International Journal of Molecular Sciences

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Open AccessEditorial

Unraveling the Complexities of Mast Cells in Health and Disease

by Davide Firinu

Int. J. Mol. Sci. 2024, 25(7), 3791; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25073791 - 28 Mar 2024

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Abstract

As we draw the curtain on this Special Issue dedicated to the intricate roles of mast cells (MCs) in health and disease, we reflect on the insights garnered from the array of research articles featured within the published papers of the International Journal [...] Read more.

As we draw the curtain on this Special Issue dedicated to the intricate roles of mast cells (MCs) in health and disease, we reflect on the insights garnered from the array of research articles featured within the published papers of the International Journal of Molecular Sciences (IJMS) [...] Full article

(This article belongs to the Special Issue Mast Cells in Immunity and Diseases)

Research

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9 pages, 905 KiB

Open AccessCommunication

Association between High HbA1c Levels and Mast Cell Phenotype in the Infrapatellar Fat Pad of Patients with Knee Osteoarthritis

by Ayumi Tsukada, Ken Takata, Jun Aikawa, Dai Iwase, Manabu Mukai, Yui Uekusa, Yukie Metoki, Gen Inoue, Masayuki Miyagi, Masashi Takaso and Kentaro Uchida

Int. J. Mol. Sci. 2024, 25(2), 877; https://doi.org/10.3390/ijms25020877 - 10 Jan 2024

Cited by 1 | Viewed by 734

Abstract

Diabetes mellitus (DM) has been suggested as a potential risk factor for knee osteoarthritis (KOA), and its underlying mechanisms remain unclear. The infrapatellar fat pad (IPFP) contributes to OA through inflammatory mediator secretion. Mast cells’ (MCs) role in diabetic IPFP pathology is unclear. [...] Read more.

Diabetes mellitus (DM) has been suggested as a potential risk factor for knee osteoarthritis (KOA), and its underlying mechanisms remain unclear. The infrapatellar fat pad (IPFP) contributes to OA through inflammatory mediator secretion. Mast cells’ (MCs) role in diabetic IPFP pathology is unclear. In 156 KOA patients, hemoglobin A1c (HbA1c) was stratified (HbA1c ≥ 6.5, n = 28; HbA1c < 6.5, n = 128). MC markers (TPSB2, CPA3) in IPFP were studied. Propensity-matched cohorts (n = 27 each) addressed demographic differences. MC-rich fraction (MC-RF) and MC-poor fraction (MC-PF) were isolated, comparing MC markers and genes elevated in diabetic skin-derived MC (PAXIP1, ARG1, HAS1, IL3RA). TPSB2 and CPA3 expression were significantly higher in HbA1c ≥ 6.5 vs. <6.5, both before and after matching. MC-RF showed higher TPSB2 and CPA3 expression than MC-PF in both groups. In the HbA1c ≥ 6.5 group, PAXIP1 and ARG1 expression were significantly higher in the MC-RF than MC-PF. However, no statistical difference in the evaluated genes was detected between the High and Normal groups in the MC-RF. Elevated TPSB2 and CPA3 levels in the IPFP of high HbA1c patients likely reflect higher numbers of MCs in the IPFP, though no difference was found in MC-specific markers on a cell-to-cell basis, as shown in the MC-RF comparison. These findings deepen our understanding of the intricate interplay between diabetes and KOA, guiding targeted therapeutic interventions. Full article

(This article belongs to the Special Issue Mast Cells in Immunity and Diseases)

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9 pages, 713 KiB

Open AccessArticle

Fatal Hymenoptera Venom–Triggered Anaphylaxis in Patients with Unrecognized Clonal Mast Cell Disorder—Is Mastocytosis to Blame?

by Matija Rijavec, Jezerka Inkret, Urška Bidovec-Stojković, Tanja Carli, Nina Frelih, Andreja Kukec, Peter Korošec and Mitja Košnik

Int. J. Mol. Sci. 2023, 24(22), 16368; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242216368 - 15 Nov 2023

Cited by 5 | Viewed by 980

Abstract

Hymenoptera venom–triggered anaphylaxis (HVA) affects up to 8.9% of the general population and is the most frequent cause of anaphylaxis in adults, accounting for approximately 20% of all fatal anaphylaxis cases. Quite often, a fatal reaction is a victim’s first manifestation of HVA. [...] Read more.

