Mast Cells in Diseases
MCs are involved in the initiation and perpetuation of a number of inflammatory conditions. These conditions range from those associated with an intrinsic or primary defect in MCs due to inherited or acquired polymorphisms and mutations within the MC compartment; to diseases where MCs are activated and recruited through an extrinsic mechanism such as formation of antigen-dependent and IgE-mediated MC activation; to clinical conditions where MCs are implicated through the release of MC mediators but where the mechanism of activation and recruitment is not well understood, thus “idiopathic” (Table I) 86.
There are several well characterized molecular aberrancies affecting the MC compartment. Some are associated with recognized clinical diseases due to effects on MC proliferation and survival, MC reactivity or MC mediator production. Mastocytosis is perhaps the most widely known disease associated with a primary defect in the MC compartment. It is a clonal disease involving expansion of tissue MCs. Mastocytosis is most commonly associated with an acquired gain-of-function KIT p.D816V missense variant, resulting in ligand-independent MC activation. This leads to both unrestrained growth of MCs and a lowered threshold for activation. Individuals with mastocytosis may present with flushing, pruritus, gastrointestinal complaints or systemic anaphylaxis that may occur following exposure to Hymenoptera venom or for unidentified reasons. Mastocytosis may present as cutaneous disease only, or as a systemic disease with or without cutaneous manifestations87.
A group of patients with recurrent anaphylaxis has clonal MCs as demonstrated by evidence of one or two minor criteria for mastocytosis including aberrant MC morphology, CD25 expression and/or presence of theKIT D816V point mutation. By consensus, such patients are currently said to have monoclonal MC activation syndrome (MMAS)88. If the marrow findings are observed in the absence of evidence of systemic MC activation, the term monoclonal MC disorder of uncertain significance has been suggested.
There are now a growing number of heritable genetic conditions that lead to increased MC reactivity. One such example is manifested as a physical urticaria. A missense substitution from cysteine to tyrosine (pC492Y) in the adhesion G protein-coupled receptor E2 (ADGRE2) is present in autosomal dominant vibratory urticaria (VU) characterized by localized hives and systemic manifestations in response to a local stimulus of frictional nature 89. ADGRE2 (CD312) belongs to a large family of adhesion GPCRs generally with an extracellular domain facilitating interactions with proteins from the extracellular matrix. In this case, activation of MCs after a vibratory stimulus is evidenced by MC degranulation and increase in histamine in the venous blood from the affected areas. Thus, ADGRE2 functions as a mechanoreceptor and induces cutaneous MC degranulation. Although the physiological relevance of the limited MC responses to friction in normal individuals is not completely understood, possibilities are that ADGRE2 may alert both resident and immune cells to combat potential injury and wound healing. It may also play a role in pain modulation and perhaps help sense a parasite migrating through dermal tissues.
Hereditary alpha tryptasemia (HαT) is a Mendelian genetic trait that bears mention as intrinsic to the MC and influencing mediator production. It is caused by increased TPSAB1 copy number encoding alpha-tryptase 90. The MC tryptase loci in humans may encode α or β tryptases (TPSAB1) and β-tryptases (TPSB2). One locus expresses either α or β-tryptase, while the other locus can express only β tryptase, resulting in α:β tryptase gene ratios of 0∶4, 1∶3 or 2∶2 in different individuals. Recent studies suggest that germline duplications and triplications of α-tryptase are linked to subjects with dominantly inherited elevated basal serum tryptase levels which may affect up to 5% of the general population. Symptoms reported by up to two-thirds of these patients are suggestive of MC mediator release and include cutaneous flushing and irritable bowel syndrome 91. Also reported are connective tissue abnormalities and dysautonomia. Individuals with multiple duplications show higher tryptase levels in serum, are more symptomatic, and have higher risk for severe anaphylaxis92,93. Recent mechanistic studies have demonstrated that unique enzymatic properties of alpha-tryptase containing heterotetrameric tryptases may contribute to this association94.
Extrinsic or secondary MC activation occurs primarily in allergic diseases, diseases associated with complement activation, and in association with activation of MCs through MRGPRX2. Symptoms may be infrequent to frequent and resultant disease sporadic or chronic depending on the activating mechanism. The immediate effects of MC degranulation, if localized to skin, include a weal and flare reaction or, in airways, contraction of airway smooth muscle, mucus secretion, and an increase in vascular permeability. If systemic, the results may include severe hypotension and extensive vascular leakage. The early responses often transition into a late phase reaction hours later associated with an influx of circulating cell types which promote further inflammation.
The idiopathic MC category includes urticaria, angioedema and anaphylaxis where there is no identifiable etiology, but where MC activation is documented through MC mediator release or evidence of MC degranulation in tissues involved. (Table I). The term idiopathic MC activation syndrome (Idiopathic MCAS) has been applied as a diagnosis for individuals who present with such episodic allergic-like signs and symptoms such as flushing, urticaria, diarrhea, and wheezing involving two or more organ systems, where the etiology is unknown95. Diagnostic criteria include response to anti-mediator therapy and an elevation in a validated urinary or serum marker of MC activation, such as serum tryptase with an episode. Primary and secondary MC disorders must be eliminated as possible causes of the clinical findings. However, the search should continue for the etiology of these idiopathic disorders including the possibility that MC activation may relate to a yet-to-be identified endogenous or environmental stimulus or an intrinsic MC defect resulting in a hyperactive MC phenotype.