Mast cell – Definition, Structure, Functions

What are mast cells? – mast cells definition

• Mast cells (also known as mastocytes or labrocytes) are resident cells of connective tissue that contain numerous histamine- and heparin-rich granules.
• Myeloid lineage gives rise to mast cells, which are immune cells. After originating in the bone marrow, progenitor cells disperse and populate other tissues.
• The progenitor evolves into a mature mast cell under the influence of stem cell factors produced locally by numerous cells in the tissue. Mature mast cells are only found in tissues and not in the bloodstream.
• Mast cells are located in loose (areolar) connective tissue in practically every organ of the body. They play a crucial function in the induction of the inflammatory cascade.
• Mast cells can be induced to degranulate by innate or adaptive immunological pathways, releasing inflammatory mediators into the extracellular environment.
• Mast cells are linked to numerous illnesses, such as type I hypersensitivity reactions, mastocytosis, mast cell activation syndrome, and urticaria.
• It is a type of granulocyte generated from myeloid stem cells that is a component of the immunological and neuroimmune systems.
• Paul Ehrlich first discovered mast cells in 1877. Mast cells have a crucial protective role, since they are integrally involved in wound healing, angiogenesis, immunological tolerance, defence against infections, and vascular permeability in brain tumours, while being best known for their role in allergies and anaphylaxis.
• Both in form and function, the mast cell resembles the basophil, another type of white blood cell.
• Once believed to be tissue-resident basophils, it has been demonstrated that mast cells and basophils arise from distinct hematopoietic lineages and hence cannot be the same cells.

Structure of Mast cell

• Mast cells are mononuclear cells. They are characterised by the presence of numerous tiny secretory granules ranging in size from 0.2 to 0.8 micrometres.
• Frequently, the granules are so dense that they obscure the nucleus. On the plasma membrane are IgE receptors.
• These crosslinks bind the Fc region of circulating IgE and trigger cell degranulation.
• The composition of the secretory granules of the two major types of mast cells distinguishes them. Granules in MC(T) cells are primarily composed of tryptase.
• The bulk of MC(T) cells are located in close proximity to mucosal tissue that is exposed to the outside environment, such as gastrointestinal or respiratory mucosa.
• These cells primarily contribute to the immunological response. The secretory granules of MC(TC) cells include tryptase as well as chymase and carboxypeptidase.
• The bulk of MC(TC) cells are located in the submucosa and connective tissue adjacent to the conjunctiva and skin, typically in close proximity to blood and lymphatic arteries. These cells are crucial for tissue healing.

Types of Mast Cells

Mast cells are a type of immune cells that play an important role in the body’s defense against pathogens and in allergic reactions. There are several types of mast cells that differ based on their location and the types of molecules they produce.

The two main types of mast cells are:

1. Connective tissue mast cells

These mast cells are found in connective tissues throughout the body, such as the skin, lungs, and digestive tract. They are responsible for the immediate response to allergens and parasites, and release histamine, prostaglandins, and leukotrienes, which cause inflammation and smooth muscle contraction.

2. Mucosal mast cells

These mast cells are found in the mucous membranes that line the respiratory and digestive tracts, as well as the genitourinary tract. They are involved in immune surveillance and response to pathogens, and release cytokines, chemokines, and proteases.

In addition to these two main types, there are also other subtypes of mast cells that have been identified based on their location, function, and expression of specific proteins. These include perivascular mast cells, skin mast cells, and serosal mast cells, among others.

Morphologies of mast cell – mast cells microscope

Under Light Microscope

Mast cells are irregularly or oval-shaped cells. Often, thick granular cytoplasm obscures the nucleus and other organelles under optical microscopy. The nucleus is central and the cell is mononuclear when it is visible. Mast cells are located in connective tissue throughout the body. Some are randomly distributed throughout the tissue. They tend to congregate close to blood arteries, where cells are more elongated. Concentrates can also be detected at hair follicles, sebaceous glands, and sweat glands in the skin.

By means of light microscopy, three morphologies of mast cells have been identified;

• Near blood arteries and deep into the dermis and subcutaneous tissue, one can find Intact Cells. Granules are densely packed, making it difficult to discern other cellular features. As stated previously, these cells have a spindle-like morphology.
• Spreading Cells are located in the superficial connective tissue, in close proximity to the upper dermis. However, there are fewer granules than in a complete cell type. This makes it possible to distinguish between each granule.
• Degranulated Cells are not metachromatic anymore. They are stained with a faint pink hue and have a blue nucleus.

