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1.
Artigo em Inglês | MEDLINE | ID: mdl-38851398

RESUMO

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities which have gained increased attention from patients and medical providers. While several descriptive publications about MCAS exist, there are many gaps in knowledge resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell (MC) activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to MC activation in MCAS patients remain to be elucidated. The purpose of this manuscript is to summarize the known literature, identify gaps in knowledge, and highlight research needs. Several topics are covered: 1) Contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; 2) Mechanistic research; 3) Management of typical and refractory symptoms, and 4) MCAS-specific education for patients and healthcare providers.

2.
Clin Otolaryngol ; 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38775022

RESUMO

BACKGROUND: Postoperative cerebrospinal fluid (CSF) leak remains a concerning complication of the endoscopic endonasal approach (EEA) for skull base pathology. Signs and symptoms suggesting CSF leak often trigger additional workup during the postoperative course. We systematically evaluate associations between subjectively reported clinical signs/symptoms noted during the immediate postoperative period and incidence of postoperative CSF leaks. METHODS: Retrospective chart review was conducted at a tertiary academic medical centre including 137 consecutive patients with intraoperative CSF leak during EEA with primary repair between July 2018 and August 2022. Postoperative CSF leak associations with clinical signs and symptoms were evaluated using positive (PPV) and negative predictive values (NPV), sensitivity, specificity and odds ratio (OR) via univariate logistic regression. RESULTS: Seventy-nine patients (57.7%) had high-flow leaks repaired and 5 (3.6%) developed CSF leaks postoperatively. Of reported symptoms, rhinorrhea was most common (n = 52, 38.0%; PPV [95% CI] = 7.6% [4.8%, 11.9%]), followed by severe headache (n = 47, 34.3%; 6.3% [3.1%, 12.5%]), dizziness (n = 43, 31.4%; 2.3% [0.4%, 12.1%]), salty or metallic taste (n = 20, 14.6%; 9.9% [3.3%, 25.8%]), and throat drainage (n = 10, 7.3%; 9.9% [1.7%, 41.4%]). Nausea or vomiting constituted the most reported sign concerning for CSF leak (n = 73, 53.3%; PPV [95% CI] = 4.1% [2.0%, 8.1%]). On univariate regression, no sign or symptom, including rhinorrhea (OR [95% CI] = 7.00 [0.76-64.44]), throat drainage (3.42 [0.35-33.86]), salty/metallic taste (4.22 [0.66-27.04]), severe headache (3.00 [0.48-18.62]), dizziness (0.54 [0.06-4.94]), fever (3.16 [0.50-19.99]), and nausea/vomiting (1.33 [0.22-8.21]), associated with postoperative CSF leak. CONCLUSIONS: A range of subjectively reported symptoms and signs failed to predict postoperative CSF leak. Further investigation is warranted to inform appropriate attention and response.

3.
Mol Ther ; 30(1): 295-310, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34371183

RESUMO

Activating mutations in c-KIT are associated with the mast cell (MC) clonal disorders cutaneous mastocytosis and systemic mastocytosis and its variants, including aggressive systemic mastocytosis, MC leukemia, and MC sarcoma. Currently, therapies inhibiting KIT signaling are a leading strategy to treat MC proliferative disorders. However, these approaches may have off-target effects, and in some patients, complete remission or improved survival time cannot be achieved. These limitations led us to develop an approach using chemically stable exon skipping oligonucleotides (ESOs) that induce exon skipping of precursor (pre-)mRNA to alter gene splicing and introduce a frameshift into mature KIT mRNA transcripts. The result of this alternate approach results in marked downregulation of KIT expression, diminished KIT signaling, inhibition of MC proliferation, and rapid induction of apoptosis in neoplastic HMC-1.2 MCs. We demonstrate that in vivo administration of KIT targeting ESOs significantly inhibits tumor growth and systemic organ infiltration using both an allograft mastocytosis model and a humanized xenograft MC tumor model. We propose that our innovative approach, which employs well-tolerated, chemically stable oligonucleotides to target KIT expression through unconventional pathways, has potential as a KIT-targeted therapeutic alone, or in combination with agents that target KIT signaling, in the treatment of KIT-associated malignancies.