Hymenoptera venom–triggered anaphylaxis (HVA) affects up to 8.9% of the general population and is the most frequent cause of anaphylaxis in adults, accounting for approximately 20% of all fatal anaphylaxis cases. Quite often, a fatal reaction is a victim’s first manifestation of HVA. Mastocytosis represents one of the most important risk factors for severe HVA. We analyzed patients with documented fatal HVA for the presence of underlying clonal mast cell disorder (cMCD). Here, we report three cases of fatal HVA, with undiagnosed underlying cMCD identified by the presence of the peripheral blood and/or bone marrow KIT p.D816V missense variant postmortem. In the first case, anaphylaxis was the initial episode and was fatal. In the other two cases, both patients were treated with specific venom immunotherapy (VIT), nevertheless, one died of HVA after VIT discontinuation, and the other during VIT; both patients had cardiovascular comorbidities and were taking beta-blockers and/or ACE inhibitors. Our results point to the importance of screening all high-risk individuals for underlying cMCD using highly sensitive molecular methods for peripheral blood KIT p.D816V variant detection, including severe HVA and possibly beekeepers, for proper management and the need for lifelong VIT to prevent unnecessary deaths. Patients at the highest risk of fatal HVA, with concomitant cardiovascular and cMCD comorbidities, might not be protected from field stings even during regular VIT. Therefore, two adrenaline autoinjectors and lifelong VIT, and possibly cotreatment with omalizumab, should be considered for high-risk patients to prevent fatal HVA episodes. Full article

(This article belongs to the Special Issue Mast Cells in Immunity and Diseases)

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26 pages, 1342 KiB

Open AccessArticle

Salivary Cystatin D Interactome in Patients with Systemic Mastocytosis: An Exploratory Study

by Simone Serrao, Cristina Contini, Giulia Guadalupi, Alessandra Olianas, Greca Lai, Irene Messana, Massimo Castagnola, Giulia Costanzo, Davide Firinu, Stefano Del Giacco, Barbara Manconi and Tiziana Cabras

Int. J. Mol. Sci. 2023, 24(19), 14613; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241914613 - 27 Sep 2023

Cited by 1 | Viewed by 1559

Abstract

Mastocytosis, a rare blood disorder characterized by the proliferation of clonal abnormal mast cells, has a variegated clinical spectrum and diagnosis is often difficult and delayed. Recently we proposed the cathepsin inhibitor cystatin D-R₂₆ as a salivary candidate biomarker of systemic mastocytosis [...] Read more.

Mastocytosis, a rare blood disorder characterized by the proliferation of clonal abnormal mast cells, has a variegated clinical spectrum and diagnosis is often difficult and delayed. Recently we proposed the cathepsin inhibitor cystatin D-R₂₆ as a salivary candidate biomarker of systemic mastocytosis (SM). Its C₂₆ variant is able to form multiprotein complexes (mPCs) and since protein–protein interactions (PPIs) are crucial for studying disease pathogenesis, potential markers, and therapeutic targets, we aimed to define the protein composition of the salivary cystatin D-C₂₆ interactome associated with SM. An exploratory affinity purification-mass spectrometry method was applied on pooled salivary samples from SM patients, SM patient subgroups with and without cutaneous symptoms (SM+C and SM−C), and healthy controls (Ctrls). Interactors specifically detected in Ctrls were found to be implicated in networks associated with cell and tissue homeostasis, innate system, endopeptidase regulation, and antimicrobial protection. Interactors distinctive of SM−C patients participate to PPI networks related to glucose metabolism, protein S-nitrosylation, antibacterial humoral response, and neutrophil degranulation, while interactors specific to SM+C were mainly associated with epithelial and keratinocyte differentiation, cytoskeleton rearrangement, and immune response pathways. Proteins sensitive to redox changes, as well as proteins with immunomodulatory properties and activating mast cells, were identified in patients; many of them were involved directly in cytoskeleton rearrangement, a process crucial for mast cell activation. Although preliminary, these results demonstrate that PPI alterations of the cystatin D-C₂₆ interactome are associated with SM and provide a basis for future investigations based on quantitative proteomic analysis and immune validation. Full article