Under Electron Microscope

Mast cells are again characterised by an abundance of cytoplasmic granules, also known as secondary lysosomes, when viewed by scanning electron microscopy. These granules have a lipid membrane surrounding them. Under optimal conditions, one can observe profound invaginations of the cell membrane. When a cell degranulates, its plasma membrane forms channels, exposing granules located deep within the cell to the external environment.

A large number of tiny, finger-like pseudopods protrude from the cell membrane. Round, tightly packed chromatin encircles the centrally placed nucleus. The type of cell determines the ultrastructure of granules.

• Granules of intact cells have little visible structure.
• The majority of Spreading Cells’ granules are composed of tiny particle materials. Lamellae arranged in circular “scroll-like” patterns are interspersed throughout these granules.

Stain for mast cells

The most commonly used stain for mast cells is toluidine blue. This basic dye stains the metachromatic granules present in mast cells, making them easily visible under a microscope. When toluidine blue is used to stain tissue sections, mast cells appear as dark purple or blue-black granular cells. Other staining methods, such as Giemsa or Wright’s stain, can also be used to visualize mast cells, but toluidine blue is considered the gold standard for mast cell staining. Immunohistochemistry can also be used to identify mast cells by staining for specific mast cell markers, such as tryptase or chymase.

Mechanism of Activation 

• The primary mode of action of mast cells is IgE-mediated allergic responses mediated by the FcRI receptor.
• Mature B cells generate IgE antibodies in response to CD4+ Th2 cells. IgM and IgD antibodies are made by nave mature B lymphocytes.
• B cells will proliferate once they’ve been triggered by an antigen. If these B cells engage with IL-4 (which is controlled by CD4+ Th2 cells), the antibody type changes from IgM to IgE.
• IgE is predominantly found attached to FcRI receptors on mast cells, and relatively little IgE circulates as a soluble antibody. When an antigen contacts a mast cell, it causes the crosslinking of two or more FcϵRI molecules and the release of granules from the mast cell. Connective tissue beneath the epithelial layers of the epidermis, the respiratory tract, and the gastrointestinal tract all contain IgE.
• Mast cells have Fc receptors for IgA and IgG, receptors for adenosine, C3a, chemokines, cytokines, and pathogen-associated molecular patterns (PAMPs), as well as toll-like receptors (TLRs), which are all involved in mast cell activation and immune response. Cross-linking between antigen, IgE, and FcϵRI is the most frequent physiologic mechanism for mast cell activation.
• FcϵRI is composed of a β-chain that binds to IgE, a α-chain that bridges the membrane, and disulfide-linked homodimer γ chains. FcϵRI interacts with LYN tyrosine kinase, which phosphorylates immunoreceptor tyrosine bases activation motifs (ITAMs) on the B and γ chains of FcϵRI.
• Lyn stimulates Syk tyrosine kinases, which phosphorylate signalling proteins including LAT1 and LAT2 (linkers for activation of T cells). Phosphorylated PLCγ generates inositol-1,4,5-triphosphate (IP3) and diacylglycerol by hydrolyzing phosphatidylinositol-4,5-bisphosphate (DAG). Both IP3 and DAG are second messengers, and IP3 mobilises calcium from the endoplasmic reticulum.
• Calcium release activates and translocates NFκB to the cell nucleus, resulting in production of cytokines including IL-6, TNF-α, and IL-13. Zeb2 is involved in the regulation of degranulation in response to FcϵRI stimulation.
• FcϵRI activation stimulates Fyn (Src kinase). Fyn controls mast cell degranulation, complementing the Lyn signalling pathway. Fyn stimulates PI3K, which subsequently activates Akt and generates PIP3.
• This stimulates the mTOR protein, which is essential for mast cell chemotaxis and cytokine production. There are also IgG receptors known as FcγR. Since the y-chain homodimer is identical in FcRI and FcϵRI, the signal transmitted by FcϵR might crosstalk with FcϵRI.
• Repeated exposure of mast cells to antigen under controlled conditions can desensitise a patient. The slow and continuous degranulation of mast cells is believed to be one of the mechanisms, despite the fact that they are not fully understood.
• Patients who are allergic to particular medications (e.g., penicillin) but require therapy for a life-threatening bacterial infection that can only be cured with this drug undergo desensitisation.
• By exposing mast cells to escalating antigen doses, desensitisation can ensue. This method can be utilised if a patient is allergic to a vital drug and for the prevention of food-related anaphylaxis events.
• By desensitising the receptors, this can reduce the amount of FcϵRI molecules on the surface of mast cells.