Assuntos
Mastócitos , Mastocitose , Humanos , Mastócitos/metabolismo , Mastócitos/patologia , Mastocitose/genética , Mastocitose/patologia , Mastocitose/terapia , Proteínas Proto-Oncogênicas c-kit/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo
4.
J Allergy Clin Immunol ; 149(4): 1392-1401.e6, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34506850

RESUMO

BACKGROUND: CD25+ human mast cells (huMCs) have been reported in patients with monoclonal mast cell diseases and in rare association with inflammation. However, the regulation of CD25 expression on huMCs and the possible biologic consequences remain poorly understood. OBJECTIVE: We sought to identify conditions that would upregulate CD25 expression on huMCs and to explore possible functional implications. METHODS: huMCs were cultured from peripheral blood progenitor cells over 6 to 8 weeks. Expression of CD25 was determined by fluorescence-activated cell sorting and soluble CD25 by ELISA. Signal transducer and activator of transcription 5 (STAT5) phosphorylation induced by IL-2 in huMCs, regulatory T (Treg) cells, or in cocultured huMCs and Treg cells was examined by fluorescence-activated cell sorting. RESULTS: Addition of IL-3 to CD34+ progenitors at the initiation of huMC cultures in the presence of stem cell factor and IL-6 upregulated the expression of CD25 in developing huMCs and resulted in shedding of soluble CD25 into the media. Removal of IL-3 after the first week of culture did not affect subsequent expression of CD25. Furthermore, addition of IL-3 14 days after the initiation of the culture did not induce significant CD25 expression. Treatment with anti-IL-3 antibody or the Janus kinase inhibitor tofacitinib blocked IL-3-induced CD25 upregulation. Binding of IL-2 to CD25+ huMCs did not induce STAT5 phosphorylation. However, coincubation of Treg cells with CD25+ huMCs pretreated with IL-2 was sufficient to result in STAT5 phosphorylation in Treg cells. CONCLUSIONS: IL-3 promotes CD25 expression and shedding by huMCs. Although CD25+ huMCs do not respond to IL-2, they bind IL-2 and may act as a reservoir of IL-2 to then activate lymphocytes.


Assuntos
Interleucina-3 , Mastócitos , Células Cultivadas , Humanos , Interleucina-2/metabolismo , Interleucina-2/farmacologia , Interleucina-3/metabolismo , Interleucina-3/farmacologia , Fator de Transcrição STAT5/metabolismo , Linfócitos T Reguladores , Regulação para Cima
5.
J Allergy Clin Immunol ; 149(6): 1866-1874, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35421448

RESUMO

Mast cell (MC) activation is a key event in allergic reactions, other inflammatory states, and MC activation syndromes. MC-stabilizing agents, mediator-targeting drugs, and drugs interfering with mediator effects are often prescribed for these patients. However, the clinical efficacy of these drugs varies depending on the numbers of involved MCs and the underlying pathology. One straightforward approach would be to eradicate the primary target cell. To date however, no MC-eradicating treatment approach has been developed for patients with MC activation disorders. Nevertheless, recent data suggest that long-term treatment with agents effectively inhibiting KIT function results in the virtual eradication of tissue MCs and a sustained decrease in serum tryptase levels. In many of these patients, MC depletion is associated with a substantial improvement in mediator-induced symptoms. In patients with an underlying KIT D816V-positive mastocytosis, such MC eradication requires an effective inhibitor of KIT D816V, such as avapritinib. However, the use of KIT inhibitors must be balanced against their potential side effects. Here we discuss MC-eradicating strategies in various disease models, the feasibility of this approach, available clinical data, and future prospects for the use of KIT-targeting drugs in MC activation disorders.


