Mast Cell Hyperplasia Research Articles

Cang-ai volatile oil alleviates nasal inflammation via Th1/Th2 cell imbalance regulation in a rat model of ovalbumin-induced allergic rhinitis.

We previously revealed that Cang-ai volatile oil (CAVO) regulates T-cell activity, enhancing the immune response in people with chronic respiratory diseases. However, the effects of CAVO on allergic rhinitis (AR) have not been investigated. Herein, we established an ovalbumin (OVA)-induced AR rat model to determine these effects. Sprague-Dawley (SD) rats were exposed to OVA for 3weeks. CAVO or loratadine (positive control) was given orally once daily for 2weeks to OVA-exposed rats. Behavior modeling nasal allergies was observed. Nasal mucosa, serum, and spleen samples of AR rats were analyzed. CAVO treatment significantly reduced the number of nose rubs and sneezes, and ameliorated several hallmarks of nasal mucosa tissue remodeling: inflammation, eosinophilic infiltration, goblet cell metaplasia, and mast cell hyperplasia. CAVO administration markedly upregulated expressions of interferon-γ, interleukin (IL)-2, and IL-12, and downregulated expressions of serum tumor necrosis factor-α, IL-4, IL-5, IL-6, IL-13, immunoglobulin-E, and histamine. CAVO therapy also increased production of IFN-γ and T-helper type 1 (Th1)-specific T-box transcription factor (T-bet) of the cluster of differentiation-4+ T-cells in splenic lymphocytes, and protein and mRNA expressions of T-bet in nasal mucosa. In contrast, levels of the Th2 cytokine IL-4 and Th2-specific transcription factor GATA binding protein-3 were suppressed by CAVO. These cumulative findings demonstrate that CAVO therapy can alleviate AR by regulating the balance between Th1 and Th2 cells.

Humanization with CD34-positive hematopoietic stem cells in NOG-EXL mice results in improved long-term survival and less severe myeloid cell hyperactivation phenotype relative to NSG-SGM3 mice.

NSG-SGM3 and NOG-EXL mice combine severe immunodeficiency with transgenic expression of human myeloid stimulatory cytokines, resulting in marked expansion of myeloid populations upon humanization with CD34+ hematopoietic stem cells (HSCs). Humanized NSG-SGM3 mice typically develop a lethal macrophage activation syndrome and mast cell hyperplasia that limit their use in long-term studies (e.g., humanization followed by tumor xenotransplantation). It is currently unclear to what extent humanized NOG-EXL mice suffer from the same condition observed in humanized NSG-SGM3 mice. We compared the effects of human CD34+ HSC engraftment in these two strains in an orthotopic patient-derived glioblastoma model. NSG-SGM3 mice humanized in-house were compared to NOG-EXL mice humanized in-house and commercially available humanized NOG-EXL mice. Mice were euthanized at humane or study endpoints, and complete pathological assessments were performed. A semiquantitative multiparametric clinicopathological scoring system was developed to characterize chimeric myeloid cell hyperactivation (MCH) syndrome. NSG-SGM3 mice were euthanized at 16 weeks after humanization because of severe deterioration of clinical conditions. Humanized NOG-EXL mice survived to the study endpoint at 22 weeks after humanization and showed less-severe MCH phenotypes than NSG-SGM3 mice. Major differences included the lack of mast cell expansion and limited tissue/organ involvement in NOG-EXL mice compared to NSG-SGM3 mice. Engraftment of human lymphocytes, assessed by immunohistochemistry, was similar in the two strains. The longer survival and decreased MCH phenotype severity in NOG-EXL mice enabled their use in a tumor xenotransplantation study. The NOG-EXL model is better suited than the NSG-SGM3 model for immuno-oncology studies requiring long-term survival after humanization.

