11 and two boys aged 12 and 13). Normal skin was examined in two children aged 11 and 12. Histochemical, monoplex, and multiplex immunohistochemical techniques; combined protocols of simultaneous histochemical and immunohistochemical staining (the results of staining were assessed using light, epifluorescence, and confocal microscopy); and bioinformatics algorithms for the quantitative analysis of detected targets were used to evaluate mast cells and their relationship with other cells from extracellular structures in the skin dermis. Analysis of the skin MC population in children with Marfan syndrome revealed a considerably increased number of intra-organic populations with the preservation of the specific Tryptase+Chymase+CPA3+ protease profile typical of the skin. The features of the MC histotopography phenotype in MFS consisted of closer colocalization with elastic fibers, smooth muscle cells, and fibroblasts. MCs formed many intradermal clusters that synchronized the activity of cell functions in the stromal landscape of the tissue microenvironment with the help of spatial architectonics, including the formation of cell chains and the creation of fibrous niches. In MCs, the expression of specific proteases, TGF-ß, and heparin increased, with targeted secretion of biologically active substances relative to the dermal elastic fibers, which had specific structural features in MFS, including abnormal variability in thickness along their entire length, alternating thickened and thinned areas, and uneven surface topography. This paper discusses the potential role of MCs in strain analysis (tensometry) of the tissue microenvironment in MFS. Thus, the quantitative and qualitative rearrangements of the skin MC population in MFS are aimed at altering the stromal landscape of the connective tissue. The results obtained should be taken into account when managing clinical signs of MFS manifested in other pathogenetically critical structures of internal organs, including the aorta, tendons, cartilage, and parenchymal organs.