Assuntos
Transtornos da Ativação de Mastócitos , Mastocitose Sistêmica , Mastocitose , Humanos , Mastócitos/patologia , Mastocitose/tratamento farmacológico , Mastocitose/patologia , Mastocitose Sistêmica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-kit/genética , Estaurosporina/uso terapêutico
6.
J Allergy Clin Immunol ; 149(3): 1010-1017.e10, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34425177

RESUMO

BACKGROUND: Acute increases of ≥20% + 2 ng/mL (20 + 2 rule) over basal serum tryptase (BST) is the recommended threshold supporting a clinical diagnosis of anaphylaxis. Prospective studies have demonstrated high sensitivity for this algorithm after parenteral exposure, but specificity has not been evaluated. OBJECTIVE: We sought to define a serum tryptase change that distinguishes baseline variability from anaphylaxis on the basis of intraindividual variation in BST. METHODS: Ninety-three total subjects with atopy (n = 62) or hereditary α-tryptasemia (HαT) (n = 31) and ≥2 BST measurements were identified. Sequential BST variability measurements were modeled and threshold ratios that optimized sensitivity and/or specificity determined. Models were tested in 22 individuals with physician-diagnosed anaphylaxis and validated in independent cohorts of individuals with HαT (n = 33), indolent systemic mastocytosis (ISM) (n = 52), and ISM + HαT (n = 12). Mature tryptase levels were measured in HαT (n = 19) and ISM (n = 20). An online application was developed for clinical use. RESULTS: As a result of BST variability, 9.7% (9/93) of primary cohort patients, and 18% (6/33) of HαT, 30% (16/53) of ISM, and 25% (3/12) of ISM + HαT patients from validation cohorts met the 20 + 2 rule despite absent immediate hypersensitivity symptoms; mature tryptase was noncontributory among individuals with HαT or ISM at baseline. A ratio of acute tryptase/BST exceeding 1.685 provided the optimized diagnostic rule for jointly maximizing sensitivity and specificity. Statistically significant improvement in specificity relative to the 20 + 2 rule was observed among individuals with elevated BST caused by HαT and ISM. CONCLUSIONS: Using an acute tryptase/BST ratio of 1.685 improves specificity of measured changes among individuals with HαT and ISM while maintaining high sensitivity for confirmation of anaphylaxis.


Assuntos
Anafilaxia , Mastocitose Sistêmica , Mastocitose , Anafilaxia/diagnóstico , Humanos , Mastócitos , Estudos Prospectivos , Triptases
7.
J Allergy Clin Immunol ; 149(6): 1855-1865, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35430191

RESUMO

Mast cell neoplasms are an emerging challenge in the fields of internal medicine, allergy, immunology, dermatology, laboratory medicine, and pathology. In this review, we discuss the current standards for the diagnosis and prognostication of mast cell neoplasms with special reference to clinically relevant germline and somatic gene variants. In patients with cutaneous mastocytosis or with indolent systemic mastocytosis (SM), various KIT-activating mutations act as key molecular drivers of the disease. In adults, KIT p.D816V is by far the most prevalent driver, whereas other KIT mutants are detected in nearly 40% of children. In advanced SM, including aggressive SM, SM with an associated hematological neoplasm, and mast cell leukemia, additional somatic mutations in other genes, such as SRSF2, JAK2, RUNX1, ASXL1, or RAS, may be detected. These drivers are more frequently detected in SM with an associated hematological neoplasm, particularly in male patients. Recently, hereditary alpha-tryptasemia has been identified as a genetic trait more prevalent in SM compared with healthy controls. Moreover, hereditary alpha-tryptasemia is more frequent in patients with SM with Hymenoptera venom allergy and severe mediator-related symptoms than in patients with SM without symptoms. On the basis of this knowledge, we propose a diagnostic algorithm in which genetic markers are applied together with clinical and histopathologic criteria to establish the diagnosis and prognosis in SM.


Assuntos
Neoplasias Hematológicas , Mastocitose Sistêmica , Adulto , Criança , Análise Citogenética , Marcadores Genéticos , Humanos , Masculino , Mastócitos/patologia , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Mutação , Proteínas Proto-Oncogênicas c-kit/genética
8.
Br J Haematol ; 196(2): 304-315, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34374078