Hairy Cell Leukemia with Marrow Reactive Plasmacytosis and Mast Cell Hyperplasia: A Case Report and Brief Review of the Literature

Hairy cell leukemia (HCL) and HCL-like disorders, including HCL-variant, are disorders of heterogeneous mature lymphoid B-cells known for their hairy cell infiltration accompanied by a specific genetic profile, various clinical presentations, and, as they are uncommon hematological malignancies characterized by pancytopenia, the need for appropriate therapy. Sometimes HCL creates diagnostic challenges for clinicians, and its coincidence or association with mast cell and plasma cell infiltration is a rare condition. Herein, we report a case of HCL with confusing manifestations. A 44-year-old man was referred to the hospital for weakness, fatigue, and watery, non-bloody diarrhea. The laboratory tests showed pancytopenia, leading to a referral for bone marrow aspiration and biopsy. Medium to large cells exhibiting widespread cytoplasm, oval nuclei similar to monocyte nuclei (kidney-shaped) accompanied by an increased number of mast cells, and plasma cells were observed in the biopsy sample. In flow cytometry, the neoplastic cells were positive for CD19, FMC7, and the co-expression of the CD20/CD25, CD11C/CD22, and CD103 markers. In immunohistochemical staining, the mast cells were positive for CD117, the plasma cells were positive for CD138, and the hairy cells were positive for CD20. Overall, hematopathologists must be aware of various morphologic confounding factors such as lack of typical cell morphological features and increased plasma cell and mast cell infiltration in the diagnosis of patients with HCL.

Monensin inhibits mast cell mediated airway contractions in human and guinea pig asthma models

Asthma is a common respiratory disease associated with airway hyperresponsiveness (AHR), airway inflammation and mast cell (MC) accumulation in the lung. Monensin, an ionophoric antibiotic, has been shown to induce apoptosis of human MCs. The aim of this study was to define the effect of monensin on MC responses, e.g., antigen induced bronchoconstriction, and on asthmatic features in models of allergic asthma. Tracheal segments from house dust mite (HDM) extract sensitized guinea pigs were isolated and exposed to monensin, followed by histological staining to quantify MCs. Both guinea pig tracheal and human bronchi were used for pharmacological studies in tissue bath systems to investigate the monensin effect on tissue viability and antigen induced bronchoconstriction. Further, an HDM-induced guinea pig asthma model was utilized to investigate the effect of monensin on AHR and airway inflammation. Monensin decreased MC number, caused MC death, and blocked the HDM or anti-IgE induced bronchoconstriction in guinea pig and human airways. In the guinea pig asthma model, HDM-induced AHR, airway inflammation and MC hyperplasia could be inhibited by repeated administration of monensin. This study indicates that monensin is an effective tool to reduce MC number and MCs are crucial for the development of asthma-like features.

Vagal gut-brain signaling mediates amygdaloid plasticity, affect, and pain in a functional dyspepsia model.

Functional dyspepsia (FD) is associated with chronic gastrointestinal distress and with anxiety and depression. Here, we hypothesized that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. Using a previously validated rat model of FD characterized by gastric hypersensitivity, depression-like behavior, and anxiety-like behavior, we found that vagal activity — in response to gastric distention — was increased in FD rats. The FD phenotype was associated with gastric mast cell hyperplasia and increased expression of corticotrophin-releasing factor (Crh) and decreased brain-derived neurotrophic factor genes in the central amygdala. Subdiaphragmatic vagotomy reversed these changes and restored affective behavior to that of controls. Vagotomy partially attenuated pain responses to gastric distention, which may be mediated by central reflexes in the periaqueductal gray, as determined by local injection of lidocaine. Ketotifen, a mast cell stabilizer, reduced vagal hypersensitivity, normalized affective behavior, and attenuated gastric hyperalgesia. In conclusion, vagal activity, partially driven by gastric mast cells, induces long-lasting changes in Crh signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors. Together, these results support a “bottom-up” pathway involving the gut-brain axis in the pathogenesis of both gastric pain and psychiatric comorbidity in FD.

Development of Mast Cell and Eosinophil Hyperplasia and HLH/MAS-Like Disease in NSG-SGM3 Mice Receiving Human CD34+ Hematopoietic Stem Cells or Patient-Derived Leukemia Xenografts.

