Mast cells are located in nearly all tissues and play a pivotal role in allergic reactions, immunity, and inflammation.
Understanding Mast Cell Activation Syndrome (MCAS): A Growing Health Concern
Mast Cell Activation Syndrome (MCAS) is a complex and often misunderstood condition characterised by the excessive and abnormal activation of mast cells with symptoms typically presenting as fatigue, headaches, gastrointestinal issues, and skin rashes.
Mast cells play a crucial role in barrier defences under the skin and mucosa. When activated by foreign organisms or IgE antibodies they quickly release large amounts of preformed histamines and heparins. These chemical messengers trigger the local inflammatory responses such as heat, redness and swelling which we recognise during an acute injury or infection.
But mast cells can also be triggered to release a different set of cytokines to sustain long term inflammation, using pathways that often involve metabolic reprogramming (Mendoza et al., 2021). Recent discoveries show this non-IgE pathway can be influenced by environmental factors such as nano-particle pollution, chronic stress, and immune dysfunction. Normal functions of both the IgE-mediated (immediate) and non-IgE-mediated (sustained) pathways are influenced by these environmental nanoparticles resulting in an increase in the overall inflammatory load, and leading to chronic symptoms and systemic health challenges.
The complexity, diverse manifestations and growing prevalence of MCAS underscore the challenges in management of such widespread, multisystem symptoms. This emerging health issue puts environmental pollutants such as nano-silica particles under the microscope in MCAS research.
The Role of Mast Cells in Immune Regulation
Mast cells are versatile immune cells that respond to various triggers, including allergens, stress-induced hormones, and nano-particles.
According to Mendoza et al. (2021), nano-particles have the potential to induce significant metabolic and inflammatory changes, deplete glycolytic reserves and disrupting mitochondrial respiration, leading to sustained inflammation (1).
Mast cells can selectively release pro-inflammatory mediators without full degranulation, contributing to chronic inflammatory diseases like atopic dermatitis, psoriasis, and multiple sclerosis.
This differential response underscores the complexity of mast cell activation mechanisms Theoharides et al. (2012) (2). The selective release is often further amplified by neuropeptides and cytokines, creating synergistic effects that exacerbate inflammation.
The interplay between mast cells and the environment, particularly air pollution, is a growing concern, as evidenced by the role of nanoparticles in triggering mast cell activation (3).
Symptoms and Impact of MCAS
MCAS symptoms vary widely, affecting multiple organ systems. Common symptoms include:
Dermatological: Flushing, hives, and itching.
Respiratory: Shortness of breath, wheezing and nasal congestion.
Gastrointestinal: Diarrhea, nausea, and abdominal pain.
Neurological: Brain fog, headaches, dizziness, and mood disorders.
Cardiovascular: Hypotension and tachycardia.
The variability in symptoms complicates diagnosis and management. Chronic mast cell activation also increases the inflammatory load, which, over time, contributes to systemic immune dysfunction.
The Role of Environmental Factors
Modern environmental pollutants, including fine particulate matter and nano-silica particles, play a significant role in the rising prevalence of MCAS.
Nano-silica particles are even smaller than microplastics, and studies, such as those by Yang et al. (2022), have demonstrated that nano-silica particles exacerbate allergic inflammation by synergistically activating mast cells, leading to heightened allergic reaction.
These particles, often found in smog and air pollution, trigger mast cell degranulation leading to chronic immune activation and tissue damage, and have been linked to skin disorders, asthma, and other inflammatory conditions (4).
This interplay between environmental triggers and immune dysregulation highlights the urgent need for strategies to manage the inflammatory burden in individuals with MCAS.
MLD: A Promising Drug Free Therapy
As the prevalence of MCAS rises, there is an increasing demand for supportive therapies to manage symptoms and reduce the inflammatory load, including MLD Practitioners.
The specialised movements of Dr Vodder’s MLD enhance lymphatic flow to reduce the tissue inflammatory load, providing significant benefits for many of the symptoms presenting in MCAS by addressing the underlying mechanisms of inflammation.
How MLD Reduces Inflammatory Load
Enhancing Lymphatic Flow
Mast cells are closely associated with the vascular and lymphatic endothelium.
Kunder et al. (2009) demonstrated that mast cell-derived particles containing inflammatory mediators travel through lymphatic vessels to distant lymph nodes, amplifying systemic inflammation (5).
By increasing lymph flow, MLD enhances the interaction between lymphatic endothelial cells and mast-cell products, promoting the efficient clearance of inflammatory mediators.
The close interaction between lymphatic endothelial cells and mast cell products, is enhanced when lymph flow increases.