RESUMO

Historically, understanding of the human mast cell (MC) compartment has lagged behind the appreciation of other cell lineages. MCs exist in vascularised tissues but do not under normal circumstances circulate in blood, and there has been no pharmacological agent identified that totally and selectively inhibits human MC function. There are no substantiated accounts of an apparently healthy individual who is severely lacking in MCs. Thus, some of the approaches employed to understand the function of a specific immune cell are not available to the MC biologist. The disease categories that have provided the greatest insight into MC biology have been monoclonal and IgE-mediated MC disorders. This has led to the categorisation of MC diseases as intrinsic or extrinsic to the MC compartment and to the recognition of the role of mediators in MC activation disorders. Mastocytosis as a clonal disorder not only impacts the MC compartment through changes intrinsic to the MC, but also by the effects of episodes of significant release of MC mediators. The availability of newer therapeutic approaches developed to treat monoclonal MC disorders offer insights into how to more selectively approach management of MC centric diseases.


Assuntos
Mastócitos/imunologia , Mastócitos/metabolismo , Fatores Etários , Biomarcadores , Biópsia , Terapia Combinada , Diagnóstico Diferencial , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Homeostase , Humanos , Imunofenotipagem , Mastócitos/citologia , Mastocitose/diagnóstico , Mastocitose/etiologia , Mastocitose/metabolismo , Mastocitose/terapia , Técnicas de Diagnóstico Molecular , Fenótipo , Prognóstico , Resultado do Tratamento
9.
Phys Rev Lett ; 128(21): 210601, 2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35687439

RESUMO

The paradigmatic model for heterogeneous media used in diffusion studies is built from reflecting obstacles and surfaces. It is well known that the crowding effect produced by these reflecting surfaces slows the dispersion of Brownian tracers. Here, using a general adsorption desorption model with surface diffusion, we show analytically that making surfaces or obstacles attractive can accelerate dispersion. In particular, we show that this enhancement of diffusion can exist even when the surface diffusion constant is smaller than that in the bulk. Even more remarkably, this enhancement effect occurs when the effective diffusion constant, when restricted to surfaces only, is lower than the effective diffusivity with purely reflecting boundaries. We give analytical formulas for this intriguing effect in periodic arrays of spheres as well as undulating microchannels. Our results are confirmed by numerical calculations and Monte Carlo simulations.


Assuntos
Difusão , Adsorção , Método de Monte Carlo
10.
Allergy ; 77(1): 83-99, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33955017

RESUMO

Mast cells are (in)famous for their role in allergic diseases, but the physiological and pathophysiological roles of this ingenious cell are still not fully understood. Mast cells are important for homeostasis and surveillance of the human system, recognizing both endogenous and exogenous agents, which induce release of a variety of mediators acting on both immune and non-immune cells, including nerve cells, fibroblasts, endothelial cells, smooth muscle cells, and epithelial cells. During recent years, clinical and experimental studies on human mast cells, as well as experiments using animal models, have resulted in many discoveries that help decipher the function of mast cells in health and disease. In this review, we focus particularly on new insights into mast cell biology, with a focus on mast cell development, recruitment, heterogeneity, and reactivity. We also highlight the development in our understanding of mast cell-driven diseases and discuss the development of novel strategies to treat such conditions.


Assuntos
Hipersensibilidade , Mastócitos , Animais , Células Endoteliais , Humanos
11.
Immunity ; 38(5): 906-17, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23643722

RESUMO

Human linkage analyses have implicated the MS4A2-containing gene locus (encoding FcεRIß) as a candidate for allergy susceptibility. We have identified a truncation of FcεRIß (t-FcεRIß) in humans that contains a putative calmodulin-binding domain and thus, we sought to identify the role of this variant in mast cell function. We determined that t-FcεRIß is critical for microtubule formation and degranulation and that it may perform this function by trafficking adaptor molecules and kinases to the pericentrosomal and Golgi region in response to Ca2+ signals. Mutagenesis studies suggest that calmodulin binding to t-FcεRIß in the presence of Ca2+ could be critical for t-FcεRIß function. In addition, gene targeting of t-FcεRIß attenuated microtubule formation, degranulation, and IL-8 production downstream of Ca2+ signals. Therefore, t-FcεRIß mediates Ca2+ -dependent microtubule formation, which promotes degranulation and cytokine release. Because t-FcεRIß has this critical function, it represents a therapeutic target for the downregulation of allergic inflammation.