Immunocompromised mouse strains expressing human transgenes are being increasingly used in biomedical research. The genetic modifications in these mice cause various cellular responses, resulting in histologic features unique to each strain. The NSG-SGM3 mouse strain is similar to the commonly used NSG (NOD scid gamma) strain but expresses human transgenes encoding stem cell factor (also known as KIT ligand), granulocyte-macrophage colony-stimulating factor, and interleukin 3. This report describes 3 histopathologic features seen in these mice when they are unmanipulated or after transplantation with human CD34+ hematopoietic stem cells (HSCs), virally transduced hCD34+ HSCs, or a leukemia patient-derived xenograft. The first feature is mast cell hyperplasia: unmanipulated, naïve mice develop periductular pancreatic aggregates of murine mast cells, whereas mice given the aforementioned human cells develop a proliferative infiltrative interstitial pancreatic mast cell hyperplasia but with human mast cells. The second feature is the predisposition of NSG-SGM3 mice given these human cells to develop eosinophil hyperplasia. The third feature, secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)-like disease, is the most pronounced in both its clinical and histopathologic presentations. As part of this disease, a small number of mice also have histiocytic infiltration of the brain and spinal cord with subsequent neurologic or vestibular signs. The presence of any of these features can confound accurate histopathologic interpretation; therefore, it is important to recognize them as strain characteristics and to differentiate them from what may be experimentally induced in the model being studied.

Insights into mast cell hyperplasia in aspirin-exacerbated respiratory disease from transcriptional profiling of polyp mast cells

Asthma is a complex, heterogeneous lung disease arising from the interaction of genetic, environmental, and immunologic factors. An emerging feature of asthma across multiple disease endotypes is the expansion of mast cells (MCs), tissue-resident granulocytes that are believed to participate in disease progression, in the airway smooth muscle, bronchial epithelium, and alveolar parenchyma.1 Of note, 2 main subsets of human MCs have been described, both of which expand during asthma: MCTC that contain the proteases tryptase and chymase and mainly reside in peripheral connective tissues and MCT that contain tryptase in the absence of chymase and reside within the epithelium.

Mast cell hyperplasia in Opisthorchis viverrini-associated cholecystitis.

Despite significant advances in understanding the role of the immune response in Opisthorchis viverrini-associated carcinogenesis, little is known about how infection induces gall bladder disease. This study investigated whether mast cells are activated in cholecystitis associated with O. viverrini, gall bladder specimens from ninety-two patients who had undergone cholecystectomy at the Khon Kaen Regional Hospital, Khon Kaen, Thailand. Two representative sections from the body of fresh gall bladder tissue were fixed in Carnoy's solution and embedded in paraffin wax. The paraffin sections were stained for mast cells and IgE plasma cells by the double histochemical and immunohistochemical method. The cells in the epithelium, lamina propria, muscular layer, and subserosa were counted and expressed as cells per square millimeter. The gall bladder bile was examined for the presence of O. viverrini eggs. Significantly higher mean mast cell numbers were found in the lamina propria (221.41 ± 16.01 vs 116.97 ± 14.61 cells per mm2; P < 0.005) of egg positive compared to egg negative groups, respectively. No comparable differences in mast cell number were observed in other layers. IgE plasma cells were rarely seen. The results suggest that mast cell hyperplasia occurs during cholecystitis in association with opisthorchiasis and may play a role in the pathogenesis of the disease.

Clinical Cutaneous Features of Patients Infected With SARS-CoV-2 Hospitalized for Pneumonia: A Cross-sectional Study.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a current pandemic worldwide. This virus can reach all organs and disturbs the immune system, leading to a cytokine storm in severe forms. We aimed to report cutaneous features among coronavirus disease 2019 (COVID-19) hospitalized patients.MethodsWe performed a cross-sectional study on 1 given day among all patients hospitalized in acute care for COVID-19 and included all patients with cutaneous features. Follow-up 48 hours later was obtained.ResultsAmong 59 adult patients hospitalized on the day of the study in an infectious diseases ward for SARS-CoV-2 infection who were confirmed by molecular assay and/or radiological findings (computed tomography scan), 40 were included. Several cutaneous manifestations were found: macular exanthema (80%), face edema (32%), livedo (13%), urticarial rash (8%), purpura (5%), oral lichenoid lesions (33%), and conjunctivitis (18%). Cutaneous biopsy was performed in 17 patients. Histological findings showed mast cell hyperplasia (100%), superficial perivascular infiltrate of lymphocytes (94%), and superficial edema (47%) consistent with capillary leak.ConclusionsVarious dermatological signs can be encountered during COVID-19. A macular rash was the most frequent. All cutaneous features could be related to a vascular leak process.