Role of Mast cell in Angiogenesis

• Mast cells play a role in promoting angiogenesis. Mast cells produce pro-angiogenic factors including VEGF, bFGF, TGF-beta, TNF-alpha, and IL-8.
• In addition, mast cells release proteases and heparin, which cause pro-angiogenic factors to be released and bind to heparin.
• Histamine, which is produced by mast cells, causes microvasculature permeability and angiogenesis.
• There is additional evidence that mast cells promote tumour angiogenesis.

Role of Mast cell in Homeostasis

• Mast cells help to immune system balance. Due to their placement on the skin and mucosa, they act as the first line of defence against antigens entering the body.
• Mast cells play a crucial role in maintaining the intestinal commensal bacteria’s equilibrium.
• The digestive system is continuously exposed to antigens, including commensal and pathogenic bacteria and dietary antigens.
• The digestive system’s epithelial cells function as a barrier against these antigens. ATP signalling is essential for the development of follicular helper T cells involving mast cells.
• Therefore, mast cells play a role in IgA maturation and overall gut bacterial balance.

Role of Mast cell in Innate and Adaptive Immunity

• Mast cells are crucial to both innate and adaptive immunity. Mast cells identify hazardous antigens by attaching directly to pathogens or interacting with PAMPs on the surface of mast cells.
• TLRs and complement receptors are the most prevalent receptors on mast cells. Once the antigen connects to the mast cell’s receptors, it triggers the release of inflammatory mediators, which aid in the elimination of the pathogen that activated the cell.
• The mechanism through which this occurs is dependent on the PAMP that is detected. Gram-positive bacteria and, to a lesser extent, Gram-negative bacteria and mycobacteria activate TLR2, causing the mast cell to release cytokines such as IL-4.
• TLR4 binds to LPS from Gram-negative bacteria, resulting in the production of proinflammatory cytokines (TNFα, IL-1, and IL-6) without degranulation.
• Alternatively, the Gram-positive bacterial product peptidoglycan induces mast cell degranulation and histamine release by activating TLR2.
• By releasing inflammatory mediators that increase vascular permeability, increase fluid buildup, and draw immune cells such as eosinophils, NK cells, and neutrophils, mast cells contribute in the eradication of germs.
• In addition, mast cells produce directly antimicrobial substances, including cathelidcidins, defensins, and psidins. Mast cells also contribute to antiviral responses by recruiting IFN-α and IFNβ—producing CD8+ T cells.
• When activated by IgE, one of the earliest discovered activities of the mast cell was to establish an anti-parasitic environment. Mast cell release of mediators enhances vascular permeability and smooth muscle contraction, so aiding in the expulsion of parasites from the gastrointestinal tract by producing vomiting or diarrhoea, and from the respiratory tract by coughing.
• Mast cells participate in adaptive immunity as well. Mast cells use MHCI and MHCII to digest and deliver antigens.
• Mast cells stimulate dendritic cells, which serve as antigen-presenting cells as well. When mast cells are activated by TLF-7, they release IL-1 and TNFα, causing dendritic cells to migrate from the skin to lymph nodes and activate cytotoxic T cells.
• In addition, mast cells emit TNFα, which can directly activate cytotoxic T lymphocytes. 

Mast Cells Function

• The inflammatory cascade is the classic and best-known function of mast cells. Mast cells serve as a component of the body’s innate immune system.
• When membrane-bound IgE hits a foreign material and two Fc receptors crosslink, the mast cell promptly degranulates and releases a huge quantity of mediators into the surrounding extracellular space.
• Granules are surrounded by a lipid membrane that merges with the plasma membrane. Histamine is the most significant cytokine secreted.
• Histamine promotes chemotaxis of white blood cells, constriction of airway smooth muscle, and enhanced vascular permeability. Tryptase, chymase, and TNF-alpha are other mediators secreted from the granules.
• The mast cell then synthesises and releases pro-inflammatory prostaglandins and leukotrienes derived from lipids. Lastly, an increase in gene transcription increases cytokine production.
• The innate immune system utilises the inflammatory impact of mast cells as its first line of defence.
• MC(T) cells are the primary immune response cell type. When a foreign protein is met, the mast cell’s pro-inflammatory activities result in the recruitment of circulating immune cells.
• Cytokines have direct effects on local tissue, such as an increase in mucus production or an increase in intestinal peristalsis, in order to prevent pathogen invasion.
• Additionally, mast cells contribute to tissue healing and angiogenesis. Upon damage, MC(TC) independently of IgE pathways produce procoagulant cytokines, leukotrienes, and platelet-activating factor.
• Later, heparin, tryptase, and t-PA from the cell modify blood flow in order to improve the delivery of nutrients and immune cells. Inflammatory mediators stimulate fibroblast and endothelial cell differentiation and proliferation.
• Additionally, mast cells contain numerous angiogenic cytokines, such as VEGF and FGF 2. Mast cells have also been linked to the constriction of wounds and regeneration of nerve fibres.
• Mast cells have never been shown to be deficient, indicating that their functions are vital to survival.

