Secretory and Membrane-Associated Biomarkers of Mast Cell Activation and Proliferation

Abstract

Mast cells (MCs) are immune cells distributed in many organs and tissues and involved in the pathogenesis of allergic and inflammatory diseases as a major source of pro-inflammatory and vasoactive mediators. MC-related disorders are heterogeneous conditions characterized by the proliferation of MC within tissues and/or MC hyper-reactivity that leads to the uncontrolled release of mediators. MC disorders include mastocytosis, a clonal disease characterized by tissue MC proliferation, and MC activation syndromes that can be primary (clonal), secondary (related to allergic disorders), or idiopathic. Diagnosis of MC disorders is difficult because symptoms are transient, unpredictable, and unspecific, and because these conditions mimic many other diseases. Validation of markers of MC activation in vivo will be useful to allow faster diagnosis and better management of MC disorders. Tryptase, being the most specific MC product, is a widely used biomarker of proliferation and activation. Other mediators, such as histamine, cysteinyl leukotrienes, and prostaglandin D2, are unstable molecules and have limitations in their assays. Surface MC markers, detected by flow cytometry, are useful for the identification of neoplastic MC in mastocytosis but, so far, none of them has been validated as a biomarker of MC activation. Further studies are needed to identify useful biomarkers of MC activation in vivo.

Keywords: biomarkers; flow cytometry; immunophenotyping; mast cell activation; mast cells; mastocytosis; soluble mediators.

Figure 1

Secretory and membrane-associated MC biomarkers. Circulating biomarkers of MC activation are reported for molecules validated in clinical practice (upper left) or for research use only (bottom left). Cellular biomarkers of normal/reactive (upper right) and neoplastic (bottom right) MC are displayed. Abbreviations. PGD2, prostaglandin D2; IL, interleukin; TNFα, tumor necrosis factor alpha; PAF, platelet activating factor. ++, bright expression; +, expressed; -/+, dim expression; -, not expressed.

Figure 2

Flow cytometry gating strategy for MC immunophenotyping. MCs can be first identified as CD117^high cells with low side scattering (SSC) and CD45^high expression. On gated MCs, expression of normal markers, such as for CD33, CD16, CD11b, CD13, and CD64, of aberrant markers, including CD2 and CD25, or of increased expression of precursor makers, such as CD34 and HLA-DR, can be performed.