Protective Effect of Glycomacropeptide on Food Allergy with Gastrointestinal Manifestations in a Rat Model through Down-Regulation of Type 2 Immune Response.

Glycomacropeptide (GMP) is a bioactive peptide derived from milk κ-casein with immune-modulatory and anti-inflammatory properties. Food allergy (FA) is an adverse immune reaction with a broad spectrum of manifestations. Allergen intake induces persistent intestinal inflammation and tissue damage. In this study, the anti-allergic activity of GMP was evaluated using a rat ovalbumin (OVA)-induced FA model with gastrointestinal manifestation. Rats were orally GMP treated from 3 days prior and during FA development. The severity of food anaphylaxis and diarrheal episodes, antibody production and histamine level were measured. Histopathological changes, inflammation and predominant cytokine profile at intestine were analyzed. Oral GMP intake decreased clinical signs and diarrhea severity induced by allergen, with a significant reduction in intestinal edema and expression level of IL-1β and TNF-α. Prophylaxis with GMP also diminished serum anti-OVA IgE and IgG1, and histamine levels. GMP treatment markedly decreased eosinophil infiltration, mast cell and goblet cell hyperplasia, total IgE expression in intestine, and prevented histological changes in villi, crypts and internal muscularis layer. The treatment effectively suppressed IL-5, IL-13 and GATA3 expression and skewed the intestinal cytokine profile toward type 1 and regulatory. These results suggest that GMP may protect against FA through down-regulating the type 2 inflammatory response.

A new house dust mite-driven and mast cell-activated model of asthma in the guinea pig.

Animal models are extensively used to study underlying mechanisms in asthma. Guinea pigs share anatomical, pharmacological and physiological features with human airways and may enable the development of a pre-clinical in vivo model that closely resembles asthma. To develop an asthma model in guinea pigs using the allergen house dust mite (HDM). Guinea pigs were intranasally sensitized to HDM which was followed by HDM challenges once weekly for five weeks. Antigen-induced bronchoconstriction (AIB) was evaluated as alterations in Rn (Newtonian resistance), G (tissue damping) and H (tissue elastance) at the first challenge with forced oscillation technique (FOT), and changes in respiratory pattern upon each HDM challenge were assessed as enhanced pause (Penh) using whole-body plethysmography. Airway responsiveness to methacholine was measured one day after the last challenge by FOT. Inflammatory cells and cytokines were quantified in bronchoalveolar lavage fluid, and HDM-specific immunoglobulins were measured in serum by ELISA. Airway pathology was evaluated by conventional histology. The first HDM challenge after the sensitization generated a marked increase in Rn and G, which was abolished by pharmacological inhibition of histamine, leukotrienes and prostanoids. Repeated weekly challenges of HDM caused increase of Penh and a marked increase in airway hyperresponsiveness for all three lung parameters (Rn , G and H) and eosinophilia. Levels of IgE, IgG1 , IgG2 and IL-13 were elevated in HDM-treated guinea pigs. HDM exposure induced infiltration of inflammatory cells into the airways with a pronounced increase of mast cells. Subepithelial collagen deposition, airway wall thickness and goblet cell hyperplasia were induced by repeated HDM challenge. Repeated intranasal HDM administration induces mast cell activation and hyperplasia together with an asthma-like pathophysiology in guinea pigs. This model may be suitable for mechanistic investigations of asthma, including evaluation of the role of mast cells.