Assuntos
Sinalização do Cálcio/imunologia , Degranulação Celular/imunologia , Mastócitos/imunologia , Microtúbulos/metabolismo , Receptores de IgE/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cálcio/metabolismo , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/imunologia , Complexo de Golgi/metabolismo , Humanos , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Interleucina-8/metabolismo , Mastócitos/metabolismo , Prostaglandina D2/biossíntese , Prostaglandina D2/imunologia , Isoformas de Proteínas/imunologia , Interferência de RNA , Splicing de RNA , RNA Mensageiro , RNA Interferente Pequeno , Receptores de IgE/genética
12.
Inorg Chem ; 61(49): 19983-19997, 2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36445832

RESUMO

In the current work, we demonstrate ligand design concepts that significantly improve the superoxide dismutase (SOD) activity of a zinc complex; the catalysis is enhanced when two quinol groups are present in the polydentate ligand. We investigate the mechanism through which the quinols influence the catalysis and determine the impact of entirely removing a chelating group from the original hexadentate ligand. Our results suggest that SOD mimicry with these compounds requires a ligand that coordinates Zn(II) strongly in both its oxidized and reduced forms and that the activity proceeds through Zn(II)-semiquinone complexes. The complex with two quinols displays greatly enhanced catalytic ability, with the activity improving by as much as 450% over a related complex with a single quinol. In the reduced form of the diquinol complex, one quinol appears to coordinate to the zinc much more weakly than the other. We believe that superoxide can more readily displace this portion of the ligand, facilitating its coordination to the metal center and thereby hastening the SOD reactivity. Despite the presence of two redox-active groups that may communicate through intramolecular hydrogen bonding and redox tautomerism, only one quinol undergoes two-electron oxidation to a para-quinone during the catalysis. After the formation of the para-quinone, the remaining quinol deprotonates and binds tightly to the metal, ensuring that the complex remains intact in its oxidized state, thereby maintaining its catalytic ability. The Zn(II) complex with the diquinol ligand is highly unusual for a SOD mimic in that it performs more efficiently in phosphate solution.


Assuntos
Fosfatos , Superóxido Dismutase , Ligantes , Superóxido Dismutase/metabolismo , Oxirredução , Zinco/metabolismo
13.
J Trauma Stress ; 35(4): 1087-1098, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35201638

RESUMO

Hmong adults who are Vietnam War refugees have been exposed to refugee-related trauma, but little is known about associations between patterns of trauma exposure and mental health outcomes in Hmong adults. We examined patterns of trauma exposure and mental health symptoms (i.e., somatization, depression, anxiety, and probable posttraumatic stress disorder [PTSD]) in three generations of Hmong adults (N = 219). Trauma exposure and probable PTSD were measured using the Harvard Trauma Questionnaire-Hmong Version. Somatization, depression, and anxiety symptoms were measured using the Brief Symptom Inventory. Latent class analysis (LCA) and auxiliary analysis of sociodemographic characteristics and mental health symptoms were performed. The best-fitting LCA model described three distinct classes: complex and pervasive trauma (60.3%), combat situation and deprivation trauma (26.0%), and low exposure to refugee-related trauma (13.7%). Participants in the complex and pervasive trauma class were the oldest, had the shortest U.S. residency, were the least proficient in English, and reported the most severe mental health symptoms; those in the combat situation and deprivation trauma class were the youngest, moderately proficient in English, and reported moderate mental health symptoms; and those in the low exposure to refugee-related trauma class were the most proficient in English, had the longest U.S. residency, and reported the least severe mental health symptoms. Our findings call for surveillance and a trauma-informed approach for Hmong elders with limited English proficiency, who have a high risk of experiencing accumulative effects of refugee-related trauma and are susceptible to poor mental health outcomes.


