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This article writter by MN Editors on November 05, 2022

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· 8 min read >

Immunology

Mast cell – Definition, Structure, Functions

Mast cell Structure of Mast cell Types of Mast Cells Morphologies of mast cell Under Light Microscope Mast cells are irregularly or...

Mast cell - Definition, Structure, Functions
Mast cell - Definition, Structure, Functions

Mast cell

  • 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 in humans can be subdivided into two distinct types: mucosal and connective tissue mast cells.
  • Mast cells of connective tissue are usually present in loose connective tissue and skin, although they can also be found in other connective tissues.
  • The mucosal form of mast cell is present in the mucosa of the digestive tract and peripheral airways.
  • The specific component that causes mast cells to differentiate into two distinct kinds remains unknown.
  • Nevertheless, allergens and other nonallergic signals can activate both of these types of mast cells. Both types contain the IgE receptors responsible for the activation of the cells’ degranulation.
  • The response to nonallergic signals, the mediators and their release, the proteoglycan contents, and the composition of the granular enzymes distinguish the two mast cells.
  • In the case of rodents, it is simple to distinguish between the two types of cells since their stains are of different sizes and are present in discrete regions.
  • In humans, the presence of chymase, a chymotryptic protease, allows for the development of mast cells.
  • The protease is only found in mast cells of connective tissue, whereas tryptic protease or tryptase is present in all human mast cells.

Morphologies of mast cell

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.

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. 

Function of Mast cell

  • 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.

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/
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