Systemic Mastocytosis: A Rare Cause of Diarrhea

Mastocytosis is a spectrum of neoplastic, clonal cell disorders that are characterized by mast cell hyperplasia and accumulation. Disease and clinical presentation can vary depending on the extent of spread, ranging from skin-limited cutaneous mastocytosis to systemic mastocytosis that can mimic other disease processes. Symptoms may include pruritus, flushing, hypotension, headaches, abdominal pain, nausea, vomiting, and diarrhea. Although gastrointestinal (GI) symptoms are present in a majority of patients with systemic disease, the actual percentage of gut mast cell infiltration remains unknown. Here we describe a case of diarrhea secondary to GI involvement of systemic mastocytosis. A 55-year-old woman with a known history of systemic mastocytosis and medical noncompliance complained of persistent chronic diarrhea for one year. She was evaluated for other causes of diarrhea but all additional testing was unrevealing. She ultimately underwent upper endoscopy and colonoscopy in which biopsy and histologic analysis confirmed the presence of mastocyte infiltration. She was restarted on her medical therapy and her symptoms resolved. In conclusion, systemic mastocytosis is an uncommon cause of chronic diarrhea. However, in select patients, it is important to obtain a thorough medical history and exclude other potential causes.

Mast cell hyperplasia underlies respiratory syncytial virus infection-induced predisposition for asthma

Abstract Asthma is a chronic inflammatory airway disease, which affects approximately 300 million people worldwide. A growing number of epidemiological cohort studies supports an association between pediatric allergic asthma susceptibility and prior respiratory syncytial virus (RSV) infection. In this study, we aimed to experimentally test whether RSV infection promotes the subsequent development of allergic asthma. Either wild type mice or mast cell-deficient congenic KitW-sh mice were infected with RSV or sterile vehicle. After infection clearance, the mice were sensitized to Ragweed (A. artemisiifolia) pollen allergens and subsequently challenged intranasally with Ragweed to induce asthma. Disease severity was measured as airway hyperreactivity to inhaled β-methylcholine using a mechanical ventilator. RSV caused an acute and productive infection in mice, which was associated with a rapid cytokine response in the lungs. In our murine allergic asthma model, the wild type animals which had previously cleared the RSV infection developed more severe disease, when compared to mice that have not experienced RSV. We found that there was a sustained increase in the numbers of airway mast cells following the resolution of an acute RSV infection. The induction of allergic asthma disease in our animal model was dependent on mast cells, as it was strongly attenuated in mast cell-deficient KitW-sh mice. Furthermore, there was no potentiation of allergic asthma severity by a previous RSV infection in Sash mice, indicating this process is mast cell-dependent. Thus, RSV induces airway mast cell hyperplasia, which predisposes mice for more severe allergic responses.

Intestinal mastocytosis in Trichinella spiralis infection: immunohistochemical study in murine model

Background: Trichinella spiralis(T. spiralis) is a zoonotic nematode and food borne parasite. The intestinal phase is critical for trichinellosis as it determines both process and consequences of the disease. T. spiralis-induced mucosal mast cells (MMCs) hyperplasia in the small intestine may contribute to expulsion of adult worms. CD117 marker (C-kit) which is expressed by mast cells (MC) as well as a variety of neoplasms is considered a better marker for mast cell populations. Objective: Our aim was to clarify the contribution of MMCs in the effector phase of the immune response to intestinal phase of T.spiralis during the course of infection in mice. Material and Methods: MMCs hyperplasia reaction was investigated in the intestine of mice infected with T. spiralis by immunohistochemical study using CD117 marker and analysis of results by ImageJ software. Results: The results showed that MMCs continued to increase until 14 days post infection (dpi), coinciding with time of worm expulsion; and started to decline afterward. The minimal number of MMCs was detected 35dpi. Conclusion: Our findings suggest that T. spiralis infection causes a series of pathological and time-associated changes within intestinal immune cell populations in infected mice during the intestinal phase. MMCs hyperplasia is a clear contributor to the worm expulsion

Conjugated linoleic acid attenuates 2,4-dinitrofluorobenzene-induced atopic dermatitis in mice through dual inhibition of COX-2/5-LOX and TLR4/NF-κB signaling

