Evolution of mast cell research associated with the Laboratory of Allergic Diseases, 1985-2022: Summary of the 2023 NIAID Symposium.

Present and former investigators of the Mast Cell Biology Section (MCBS) of the Laboratory of Allergic Diseases (LAD) and their colleagues organized a daylong symposium in October 2023 to honor the outstanding contributions of the MCBS headed by Dr Dean D. Metcalfe, who recently retired from his leadership role in this department. The symposium featured an overview of discoveries that advanced the scientific understanding of the human mast cell (MC) lineage and compartment over the preceding 3 decades.

Prevalence of myeloid gene alterations in paediatric cutaneous and systemic mastocytosis.

Paediatric mastocytosis is a heterogeneous disorder with different clinical subtypes and an often indolent disease course. The molecular landscape of genetic mutations, beyond KIT D816V, remains under exploration. We thus investigated the prevalence of myeloid genetic mutations in peripheral blood samples of 69 paediatric patients with cutaneous mastocytosis and systemic mastocytosis (SM) using next-generation sequencing.

Treatment of indolent systemic mastocytosis with sarilumab is not supported in a randomized trial.

Background: Indolent systemic mastocytosis is a clonal mast cell disease that results in an increase in mast cells in the skin, bone marrow, and other organ systems. IL-6 has been shown to promote mast cell maturation, proliferation, and reactivity . Serum levels of IL-6 correlate with severity of disease and risk of progression of systemic disease.

Fire ant-venom anaphylaxis prevalence in the general population and patients with systemic mastocytosis.

Background: Stinging Hymenoptera can induce fatal anaphylaxis, especially in patients with systemic mastocytosis. Fire ants, and from South America have recently colonized three continents. Prevalence of fire ant-venom anaphylaxis in the general population and in systemic mastocytosis is unknown.

Sphingosine-1-Phosphate Receptor 4 links neutrophils and early local inflammation to lymphocyte recruitment into the draining lymph node to facilitate robust germinal center formation.

The successful development of germinal centers (GC) relies heavily on innate mechanisms to amplify the initial inflammatory cascade. In addition to their role in antigen presentation, innate cells are essential for the redirection of circulating lymphocytes toward the draining lymph node (dLN) to maximize antigen surveillance. Sphingosine-1-Phosphate (S1P) and its receptors (S1PR1-5) affect various aspects of immunity; however, the role of S1PR4 in regulating an immune response is not well understood.

Increased expression of formyl peptide receptor-1 by basophils from patients with mastocytosis.

Background: Symptoms in patients with systemic mastocytosis (SM) are associated with an increase in mast cell burden and release of mast cell-derived mediators. The most frequent presentation of SM is indolent SM (ISM), with moderate symptoms and prognosis. Basophil numbers in these patients are generally normal.

Activation of the receptor KIT induces the secretion of exosome-like small extracellular vesicles.

The receptor tyrosine kinase (RTK) KIT and its ligand stem cell factor (SCF) are essential for human mast cell (huMC) survival and proliferation. HuMCs expressing oncogenic KIT variants secrete large numbers of extracellular vesicles (EVs). The role KIT plays in regulating EV secretion has not been examined.

Mast cell activation syndrome: Current understanding and research needs.

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although 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 activation is not well understood.

Autoantibodies to type I interferons in patients with systemic mastocytosis.

Background: Autoantibodies to type I interferons have been identified in association with a variety of inflammatory and autoimmune diseases. Type I interferons have demonstrated inhibitory effects on mast cell proliferation and degranulation. Systemic mastocytosis (SM) is a disease characterized by increased mast cell burden and mediator release.

Standardized indolent systemic mastocytosis evaluations across a health care system: implications for screening accuracy.

Timely diagnosis of systemic mastocytosis (SM) remains challenging because of care heterogeneity. We implemented a standardized approach for SM screening and diagnosis using a novel health care system-wide international screening registry. A retrospective analysis assessed rates of SM, cutaneous mastocytosis (CM), and molecular diagnoses before and 2 years after care standardization.