Assuntos
Refugiados , Transtornos de Estresse Pós-Traumáticos , Adulto , Idoso , Ansiedade/epidemiologia , Asiático , Humanos , Saúde Mental , Refugiados/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia
14.
J Craniofac Surg ; 33(4): e392-e396, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34690322

RESUMO

ABSTRACT: Anomalies present in about 30% of newborn ears; 15% to 20% of them are permanent. Malformations can be treated solely surgically; however, deformations, when promptly diagnosed, can be treated with nonsurgical methods, such as splinting and molding. The deformity of an outward curved concha is not only an aesthetic issue, but may confer functional problems that impair hearing and hearing aid usage. The goal of this report was to present this unique anomaly and our novel noninvasive treatment protocol for its management. Our cohort comprised 10 newborns treated for outward curved concha during 2018 and 2019. The patients underwent nonsurgical treatment using the EarWell system. In some patients, the management was followed by molding and taping to achieve the best effect. Treatment for all the patients began before age 3 weeks (mean, 2 weeks). Treatment duration was 5.2 weeks, on average. Nine patients did not show any adverse effects. The majority of parents expressed satisfaction with the aesthetic result; 70% were extremely pleased. Early initiation of the treatment-protocol for outward curved concha deformation yielded excellent and timely results in the infants, without the necessity of an invasive procedure.


Assuntos
Anormalidades Congênitas , Pavilhão Auricular , Estudos de Coortes , Anormalidades Congênitas/cirurgia , Duração da Terapia , Pavilhão Auricular/anormalidades , Orelha Externa/anormalidades , Testes Auditivos , Humanos , Lactente , Recém-Nascido
15.
J Allergy Clin Immunol ; 147(3): 1004-1010.e2, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33220353

RESUMO

BACKGROUND: Idiopathic anaphylaxis (IA) is a diagnosis of exclusion, thus taking away the option of therapeutic management focused on eliminating the inciting agent. Epinephrine and antihistamines followed by systemic corticosteroids are the mainstays of therapy for acute events. There is no prophylactic therapy that reliably prevents anaphylaxis. OBJECTIVE: We sought to determine the efficacy of omalizumab in the management of patients with frequent episodes of IA in a double-blind, placebo-controlled trial. METHODS: We prospectively enrolled 19 patients with frequent IA (≥6 episodes/y) who then underwent a medical evaluation that included a serum tryptase determination, mutational analysis for KIT D816V, and bone marrow evaluation to rule out a clonal mast cell disorder. Computer-generated random numbers were provided by the study pharmacist. The primary end point was anaphylactic events in the 6 months after baseline. Sixteen patients completed the primary trial. RESULTS: No statistically significant difference was demonstrated between the placebo and treated groups. There was a trend for efficacy in the treatment group, particularly after 60 days. Overall, the safety profile was favorable without long-term side effects. CONCLUSIONS: Omalizumab was safely administered to a difficult-to-treat patient population with IA. The efficacy results trended modestly in favor of the treatment group, but no statistically significant differences were detected.


Assuntos
Anafilaxia/prevenção & controle , Antialérgicos/uso terapêutico , Hipersensibilidade/tratamento farmacológico , Omalizumab/uso terapêutico , Adolescente , Adulto , Idoso , Anafilaxia/etiologia , Método Duplo-Cego , Feminino , Humanos , Hipersensibilidade/complicações , Imunoglobulina E/imunologia , Imunoglobulina E/metabolismo , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Adulto Jovem
16.
J Allergy Clin Immunol ; 147(2): 622-632, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32717252