Conjugated linoleic acid (CLA), commonly found in beef, lamb and dairy products, has been reported to exhibit anti-inflammatory and antipruritus effects and to inhibit the release of chemical mediators such as histamine and eicosanoid in laboratory rodents. The chief objective of the study is to assess the efficacy of CLA on atopic dermatitis (AD) in mice and to explore possible mechanisms with CLA treatments. To develop a new therapy for AD, the anti-AD potential of CLA was investigated by inducing AD-like skin lesions in mice using 2,4-dinitrofluorobenzene. We evaluated dermatitis severity; histopathological changes; serum levels of T helper (Th) cytokines (interferon-γ, interleukin-4); changes in protein expression by western blotting and immunohistochemistry staining for cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), toll like receptor 4 (TLR-4), myeloid differentiation factor 88 (MyD88), nuclear factor-κB (NF-κB) and tumor necrosis factor α (TNF-α); and production of the proinflammatory lipid mediators, such as prostaglandin E2 and leukotriene B4, in the skin lesions. Treatment with CLA ameliorated the development of AD-like clinical symptoms and effectively inhibited epidermal hyperplasia and infiltration of mast cells and CD4+ T cells in the AD mouse skin. Total serum immunoglobulin E levels and the expression levels of Th1/Th2 cytokines and lipid mediators in dorsal skin were dramatically suppressed by CLA. Furthermore, CLA down-regulated the expressions of COX-2, 5-LOX, TLR4, MyD88, NF-κB and TNF-α. Taken together, our findings demonstrate the potential usefulness of CLA as an anti-inflammatory dietary supplement or drug for the prevention and management of AD skin diseases by modulating the COX-2/5-LOX and TLR4/MyD88/NF-κB signaling pathways.

Co-Occurrence of neurofibromatosis-1 with urticaria pigmentosa: A Coincidental association?

Neurofibromatosis-1 (NF-1) is a neuroectodermal abnormality characterized by multiple neurofibromas, café-au-lait macules, axillary freckling, and Lisch nodules. Urticaria pigmentosa (UP) is a maculopapular cutaneous mastocytosis due to mast cell hyperplasia. We report a case of NF-1 associated with UP. A 19-year-old male presented with multiple neurofibromas, café-au-lait macules, axillary freckling, and Lisch nodules. He also had UP lesions with positive Darier's sign. A clinical diagnosis of NF-1 with UP was made and confirmed histopathologically. Mastocytosis exhibits mast cell hyperplasia due to C-kit gene mutation. Mast cell mediatiors directly contribute to neurofibroma growth. C-kit receptor abnormality is implicated in the formation of neurofibromas as well as in UP. With possible interconnected underlying pathology of mast cell hyperplasia and increased mast cell mediators in both UP and NF-1, a possible association of NF and UP beyond simple coincidence should be considered.

Oral λ-carrageenan intake alleviates skin symptoms in a hapten induced atopic dermatitis-like model.

Lambda carrageenan is a widely used food additive. It has been shown that its oral intake induces suppression of T cell proliferation and antibody-mediated and cell-mediated immune response in experimental animals. In this study, we estimated the effect of oral ingestion of 0.001% λ-carrageenan on trinitrochlorobenzen-induced atopic dermatitis model mouse. Oral carrageenan ingestion alleviated ear swelling of hapten challenged mice and significantly suppressed mast cell hyperplasia in the topical skin. Serological analysis revealed that the treatment suppressed total IgE and antigen-specific IgG, and also suppressed both allergy driving cytokine interleukin-4 and counter-acting cytokine interferon-γ levels. It is suggested that the oral ingestion of λ-carrageenan may suppress the immunological response to the allergen and might be useful to treat atopic dermatitis.

CD8+ T cells regulated by CD4+CD25+ regulatory T cells in the early stage exacerbate the development of Dermatophagoides farinae-induced skin lesions via increasing mast cell infiltration in mice