In this way MLD facilitates the efficient transport of inflammatory mediators to draining lymph nodes helping to modulate immune responses and reduce systemic inflammation (5).
Removing Tissue Cytokines
Chronic mast cell activation leads to the accumulation of pro-inflammatory cytokines in tissues, perpetuating inflammation, and MLD facilitates the removal of these cytokines. By increasing the clearance of tissue cytokines and small particulates, MLD minimises the prolonged activation of mast cells, reduces cytokine levels and alleviates symptoms associated with MCAS.
Immune Modulation via Mechano-Transduction
The precise and gentle movements of MLD exert mechanical pressure on the skin and connective tissues, directly stimulating immune interactions within the loose connective tissue.
This process, known as mechano-transduction, may directly influence immune cell behaviour, including mast cells, leading to reduced inflammatory responses. The potential to directly regulate mast cell activity offers a unique therapeutic avenue for MCAS patients and warrants appropriate investigation.
Evidence-Based Benefits of MLD
Clinical observations and research indicate that MLD can:
Alleviate symptoms such as swelling, pain, and fatigue.
Support detoxification and immune system regulation.
Improve quality of life for individuals with MCAS and other inflammatory conditions.
The Science Behind MLD’s Effectiveness
Scientific insights support the hypothesis that MLD can counteract the effects of MCAS:
Mast Cell-Endothelial Interaction: Mast cells are closely associated with vascular and lymphatic vessels, releasing mediators that influence permeability and immune cell recruitment (6). By optimizing lymphatic drainage, MLD mitigates these localised and systemic effects.
Reduction of Oxidative Stress: Pollution-induced mast cell activation often involves oxidative stress pathways (4). By promoting removal of toxic particles, MLD reduces the oxidative burden, further dampening mast cell responses.
Addressing Non-IgE Pathways: Non-IgE-mediated mast cell activation often depletes energy reserves, adding to systemic stress (1). MLD may indirectly improve cellular metabolism by alleviating the inflammatory load and promoting autonomic balance.
Conclusion: Managing MCAS with a Holistic Approach
MCAS represents a growing health concern exacerbated by modern environmental factors, immune dysregulation, and chronic inflammation. While understanding its underlying mechanisms continues to evolve, therapies like MLD offer promising avenues to manage MCAS by reducing the inflammatory burden and enhancing immune regulation.
As we navigate the intricate interplay between mast cells, environmental triggers, and therapeutic interventions, integrating evidence-based approaches such as MLD into MCAS management will be key to improving outcomes for individuals affected by this challenging condition.
References
Mendoza RP, Anderson CC, Fudge DH, Roede JR, Brown JM: Metabolic Consequences of IgE- and Non-IgE–Mediated Mast Cell Degranulation. The Journal of Immunology 2021, 207(11):2637-2648. Abstract, Mast cells are important effector cells in the immune system and undergo activation (i.e., degranulation) by two major mechanisms: IgE-mediated and non-IgE–mediated mechanisms. Although IgE-mediated degranulation is well researched, the cellular mechanisms of non-IgE–mediated mast cell activation are poorly understood despite the potential to induce similar pathophysiological effects. To better understand non-IgE mast cell degranulation, we characterized and compared cellular metabolic shifts across several mechanisms of degranulation (allergen-induced [IgE-mediated], 20 nm of silver nanoparticle-mediated [non-IgE], and compound 48/80-mediated [non-IgE]) in murine bone marrow–derived mast cells. All treatments differentially impacted mitochondrial activity and glucose uptake, suggesting diverging metabolic pathways between IgE- and non-IgE–mediated degranulation. Non-IgE treatments depleted mast cells’ glycolytic reserve, and compound 48/80 further inhibited the ability to maximize mitochondrial respiration. This cellular reprogramming may be indicative of a stress response with non-IgE treatments. Neither of these outcomes occurred with IgE-mediated degranulation, hinting at a separate programmed response. Fuel flexibility between the three primary mitochondrial nutrient sources was also eliminated in activated cells and this was most significant in non-IgE–mediated degranulation. Lastly, metabolomics analysis of bone marrow–derived mast cells following degranulation was used to compare general metabolite profiles related to energetic pathways. IgE-mediated degranulation upregulated metabolite concentrations for the TCA cycle and glycolysis compared with other treatments. In conclusion, mast cell metabolism varies significantly between IgE- and non-IgE–mediated degranulation suggesting novel cell regulatory mechanisms are potentially driving unexplored pathways of mast cell degranulation.