RESUMO

BACKGROUND: An elevated basal serum tryptase level is associated with severe systemic anaphylaxis, most notably caused by Hymenoptera envenomation. Although clonal mast cell disease is the culprit in some individuals, it does not fully explain this clinical association. OBJECTIVE: Our aim was to determine the prevalence and associated impact of tryptase genotypes on anaphylaxis in humans. METHODS: Cohorts with systemic mastocytosis (SM) and venom as well as idiopathic anaphylaxis from referral centers in Italy, Slovenia, and the United States, underwent tryptase genotyping by droplet digital PCR. Associated anaphylaxis severity (Mueller scale) was subsequently examined. Healthy volunteers and controls with nonatopic disease were recruited and tryptase was genotyped by droplet digital PCR and in silico analysis of genome sequence, respectively. The effects of pooled and recombinant human tryptases, protease activated receptor 2 agonist and antagonist peptides, and a tryptase-neutralizing mAb on human umbilical vein endothelial cell permeability were assayed using a Transwell system. RESULTS: Hereditary α-tryptasemia (HαT)-a genetic trait caused by increased α-tryptase-encoding Tryptase-α/ß1 (TPSAB1) copy number resulting in elevated BST level-was common in healthy individuals (5.6% [n = 7 of 125]) and controls with nonatopic disease (5.3% [n = 21 of 398]). HαT was associated with grade IV venom anaphylaxis (relative risk = 2.0; P < .05) and more prevalent in both idiopathic anaphylaxis (n = 8 of 47; [17%; P = .006]) and SM (n = 10 of 82 [12.2%; P = .03]) relative to the controls. Among patients with SM, concomitant HαT was associated with increased risk for systemic anaphylaxis (relative risk = 9.5; P = .007). In vitro, protease-activated receptor-2-dependent vascular permeability was induced by pooled mature tryptases but not α- or ß-tryptase homotetramers. CONCLUSIONS: Risk for severe anaphylaxis in humans is associated with inherited differences in α-tryptase-encoding copies at TPSAB1.


Assuntos
Anafilaxia/genética , Mastocitose Sistêmica/genética , Triptases/sangue , Adolescente , Adulto , Idoso , Venenos de Artrópodes/efeitos adversos , Criança , Variações do Número de Cópias de DNA , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Triptases/genética , Adulto Jovem
17.
J Allergy Clin Immunol ; 147(6): 2043-2052, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33745886

RESUMO

The American Initiative in Mast Cell Diseases (AIM) held its inaugural investigator conference at Stanford University School of Medicine in May 2019. The overarching goal of this meeting was to establish a Pan-American organization of physicians and scientists with multidisciplinary expertise in mast cell disease. To serve this unmet need, AIM envisions a network where basic, translational, and clinical researchers could establish collaborations with both academia and biopharma to support the development of new diagnostic methods, enhanced understanding of the biology of mast cells in human health and disease, and the testing of novel therapies. In these AIM proceedings, we highlight selected topics relevant to mast cell biology and provide updates regarding the recently described hereditary alpha-tryptasemia. In addition, we discuss the evaluation and treatment of mast cell activation (syndromes), allergy and anaphylaxis in mast cell disorders, and the clinical and biologic heterogeneity of the more indolent forms of mastocytosis. Because mast cell disorders are relatively rare, AIM hopes to achieve a coordination of scientific efforts not only in the Americas but also in Europe by collaborating with the well-established European Competence Network on Mastocytosis.


Assuntos
Mastocitose/diagnóstico , Mastocitose/etiologia , Mastocitose/terapia , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Mastocitose/complicações , Pesquisa , Pesquisa Translacional Biomédica
18.
Ann Allergy Asthma Immunol ; 127(6): 638-647, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34400315

RESUMO

OBJECTIVE: To describe our current understanding of hereditary α-tryptasemia (HαT), how HαT fits into the evolutionary context of tryptases and contemporary framework of mast cell-associated disorders, and to discuss the future clinical and therapeutic landscape for symptomatic individuals with HαT. DATA SOURCES: Primary peer-reviewed literature. STUDY SELECTIONS: Basic, clinical, and translational studies describing tryptase gene composition, generation, secretion, and elevation and the associated clinical impacts of HαT and treatment of such individuals were reviewed. RESULTS: HαT is a common autosomal dominant genetic trait caused by increased TPSAB1 copy number encoding α-tryptase. Approximately 1 in 20 White individuals have HαT, making it by far the most common cause for elevated basal serum tryptase levels. Although many individuals with HαT may not manifest associated symptoms, the prevalence of HαT is increased in patients with clonal and nonclonal mast cell-associated disorders wherein it is linked to more prevalent and/or severe anaphylaxis and increased mast cell mediator-associated symptoms. Increased generation of mature α/ß-tryptase heterotetramers, and their unique physiochemical properties, may be responsible for some of these clinical findings. CONCLUSION: HαT is a common modifier of mast cell-associated disorders and reactions. Nevertheless, whether HαT may be an independent cause of clinical phenotypes with which it has been associated remains unproven. Correct identification of HαT is critical to accurate interpretation of serum tryptase levels in the clinical evaluation of patients. Beyond HαT, we foresee tryptase genotyping as an important parameter in the standard workup of patients with mast cell-associated disorders and development of therapeutic modalities targeting these patients and associated clinical phenotypes.