Atopic dermatitis is a chronic inflammatory skin disease associated with CD4+ Th2 cell-shifted immune responses. Although the infiltration of skin lesions by CD8+ T cells has been recognized, their roles have not been fully defined. In this study, we examined the relationship between CD4+ and CD8+ cells in antigen-induced skin lesions of mice. BALB/c mice were repeatedly challenged with Dermatophagoides farinae (Der f) applied to the right ear nine times. Pre-treatment with anti-CD4 monoclonal antibody (mAb) during the third to sixth challenges, but not the post-treatment during the sixth to ninth challenges, exacerbated the development of Der f-induced ear swelling; pre-treatment with anti-CD25 mAb, which depletes regulatory T cells (Tregs), also exacerbated the lesions. Furthermore, the number of CD8+ T cells in lymph nodes was augmented by these pre-treatments. These findings prompted us to examine the effect of anti-CD8 mAb. Pre-treatment with anti-CD8 mAb, but not post-treatment, strongly inhibited the development of Der f-induced ear swelling; additionally, the epidermal hyperplasia and infiltration of mast cells were inhibited by the pre-treatment. Collectively, we revealed that CD8+ T cells regulated by CD4+CD25+ Tregs in the early stage are key contributors to the development of Der f-induced skin lesions via increasing mast cell infiltration, indicating that CD8+ T and Tregs could be potential therapeutic targets for atopic dermatitis.

The HMGCR Inhibitor Fluvastatin Induces Apoptosis and Autophagy in Primary and Neoplastic Mast Cells

Abstract Mast cell hyperplasia is noted in many inflammatory and allergic diseases. Mast cells can also generate a subtype of acute myelogenous leukemia. Understanding and treating mast cell hyperplasia and leukemia could be beneficial to both inflammatory and malignant diseases. Recently the family of statin drugs, widely employed as HMG CoA Reductase (HMGCR) inhibitors to lower serum cholesterol, have been found to be immunosuppressive. However, statin effects on mast cell survival are not known. We report that fluvastatin induces apoptosis in mouse bone marrow-derived mast cells (BMMC) and mastocytoma cells. Apoptosis was suppressed in p53 KO and Bcl-2 Tg BMMC, consistent with detectable mitochondrial damage and Caspase-9 activation. Because apoptosis induction could be mimicked by suppressing geranylgeranyl transferase (GGT), and fluvastatin effects were reversed by adding the product of the GGT reaction, loss of GGT-mediated protein lipidation is the likely mechanism of cell death. In addition to apoptosis, fluvastatin also induced autophagy. Chemical blockade of autophagy enhanced fluvastatin-mediated apoptosis in primary mast cells, but reduced it in mastocytomas. These data suggest that the FDA-approved statin drugs may be useful in suppressing mast cell hyperplasia and leukemia.

Mast Cells in Patients with Hereditary α-Tryptasemia Promote HLA-DR Expression and a Th2-Polarizing Microenvironment in the Gastrointestinal Tract

Abstract Hereditary α-tryptasemia (HαT) is a recently identified, genetic disorder characterized by multisystem comorbidities resulting from increased monoallelic α-tryptase copy number (CN) at TPSAB1 (α-TPSAB1). Affected individuals frequently exhibit heterogeneous multisystem symptoms and comorbidities which negatively impact daily functioning and quality of life. In the cohorts examined thus far, functional dyspepsia and irritable bowel syndrome, were most frequently reported. However, the mechanism by which increased α-TPSAB1 CN produces GI disease is unknown. Tryptase is almost exclusively produced by mast cells (MC). In the gut, MC play important roles in immune responses, leukocyte recruitment, neuroimmune inflammation, and tissue repair. MC can also promote T-cell activation and polarization via cytokine secretion, co-stimulatory marker expression and MHC II antigen presentation. MCs also release exosomes, nanosized vesicles secreted by most cell types present in biological fluids such as blood, cerebrospinal fluid, and urine, which have a reported influence on T cell differentiation. In early experiments, we found increased numbers of GI MCs, activated T cells, and urinary exosomes in HαT patients compared to healthy donors. Thus, we evaluated MC surface antigen expression, exosome proteomics, and cytokine expression of exosome-treated T cells. We found increased HLA-DR and FcɛR1α expression in HαT-patient GI MCs, increased Th2 associated signaling proteins in HαT urinary exosomes, and elevated Th2 cytokine expression in HαT-exosome treated T cells. These results suggest that HαT GI morbidity involves aggravated MC hyperplasia and antigen presentation which promotes T cell activation and Th2 polarization.