Mastocytosis and Mast Cell Activation Disorders: Clearing the Air

Abstract

Mast cells are derived from hematopoietic stem cell precursors and are essential to the genesis and manifestations of the allergic response. Activation of these cells by allergens leads to degranulation and elaboration of inflammatory mediators, responsible for regulating the acute dramatic inflammatory response seen. Mast cells have also been incriminated in such diverse disorders as malignancy, arthritis, coronary artery disease, and osteoporosis. There has been a recent explosion in our understanding of the mast cell and the associated clinical conditions that affect this cell type. Some mast cell disorders are associated with specific genetic mutations (such as the D816V gain-of-function mutation) with resultant clonal disease. Such disorders include cutaneous mastocytosis, systemic mastocytosis (SM), its variants (indolent/ISM, smoldering/SSM, aggressive systemic mastocytosis/ASM) and clonal (or monoclonal) mast cell activation disorders or syndromes (CMCAS/MMAS). Besides clonal mast cell activations disorders/CMCAS (also referred to as monoclonal mast cell activation syndromes/MMAS), mast cell activation can also occur secondary to allergic, inflammatory, or paraneoplastic disease. Some disorders are idiopathic as their molecular pathogenesis and evolution are unclear. A genetic disorder, referred to as hereditary alpha-tryptasemia (HαT) has also been described recently. This condition has been shown to be associated with increased severity of allergic and anaphylactic reactions and may interact variably with primary and secondary mast cell disease, resulting in complex combined disorders. The role of this review is to clarify the classification of mast cell disorders, point to molecular aspects of mast cell signaling, elucidate underlying genetic defects, and provide approaches to targeted therapies that may benefit such patients.

Keywords: allergic reaction; anaphylactic shock; angioedema; histamine; hypotension; mast cell; mastocytosis; tryptase.

Figure 1

Activation of MCs occurs when allergen specific IgE is bound by the allergen and interacts with the high affinity receptor for immunoglobulin (IgE), referred to as FcεRI, carried on their surfaces in the presence of mutations and other molecular-genetic defects. This culminates in the release of preformed and newly synthesized mediators from mast cells and basophils that sets off a sequence of inflammatory events manifesting clinically as anaphylaxis and leading to shock. MC-derived cytokines, histamine, leukotrienes, prostanoids, and PAF regulate vascular instability and barrier dysfunction of endothelial cells and contribute to edema formation. Hypovolemia, angioedema, hypotension, and cardiorespiratory failure ensue. Inset shows examples of urticaria and angioedema.

Figure 2

(A) Stem cell factor (SCF) is a hematopoietic growth factor that binds to its receptor, KIT, a transmembrane tyrosine kinase-linked receptor on mast cells. Signaling downstream involves activation of key kinases (Phospholipase Cγ (PLCγ), protein kinase C (PKC), and linked signaling proteins: Janus kinase 2 (a non-receptor tyrosine kinase, JAK2), signal transducer and activator of transcription 1 (STAT1), and other signal transduction mediators). These lead to action of mitogen-activated protein kinases (MAP kinase). Somatic mutations in c-KIT that code for the KIT receptor have been linked to the development of systemic mastocytosis, a clonal hematological disorder. The most common of these mutations is the D816V mutation that leads to enhanced survival and proliferation of mast cells, a feature of clonal mast cell disorders including mastocytosis and mast cell activation disorders. (B) KIT is the cellular counterpart of the v-KIT oncogene derived from a feline leukemia virus. It is encoded in the W or c-KIT locus on human chromosome 4q11-q12. KIT is composed of an immunoglobulin-like extracellular domain (ILECD), that is involved in ligand binding (LBR), an anchoring transmembrane domain (TMD), a juxta-membranous domain (JMD), and intracellular domains (ICD). KID = kinase insert domain. Binding of stem cell factor to KIT results in receptor dimerization and activation of protein kinase activity.

Figure 3

Representative clinicopathological features of mastocytosis. Cutaneous mastocytosis is subcategorized as maculopapular cutaneous mastocytosis (MPCM), also known as urticaria pigmentosa or diffuse cutaneous mastocytosis (DCM), and mastocytoma of the skin. MPCM is the most common presentation of CM with hyperpigmented nodules, papules, or macules distributed randomly, and appearing most commonly on the trunk. The figure shows representative atypical mast cells, mast cell aggregates in the bone marrow (CD117 and tryptase staining), and CD25+ atypical mast cells on flow cytometry of bone marrow aspirate.

Figure 4

Criteria for diagnosis of mast cell activating syndrome (please refer to text for description). A = clinical criterion, B = laboratory criterion, C = treatment criterion. All three criteria need to be satisfied to confirm a diagnosis of mast cell activation syndrome (MCAS). The presence of clonality (KIT D816V mutation or surface expression of CD2 or CD25 clonal markers) would suggest a diagnosis of clonal (primary) mast cell activating syndrome also referred to as the monoclonal mast cell activation syndrome (MMAS). * Tryptase (total tryptase) is usually used as a surrogate marker for mast cell activation. PG = prostaglandin, LT-leukotriene, MCA = mast cell activation. bST = basal serum tryptase.