Mast cell activation syndrome

Mast cell activation syndrome (MCAS) can result from a number of underlying causes:[1][2][3]

The most common is a severe IgE-dependent allergy (secondary MCAS).
A minority of patients have a primary clonal mast cell disease such as mastocytosis as the underlying cause (primary MCAS). These patients typically experience recurrent, unprovoked episodes of anaphylaxis. In some patients in this group, mastocytosis is present along with an allergy (mixed MCAS), often to Hymenoptera venom, and these patients are at particularly high risk of recurrent life-threatening episodes of anaphylaxis.
There is also a group of MCAS patients in whom no underlying cause can be found (idiopathic MCAS).

The recurrent acute episodes that are a defining feature of MCAS occur as a result of mediators released by activated mast cells. Mast cells are multifunctional effector cells that are present in almost all vascularized tissues.[4] They release a range of inflammatory and vasoactive mediators and cytokines in response to internal or external triggers that signify stress or danger, and the effects of these mediators vary depending on the tissue site.[1][3][5] They are also key effectors for allergic reactions via their high-affinity IgE-binding receptors, which enable a response to exposure to an allergen or other trigger.[14] Thus mast cell activation is instrumental in episodes of anaphylaxis.

Activation of mast cells leads to degranulation, new lipid mediator formation from cellular membranes, and secretion of a range of mediators, including histamine, tryptase, leukotrienes, prostaglandins, and cytokines (including interleukin-6, -9 and -13).

These mediators produce a variety of symptoms affecting different organ systems, which when they occur recurrently and in combination can result in the acute episodes that are characteristic of MCAS. For example, histamine, prostaglandin D2 (PGD2), and leukotriene E4 (LTE4) are implicated in cardiovascular symptoms such as hypotension, tachycardia, and syncope; cutaneous symptoms such as flushing, pruritus, and angioedema; and gastrointestinal symptoms such as abdominal cramping, nausea, and diarrhea.[14]
There are also many other mediators - such as the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) - that are also released by other cell types and hence are not specific for mast cell activation.
Serum tryptase is the most specific and clinically useful indicator of mast cell activation because although it is also released by basophils, mast cells contain up to 500 times more tryptase than do basophils.[15][16]
In patients with MCAS, these severe symptomatic episodes resulting from mast cell activation occur on a recurrent basis.

In most patients with primary MCAS associated with mastocytosis, clonal mast cells exhibit a gain-of-function mutation in the tyrosine kinase receptor gene KIT (most commonly in D816V) and/or aberrant expression of CD25, which means they proliferate independently of growth factors.

This leads to an abnormal accumulation of mast cells in various tissues such as the bone marrow, skin, and gastrointestinal tract.[1][14]
In primary MCAS, mast cells seem to have a lower threshold for activation, either spontaneously or triggered by a known or unknown external factor; external triggers include physical stimuli such as pressure or temperature changes, bacterial or viral infectious agents, and physical or emotional stress.[3][14]
This results in an increased risk for episodes of anaphylaxis and the risk is elevated further when an IgE-dependent allergy is also present, most often to Hymenoptera venom (mixed primary and secondary MCAS). It is poorly understood why the presence of clonally expanded mast cells might lead to greater susceptibility to anaphylactic reactions to Hymenoptera venom. Among the theories proposed are that perivascular mast cells are able to deliver vasoactive mediators into the intravascular compartment; that the venom acts directly on clonal mast cells; or that mast cell activation involves dysregulated signal-transduction pathways downstream of the mutant KIT molecules.[14][17]

In secondary MCAS, mast cells which are normal in number and function are activated by an external trigger, leading to an explosive release of mediators and the associated acute symptoms and signs.[3]

The most common trigger is an IgE-dependent allergy, although in rare cases it can be a non-IgE-dependent trigger, an autoimmune disorder, a chronic infection, or a neoplastic disorder.[1]
The IgE-dependent allergy can be to a wide range of triggers - usually after a systemic exposure - including foods, medications, or Hymenoptera venom.[18] Localized and tissue-specific mast cell activation, such as hives or bronchoconstriction alone, does not meet the criteria for MCAS as the criteria require the concurrent involvement of at least two organ systems.
Non-IgE-mediated triggers can include endogenous peptides or drugs such as vancomycin, physical stimuli, exercise, stress, or an inflammatory condition.[18]

Primary, secondary, and idiopathic MCAS subtypes

MCAS is divided into three subtypes, according to the underlying etiology:[2][3][5]

Primary MCAS - associated with a mast cell disorder involving clonal mast cells that are KIT-mutated and/or exhibit aberrant CD25 expression (e.g., systemic mastocytosis)
Secondary MCAS - where atopic allergy, an alternative hypersensitivity disorder, or another non-neoplastic underlying disease (e.g., an autoimmune condition) causes the activation of normal mast cells. The acute symptomatic episodes are triggered by an allergen or other trigger
Idiopathic MCAS - in patients who meet all three diagnostic criteria for MCAS, but no underlying cause is found (i.e., no clonal mast cells are detected, no trigger for mast cell activation is identified, and no inflammatory disorder is present that might explain mast cell activation).

Some patients have mixed primary and secondary MCAS.

Pathophysiology

Classification

Primary, secondary, and idiopathic MCAS subtypes