Theoharides TC, Alysandratos K-D, Angelidou A, Delivanis D-A, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A et al: Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2012, 1822(1):21-33. Abstract, Mast cells are well known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases where they are activated by non-allergic triggers, such as neuropeptides and cytokines, often exerting synergistic effects as in the case of IL-33 and neurotensin. Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces selective release of IL-6, while corticotropin-releasing hormone secreted under stress induces the release of vascular endothelial growth factor. Many inflammatory diseases involve mast cells in cross-talk with T cells, such as atopic dermatitis, psoriasis and multiple sclerosis, which all worsen by stress. How mast cell differential responses are regulated is still unresolved. Preliminary evidence suggests that mitochondrial function and dynamics control mast cell degranulation, but not selective release. Recent findings also indicate that mast cells have immunomodulatory properties. Understanding selective release of mediators could explain how mast cells participate in numerous diverse biologic processes, and how they exert both immunostimulatory and immunosuppressive actions. Unraveling selective mast cell secretion could also help develop unique mast cell inhibitors with novel therapeutic applications.
Yang YS, Cao MD, Wang A, Liu QM, Zhu DX, Zou Y, Ma LL, Luo M, Shao Y, Xu DD et al: Nano-silica particles synergistically IgE-mediated mast cell activation exacerbating allergic inflammation in mice. Front Immunol 2022, 13:911300. Abstract, Background, Allergic respiratory diseases have increased dramatically due to air pollution over the past few decades. However, studies are limited on the effects of inorganic components and particulate matter with different particle sizes in smog on allergic diseases, and the possible molecular mechanism of inducing allergies has not been thoroughly studied. Methods, Four common mineral elements with different particle sizes in smog particles were selected, including Al2O3, TiO2, Fe2O3, and SiO2. We studied the relationship and molecular mechanism of smog particle composition, particle size, and allergic reactions using mast cells, immunoglobulin E (IgE)-mediated passive cutaneous anaphylaxis (PCA) model, and an ovalbumin (OVA)-induced asthmatic mouse model in vitro and in vivo, combined with transmission electron microscopy, scanning transmission X-ray microscopy analysis, and transcriptome sequencing. Results. Only 20 nm SiO2 particles significantly increased β-hexosaminidase release, based on dinitrophenol (DNP)-human serum albumin (HSA) stimulation, from IgE-sensitized mast cells, while other particles did not. Meanwhile, the PCA model showed that Evan’s blue extravasation in mice was increased after treatment with nano-SiO2 particles. Nano-SiO2 particles exposure in the asthmatic mouse model caused an enhancement of allergic airway inflammation as manifested by OVA-specific serum IgE, airway hyperresponsiveness, lung inflammation injury, mucous cell metaplasia, cytokine expression, mast cell activation, and histamine secretion, which were significantly increased. Nano-SiO2 particles exposure did not affect the expression of FcϵRI or the ability of mast cells to bind IgE but synergistically activated mast cells by enhancing the mitogen-activated protein kinase (MAPK) signaling pathway, especially the phosphorylation levels of the extracellular signal-regulated kinase (ERK)1/2. The ERK inhibitors showed a significant inhibitory effect in reducing β-hexosaminidase release. Conclusion, Our results indicated that nano-SiO2 particles stimulation might synergistically activate IgE-sensitized mast cells by enhancing the MAPK signaling pathway and that nano-SiO2 particles exposure could exacerbate allergic inflammation. Our experimental results provide useful information for preventing and treating allergic diseases.
Wang Y, Tang N, Mao M, Zhou Y, Wu Y, Li J, Zhang W, Peng C, Chen X, Li J: Fine particulate matter (PM2.5) promotes IgE-mediated mast cell activation through ROS/Gadd45b/JNK axis. Journal of Dermatological Science 2021, 102(1):47-57.