(This article belongs to the Special Issue Mast Cells in Immunity and Diseases)

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15 pages, 2423 KiB

Open AccessArticle

IL-10 Modulates the Expression and Activation of Pattern Recognition Receptors in Mast Cells

by Roberto Riquelme-Neira, Romina Walker-Vergara, Joan Antoni Fernández-Blanco and Patrocinio Vergara

Int. J. Mol. Sci. 2023, 24(12), 9875; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24129875 - 08 Jun 2023

Cited by 3 | Viewed by 1243

Abstract

Mast cells (MCs) are involved in several immune-related responses, including those in bacterial infections, autoimmune diseases, inflammatory bowel diseases, and cancer, among others. MCs identify microorganisms by pattern recognition receptors (PRRs), activating a secretory response. Interleukin (IL)-10 has been described as an important [...] Read more.

Mast cells (MCs) are involved in several immune-related responses, including those in bacterial infections, autoimmune diseases, inflammatory bowel diseases, and cancer, among others. MCs identify microorganisms by pattern recognition receptors (PRRs), activating a secretory response. Interleukin (IL)-10 has been described as an important modulator of MC responses; however, its role in PRR-mediated activation of MC is not fully understood. We analyzed the activation of TLR2, TLR4, TLR7 and Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in mucosal-like MCs (MLMCs) and peritoneum-derived cultured MCs (PCMCs) from IL-10^−/− and wild-type (WT) mice. IL-10^−/− mice showed a reduced expression of TLR4 and NOD2 at week 6 and TLR7 at week 20 in MLMC. In MLMC and PCMC, TLR2 activation induced a reduced secretion of IL-6 and TNFα in IL-10^−/− MCs. TLR4- and TLR7-mediated secretion of IL-6 and TNFα was not detected in PCMCs. Finally, no cytokine release was induced by NOD2 ligand, and responses to TLR2 and TLR4 were lower in MCs at 20 weeks. These findings indicate that PRR activation in MCs depends on the phenotype, ligand, age, and IL-10. Full article

(This article belongs to the Special Issue Mast Cells in Immunity and Diseases)

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Review

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22 pages, 1207 KiB

Open AccessReview

Mast Cells in Upper and Lower Airway Diseases: Sentinels in the Front Line

by Giovanni Costanzo, Giulia Anna Maria Luigia Costanzo, Lorenzo Del Moro, Emanuele Nappi, Corrado Pelaia, Francesca Puggioni, Giorgio Walter Canonica, Enrico Heffler and Giovanni Paoletti

Int. J. Mol. Sci. 2023, 24(11), 9771; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119771 - 05 Jun 2023

Cited by 4 | Viewed by 3101

Abstract

Mast cells (MCs) are fascinating cells of the innate immune system involved not only in allergic reaction but also in tissue homeostasis, response to infection, wound healing, protection against kidney injury, the effects of pollution and, in some circumstances, cancer. Indeed, exploring their [...] Read more.

Mast cells (MCs) are fascinating cells of the innate immune system involved not only in allergic reaction but also in tissue homeostasis, response to infection, wound healing, protection against kidney injury, the effects of pollution and, in some circumstances, cancer. Indeed, exploring their role in respiratory allergic diseases would give us, perhaps, novel therapy targets. Based on this, there is currently a great demand for therapeutic regimens to enfeeble the damaging impact of MCs in these pathological conditions. Several strategies can accomplish this at different levels in response to MC activation, including targeting individual mediators released by MCs, blockade of receptors for MC-released compounds, inhibition of MC activation, limiting mast cell growth, or inducing mast cell apoptosis. The current work focuses on and summarizes the mast cells’ role in pathogenesis and as a personalized treatment target in allergic rhinitis and asthma; even these supposed treatments are still at the preclinical stage. Full article

