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.