Targeted Therapy for the Predominant Form of Mastocytosis.

Mast cells are present in all vascularized tissues, often associated with blood vessels, glandular structures, and nerves, and they tend to be more numerous in tissues that interface with the external environment, including the skin and gastrointestinal tract. These mast cells are involved in both innate and acquired immunity, as well as in other biologic processes, including wound healing. Mast cell numbers within tissues are remarkably consistent, although mast cell numbers somewhat increase in association with inflammation.

The Normal Range of Baseline Tryptase Should Be 1 to 15 ng/mL and Covers Healthy Individuals With HαT.

Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1 gene encoding alpha tryptase, and renal function. Recently, there has been a growing debate about the normal range of tryptase because individuals with the hereditary alpha tryptasemia (HαT) trait may or may not be symptomatic, and if symptomatic, uncertainty exists as to whether this trait directly causes clinical phenotypes or aggravates certain conditions. In fact, most HαT-positive cases are regarded as asymptomatic concerning mast cell activation.

CRISPR/Cas9-engineering of HMC-1.2 cells renders a human mast cell line with a single D816V-KIT mutation: An improved preclinical model for research on mastocytosis.

The HMC-1.2 human mast cell (huMC) line is often employed in the study of attributes of neoplastic huMCs as found in patients with mastocytosis and their sensitivity to interventional drugs and . HMC-1.

sCD14 and Intestinal Fatty Acid Binding Protein Are Elevated in the Serum of Patients With Idiopathic Anaphylaxis.

Background: Intestinal epithelial integrity compromise has been identified in gastrointestinal (GI), atopic, and autoimmune diseases.

Objective: Episodes of idiopathic anaphylaxis (IA) are often accompanied by GI manifestations. We, therefore, sought to determine whether surrogate markers of GI permeability were aberrant in this patient population.

Research Advances in Mast Cell Biology and Their Translation Into Novel Therapies for Anaphylaxis.

Anaphylaxis is an acute, potentially life-threatening systemic allergic reaction for which there are no known reliable preventative therapies. Its primary cell mediator, the mast cell, has several pathophysiologic roles and functions in IgE-mediated reactions that continue to be poorly understood. Recent advances in the understanding of allergic mechanisms have identified novel targets for inhibiting mast cell function and activation.

Assessment of low immunoglobulin levels and clinical manifestations in patients with mastocytosis.

Background: Patients with a low IgG level alone or with low IgA or IgM levels have been reported to be susceptible to respiratory tract infections and recurrent sinusitis. Patients diagnosed with CVID have a higher prevalence of autoimmune diseases and lymphoid malignancies. Mastocytosis is a myeloproliferative disease, not typically associated with autoimmune disease or frequent infections.

New Insights into the Pathogenesis of Mastocytosis: Emerging Concepts in Diagnosis and Therapy.

Mastocytosis is a heterogeneous group of neoplasms defined by a numerical increase and accumulation of clonal mast cells (MCs) in various organ systems. The disease may present as cutaneous mastocytosis or systemic mastocytosis (SM). On the basis of histopathological and molecular features, clinical variables, and organ involvement, SM is divided into indolent SM, smoldering SM, SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia.

Selective immunocapture reveals neoplastic human mast cells secrete distinct microvesicle- and exosome-like populations of KIT-containing extracellular vesicles.

Activating mutations in the receptor KIT promote the dysregulated proliferation of human mast cells (huMCs). The resulting neoplastic huMCs secrete extracellular vesicles (EVs) that can transfer oncogenic KIT among other cargo into recipient cells. Despite potential contributions to diseases, KIT-containing EVs have not been thoroughly investigated.

Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms.

Serum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where basal serum tryptase (BST) levels >20 ng/mL are a minor criterion for diagnosis. Although clonal myeloid neoplasms are rare, the common cause for elevated BST levels is the genetic trait hereditary α-tryptasemia (HαT) caused by increased germline TPSAB1 copy number. To date, the precise structural variation and mechanism(s) underlying elevated BST in HαT and the general clinical utility of tryptase genotyping, remain undefined.