Atmospheric pollution is a current substantial challenge for public health worldwide and mainly results from volatile organic compounds, nitrogen oxides, the ozone, sulfur oxides, and particulate matter (PM). Particulate matter less than 2.5 micrometers in diameter is also called fine particles or PM2.5. Studies showed that PM2.5 is the fourth largest threats to public health in China [3]. Due to its small size, PM2.5 could enter the respiratory system and circulatory system. Accumulating evidence demonstrated that both long-term and short-term exposure to PM2.5 aggravate cardiovascular and respiratory diseases, such as atherosclerosis, asthma, chronic obstructive pulmonary disease [3,4] and even cancers [5]. Furthermore, studies also exhibited that PM2.5 triggers skin diseases, such as atopic dermatitis, eczema, acne and psoriasis [6]. Various air pollutants including particulate matter, environmental tobacco smoke, toluene, ambient ozone, nitrogen dioxide and volatile organic compounds are well known with high-risk factors to aggravating atopic dermatitis (AD) and urticaria [7]. These air pollutants may induce oxidative stress and chronic inflammation, leading to impairing skin barrier or dysfunction in the immune system. Birth cohort studies have shown that exposure to air pollutants, such as PM or environmental tobacco smoke (ETS), increases the risk of developing AD or eczema in the next generation [8]. In addition, evidence also suggests that PM2.5 aggravates AD symptoms and pruritus score; moreover, the SCORAD index has been shown to be dependent on the concentration of PM2.5 [9]. Actually, PM2.5 could initiate dysfunction of various immune cells such as T cells [10]. Evidences exhibited that exposure to diesel exhaust particles (DEP), one of the main contributors to atmospheric PM2.5, could directly induce mast cell degranulation [11]. In addition, PM2.5 breaks the balance of Th1/Th2 or Th17/Treg that significantly increases the level of IFN-γ, IL-12 and IL-17, resulting in immune imbalance or immune diseases [12]. However, the specific effect of PM2.5 on mast cells remains unclear. In this study, we investigated the effect of PM2.5 and found that PM2.5 facilitated IgE-mediated mast cells activation, including degranulation and cytokine secretion, and passive cutaneous anaphylaxis (PCA) in mice. Meanwhile, the findings also showed that PM2.5 increased the ROS level, which could activate the MEKK4/JNK pathway by upregulating Gadd45b. The knockdown of Gadd45b and the administration of a JNK1/2-specific inhibitor or ROS inhibitor attenuated the PM2.5-induced degranulation and cytokine secretion of mast cells.
Kunder CA, St John AL, Li G, Leong KW, Berwin B, Staats HF, Abraham SN: Mast cell-derived particles deliver peripheral signals to remote lymph nodes. J Exp Med 2009, 206(11):2455-2467. Abstract, During infection, signals from the periphery are known to reach draining lymph nodes (DLNs), but how these molecules, such as inflammatory cytokines, traverse the significant distances involved without dilution or degradation remains unclear. We show that peripheral mast cells, upon activation, release stable submicrometer heparin-based particles containing tumor necrosis factor and other proteins. These complexes enter lymphatic vessels and rapidly traffic to the DLNs. This physiological drug delivery system facilitates communication between peripheral sites of inflammation and remote secondary lymphoid tissues.
Kunder CA, St John AL, Abraham SN: Mast cell modulation of the vascular and lymphatic endothelium. Blood 2011, 118(20):5383-5393. Abstract, Mast cells (MCs) promote a wide range of localized and systemic inflammatory responses. Their involvement in immediate as well as chronic inflammatory reactions at both local and distal sites points to an extraordinarily powerful immunoregulatory capacity with spatial and temporal versatility. MCs are preferentially found in close proximity to both vascular and lymphatic vessels. On activation, they undergo a biphasic secretory response involving the rapid release of prestored vasoactive mediators followed by de novo synthesized products. Many actions of MCs are related to their capacity to regulate vascular flow and permeability and to the recruitment of various inflammatory cells from the vasculature into inflammatory sites. These mediators often work in an additive fashion and achieve their inflammatory effects locally by directly acting on the vascular and lymphatic endothelia, but they also can affect distal sites. Along these lines, the lymphatic and endothelial vasculatures of the host act as a conduit for the dissemination of MC signals during inflammation. The central role of the MC-endothelial cell axis to immune homeostasis is emphasized by the fact that some of the most effective current treatments for inflammatory disorders are directed at interfering with this interaction.
Abraham SN, St John AL: Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol 2010, 10(6):440-452. Abstract, Although mast cells were discovered more than a century ago, their functions beyond their role in allergic responses remained elusive until recently. However, there is a growing appreciation that an important physiological function of these cells is the recognition of pathogens and modulation of appropriate immune responses. Because of their ability to instantly release several pro-inflammatory mediators from intracellular stores and their location at the host–environment interface, mast cells have been shown to be crucial for optimal immune responses during infection. Mast cells seem to exert these effects by altering the inflammatory environment after detection of a pathogen and by mobilizing various immune cells to the site of infection and to draining lymph nodes. Interestingly, the character and timing of these responses can vary depending on the type of pathogen stimulus, location of pathogen recognition and sensitization state of the responding mast cells. Recent studies using mast cell activators as effective vaccine adjuvants show the potential of harnessing these cells to confer protective immunity against microbial pathogens.
Excellent article thank you.