How do Mast Cells work against pathogens? (Immunity)

Mast cells are essential components of the immune system and are responsible for orchestrating the body’s response to foreign substances. They play a critical role in the process of allergic reactions, which occur when the immune system reacts to typically harmless substances such as pollen, dust, or certain foods. The most important mechanism of action of mast cells is through the IgE-mediated allergic reactions via the Fc receptor.

IgE antibodies are produced by mature B cells in response to the activation by CD4+ Th2 cells. IgE is produced from IgM via class switching in response to the activation of B cells in the presence of IL-4. These antibodies bind to specific receptors on mast cells, leading to their activation.

The binding of IgE to the Fc receptors on the mast cells results in the activation of mast cells, activating the release of granules from the mast cells. The granules contain various substances such as histamine, proteases, and cytokines that can cause allergic reactions. When allergens bind to the IgE antibodies on the mast cells, it causes the release of these granules.

The binding of IgE activates the LYN tyrosine kinase in the cells, which phosphorylates the tyrosine in the binding site to activate the motifs. The LYN also activates Syk tyrosine kinase, which phosphorylates signaling proteins like LAT1 and LAT2. This signaling cascade leads to the activation of downstream pathways, leading to the release of the granules.

Phosphorylated PLCγ hydrolyzes phosphatidylinositol-4,5-biphosphate to form inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). The IP3 and DAG act as second messengers, causing the mobilization of calcium from the endoplasmic reticulum. The release of calcium from the ER causing the translocation of NFκB to the nucleus of the cell. This results in the production of various cytokines such as IL-6, TNFα, and IL-13, which then regulate the degranulation of mast cells.

Mast cell desensitization is another essential mechanism used in response to allergies to drugs or food particles. Desensitization therapy is a process of gradually exposing the body to the allergen in small doses over time, which helps to decrease the allergic reaction’s severity. This process helps to desensitize the mast cells, which become less reactive to the allergen over time.

In conclusion, the activation of mast cells through the IgE-mediated pathway plays a crucial role in the body’s allergic response. The binding of IgE to the Fc receptor leads to the activation of signaling pathways, resulting in the release of granules containing histamine, proteases, and cytokines. Mast cell desensitization is an essential mechanism used in response to allergies to drugs or food particles. Understanding the molecular mechanisms underlying the activation of mast cells is crucial for developing effective treatments for allergic diseases.

Eosinophils vs Mast cells

Eosinophils and mast cells are two types of immune cells that play different roles in the body’s immune response.

Eosinophils are a type of white blood cell that are involved in the body’s response to parasites, allergic reactions, and certain infections. They are characterized by their ability to release cytotoxic granules, such as major basic protein and eosinophil peroxidase, which can damage parasites and certain host tissues. Eosinophils also produce cytokines and chemokines that can recruit and activate other immune cells.

Mast cells, on the other hand, are a type of immune cell that are primarily involved in the body’s response to allergic reactions and certain infections. They are located throughout the body in tissues such as the skin, lungs, and digestive tract, and are characterized by their ability to release histamine, prostaglandins, and leukotrienes, which can cause inflammation, smooth muscle contraction, and other allergic symptoms. Mast cells also play a role in host defense against certain pathogens and parasites, and can produce cytokines and chemokines that can recruit and activate other immune cells.

While both eosinophils and mast cells can be involved in the body’s response to allergic reactions, they differ in their mechanisms of action and the types of molecules they produce. Eosinophils are primarily involved in the destruction of parasites and certain host tissues, while mast cells are involved in the release of inflammatory molecules that cause allergic symptoms.

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References

• Gilfillan, A.M., Austin, S.J., Metcalfe, D.D. (2011). Mast Cell Biology: Introduction and Overview. In: Gilfillan, A.M., Metcalfe, D.D. (eds) Mast Cell Biology. Advances in Experimental Medicine and Biology, vol 716. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-9533-9_1
• Krystel-Whittemore, M., Dileepan, K. N., & Wood, J. G. (2016). Mast Cell: A Multi-Functional Master Cell. Frontiers in Immunology, 6. doi:10.3389/fimmu.2015.00620 
• Fong M, Crane JS. Histology, Mast Cells. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499904/
• https://microbenotes.com/mast-cells/