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Mast Cells: Mast Cell Function, Origin and Related Conditions

A microscopy image of a mast cell packed with histamine granules.
Credit: iStock.
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When our body requires defending from “non-self” entities, it deploys immune cells. This diverse group performs a wide variety of specialized functions to prevent us becoming ill.

In this article, we focus on one type of immune cell – the mast cell. We discuss what mast cells are, how they are generated, their function in the body and conditions related to them.

What are mast cells?

Mast cells were discovered by Paul Ehrlich in 18781 and are primarily associated with the innate immune response, a non-specific arm of the immune system. They are particularly important in the allergic response, but are also involved in a wide variety of other immune functions. Typically, mast cells only constitute a small fraction of the total immune cell population in various tissues, the number varying depending on the tissue type and the specific physiological or pathological context.2 They can be distinguished from other cell types in tissue sections using toludine blue staining, which stains mast cells blue. Structurally, they are very similar to basophils, containing granules of 0.2 to 0.8 micrometers in diameter filled with histamine and heparin. These can be so dense as to occlude the spherical nucleus of the 8–20 micrometer cell.3

As with other immune cells, mast cells start life in the bone marrow and are derived from pluripotent hematopoietic stem cells. The stem cells must differentiate into a myeloid progenitor cell, or myoblast, and then subsequently into mast cells (Figure 1), by a process known as mastopoiesis, which is largely interleukin-3 (IL-3) dependent.4 Mast cell-committed progenitors (MCPs) are rare in the bone marrow; they migrate to their ultimate tissue location via the blood. The migration is regulated in a tissue-specific manner, and once there they undergo further development into mature mast cells.5,6 Mast cells are phenotypically heterogeneous and this is regulated by an array of cytokines and growth factors, including stem cell factor (SCF), a variety of interleukins, transforming growth factor beta (TGF-β), nerve growth factor (NGF) and granulocyte–macrophage colony-stimulating factor (GM-CSF).7 The life span of mast cells is dependent upon their ultimate tissue location.

Flow diagram showing the differentiation pathway for the development of a mast cell with related cell types and intermediates indicated and represented graphically.

Figure 1: Diagram showing the differentiation pathway for the development of a mast cell. Credit: Technology Networks.

Mast cell function

Mast cells have similar effector functions to basophils (although they differ in many other ways including in their lifespan, ability to proliferate and anatomical localization). Namely, they elicit host protective or allergic responses. Unlike basophils, they are predominantly found in connective tissues and at mucosal surfaces. Mast cells are capable of secreting a vast array of inflammatory mediators, including histamine, interleukins, leukotrienes, tumor necrosis factor alpha (TNF-α), prostaglandins, proteases and other enzymes, TGF-B, CCL5 and the list goes on (Figure 2).8 Mast cells can be activated by several stimuli acting on numerous cell surface receptors. The responses to different stimuli are influenced by a multitude of factors that affect the surface receptors they produce and/or signaling molecules they respond to. The most studied function of mast cells is their involvement in allergic responses via the cell surface-located, high-affinity FcϵRI IgE receptor. Antigen-specific IgE released by B cells binds the receptor, initiating a cascade of events that leads to mast cell degranulation and release of inflammatory modulators, the most important in this context being histamine. The release of histamine causes vasodilation, which allows fluid and other immune cells to enter the surrounding tissue, leading to the classical symptoms of an allergic response: itching, swelling, redness, runny nose, breathing issues and watery eyes.

Mast cell mediators and their effects, with the physiological outcomes on the body indicated.

Figure 2: Mast cell mediators and their effects. Credit: Technology Networks.

Mast cells also play a role in pathogen recognition and elimination. In the context of bacterial infections, this function is primarily associated with the expression of toll like receptors (TLR’s) and complement receptors on the mast cell surface.9 The mast cell then responds to the invading pathogen in a specific manner, releasing the appropriate inflammatory mediators. The elimination of bacteria is also aided by an increase in vascular permeability initiated by mast cells, allowing the recruitment of natural killer cells (NK cells), eosinophils and neutrophils to help kill the bacteria. This process may or may not involve degranulation and is again dependent on the pathogen. In viral infections, mast cells are involved in the elimination of viral pathogens by recruiting T cells, which produce interferons. Mast cells are also capable of producing an anti-parasitic environment and increasing vascular permeability and smooth muscle contractions that can help eliminate the parasite.

Due to the range of molecules they are capable of secreting, mast cells are involved in the regulation of many cell types, including T cells, B cells, dendritic cells, endothelial cells, epithelial cells and more. As such, they play a role in many general physiological functions, including wound healing, bone formation, angiogenesis and mineral homeostasis.

Mast cell-related conditions

Mast cell disorders (MCDs) can be idiopathic or related to another disease and can be difficult to diagnose due to their heterogeneous presentation.10 Let us consider some of the most common MCDs.

  1. Mastocytosis: This rare disorder is characterized by the abnormal accumulation of mast cells in various tissues, generally associated with somatic mutation, but can also be inherited on uncommon occasions. There are two main forms: systemic mastocytosis, which involves multiple organs, and cutaneous mastocytosis, which primarily affects the skin. The disease may be triggered by various factors, including infection, stress, physical stimuli and chemicals.

  2. Mast cell activation syndrome (MCAS): This is an idiopathic condition where mast cells are episodically activated and release an abnormal amount of chemical mediators. MCAS can cause numerous symptoms in a variety of body systems, including abdominal pain, diarrhea, vomiting, nausea, tachycardia, hypotension, pruritus, urticaria, angioedema and respiratory issues.

  3. Allergies: Mast cells play an important role in allergic reactions by releasing histamine and other immune mediators, leading to an inappropriate immune response to typically harmless substances.

  4. Anaphylaxis: This is a rare but potentially fatal reaction to an allergen; for example, food or insect stings. Mast cells release large amounts of histamine leading to widespread systemic symptoms including swelling of the throat and tongue, difficulty breathing, difficulty swallowing, wheezing, coughing, feeling faint and a drop in blood pressure.

  5. Hereditary alpha-tryptasemia (HαT): Individuals with this genetic condition have multiple copies of the TPSAB1 gene, resulting in elevated levels of alpha-tryptase, a mast cell-associated enzyme. While alpha-tryptase is released from mast cells during various physiological processes, including allergic reactions and immune responses, individuals with HαT have an increased baseline level of alpha-tryptase in the blood, producing undesirable physiological effects. Common symptoms include itching, flushing, abdominal pain, fatigue and joint pain.

  6. Mast cell tumors: Mast cell sarcoma is a rare, aggressive neoplasm composed of cytologically malignant, highly atypical, mast cells. This presents as a localized, destructive growth. However, the pathological features of this entity are not well characterized.11 Mast cell leukemia is a very aggressive form of the disease and, as the name suggests, large numbers of mast cells are found in the blood and bone marrow.

Mast cells play a critical role in the body’s response to certain stimuli and are particularly noted in allergic reactions and inflammation. They are considered to be vital to the body’s defense against multiple pathogens and have been shown to have multiple regulatory and homeostatic functions. However, when numbers become altered and their function becomes unregulated, they are associated with several detrimental and potentially life-threatening conditions. 

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