(This article belongs to the Special Issue Mast Cells in Immunity and Diseases)

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20 pages, 6447 KiB

Open AccessReview

Secretory and Membrane-Associated Biomarkers of Mast Cell Activation and Proliferation

by Roberta Parente, Valentina Giudice, Chiara Cardamone, Bianca Serio, Carmine Selleri and Massimo Triggiani

Int. J. Mol. Sci. 2023, 24(8), 7071; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087071 - 11 Apr 2023

Cited by 8 | Viewed by 1972

Abstract

Mast cells (MCs) are immune cells distributed in many organs and tissues and involved in the pathogenesis of allergic and inflammatory diseases as a major source of pro-inflammatory and vasoactive mediators. MC-related disorders are heterogeneous conditions characterized by the proliferation of MC within [...] Read more.

Mast cells (MCs) are immune cells distributed in many organs and tissues and involved in the pathogenesis of allergic and inflammatory diseases as a major source of pro-inflammatory and vasoactive mediators. MC-related disorders are heterogeneous conditions characterized by the proliferation of MC within tissues and/or MC hyper-reactivity that leads to the uncontrolled release of mediators. MC disorders include mastocytosis, a clonal disease characterized by tissue MC proliferation, and MC activation syndromes that can be primary (clonal), secondary (related to allergic disorders), or idiopathic. Diagnosis of MC disorders is difficult because symptoms are transient, unpredictable, and unspecific, and because these conditions mimic many other diseases. Validation of markers of MC activation in vivo will be useful to allow faster diagnosis and better management of MC disorders. Tryptase, being the most specific MC product, is a widely used biomarker of proliferation and activation. Other mediators, such as histamine, cysteinyl leukotrienes, and prostaglandin D2, are unstable molecules and have limitations in their assays. Surface MC markers, detected by flow cytometry, are useful for the identification of neoplastic MC in mastocytosis but, so far, none of them has been validated as a biomarker of MC activation. Further studies are needed to identify useful biomarkers of MC activation in vivo. Full article

(This article belongs to the Special Issue Mast Cells in Immunity and Diseases)

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28 pages, 857 KiB

Open AccessReview

Allergy in Cancer Care: Antineoplastic Therapy-Induced Hypersensitivity Reactions

by Bianca Galateanu, Alexandra Ioana Pușcașu, Simona Andreea Tircol, Bogdan Cosmin Tanase, Ariana Hudita, Carolina Negrei, George-Traian-Alexandru Burcea-Dragomiroiu, Lucian Negreanu, Ileana Adela Vacaroiu and Octav Ginghină

Int. J. Mol. Sci. 2023, 24(4), 3886; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043886 - 15 Feb 2023

Cited by 3 | Viewed by 4629

Abstract

As the backbone of oncological treatments, systemic chemotherapy is still one of the main pawns in cancer care, alone or in combination with newer targeted agents. All chemotherapy agents can be associated with a type of adverse event called an infusion reaction, which [...] Read more.

As the backbone of oncological treatments, systemic chemotherapy is still one of the main pawns in cancer care, alone or in combination with newer targeted agents. All chemotherapy agents can be associated with a type of adverse event called an infusion reaction, which can be characterized as unpredictable, non-dose related, and unexplained by the cytotoxic profile of the drug. For some of these events, a certain immunological mechanism can be identified by blood or skin testing. In this case, we can speak of true hypersensitivity reactions that occur as a response to an antigen/allergen. The current work summarizes the main antineoplastic therapy agents and their susceptibility to induce hypersensitivity reactions and also includes a review of clinical presentation, diagnostic methods in hypersensitivity reactions, and perspectives to overcome these negative events in the treatment of patients suffering from various types of cancer. Full article

(This article belongs to the Special Issue Mast Cells in Immunity and Diseases)

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