Assuntos
Mastocitose , Triptases , Anafilaxia , Humanos , Síndrome da Ativação de Mastócitos , Mastócitos , Mastocitose/genética , Triptases/genética
19.
J Immunol ; 203(11): 2777-2790, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31636239

RESUMO

Options for effective prevention and treatment of epidemic allergic diseases remain limited, and particularly so for IgE-mediated food allergies. We previously found that mouse low-affinity anti-human IgE mAbs with KD in the 10-6-10-8 M range were capable of blocking allergic reactivity without triggering immediate allergic mediator release. In this study, we humanized three parent low affinity allergic response inhibitor (LARI) mouse anti-human IgE mAbs and characterized their biological and immunological features, refined the lead candidate for further clinical development, examined their safety profiles, determined their therapeutic efficiency, and explored the mechanism of action potentially responsible for their therapeutic effects. LARI profoundly blocked cat- and peanut-allergic IgE-mediated basophil activation, inhibited acute release of both prestored and newly synthesized mediator from human mast cells, suppressed peanut-specific IgE-mediated passive cutaneous anaphylaxis, and attenuated dansyl IgE-mediated systemic anaphylaxis in human FcεRIα transgenic mice. Safety testing demonstrated that concentrations of LARI well above therapeutic levels failed to trigger immediate release of prestored and newly synthesized allergic mediators, failed to promote robust cytokine/chemokine production from allergic effector cells, and did not elicit allergic reactivity in an animal model of cutaneous and systemic anaphylaxis. Mechanistic studies revealed that LARI downregulated surface FcεRI receptors and IgE via internalization of the IgE/FcεRI, promoted a partial mediator depletion pathway leading to slow release of small amount of mediators, and functioned as a partial antagonist to inhibit FcεRI signaling phosphorylation of Syk, Akt, Erk, and p38 MAPK. These studies demonstrate that targeting surface-bound IgE with LARI profoundly suppresses human allergic reactivity while displaying an excellent safety profile.


Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Receptores de IgE/imunologia , Humanos
20.
Proc Natl Acad Sci U S A ; 115(45): E10692-E10701, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30352845

RESUMO

Extracellular vesicles (EVs) have been implicated in the development and progression of hematological malignancies. We thus examined serum samples from patients with systemic mastocytosis (SM) and found EVs with a mast cell signature including the presence of tryptase, FcεRI, MRGX2, and KIT. The concentration of these EVs correlated with parameters of disease including levels of serum tryptase, IL-6, and alkaline phosphatase and physical findings including hepatosplenomegaly. Given reports that EVs from one cell type may influence another cell's behavior, we asked whether SM-EVs might affect hepatic stellate cells (HSCs), based on the abnormal liver pathology associated with mastocytosis. We found that KIT was transferred from SM-EVs into an HSC line eliciting proliferation, cytokine production, and differentiation, processes that have been associated with liver pathology. These effects were reduced by KIT inhibition or neutralization and recapitulated by enforced expression of KIT or constitutively active D816V-KIT, a gain-of-function variant associated with SM. Furthermore, HSCs in liver from mice injected with SM-EVs had increased expression of α-SMA and human KIT, particularly around portal areas, compared with mice injected with EVs from normal individuals, suggesting that SM-EVs can also initiate HSC activation in vivo. Our data are thus consistent with the conclusion that SM-EVs have the potential to influence cells outside the hematological compartment and that therapeutic approaches for treatment of SM may be effective in part through inhibition of effects of EVs on target tissues, findings important both to understanding complex disease pathology and in developing interventional agents for the treatment of hematologic diseases.


Assuntos
Vesículas Extracelulares/metabolismo , Mastócitos/metabolismo , Mastocitose/patologia , Fator de Células-Tronco/metabolismo , Diferenciação Celular , Proliferação de Células , Feminino , Humanos , Mastocitose/metabolismo
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