Mast cells in allergy: Innate instructors of adaptive responses
Introduction
When Paul Ehrlich as a 24-year-old student presenting his doctoral thesis in 1878, described a type of “granular cells of the connective tissue”, which he named “Mastzellen” (Riley, 1954; Vyas and Krishnaswamy, 2006), he was inaugurating a vivid and multidirectional research to explore the development, phenotype, physiology and pathophysiology of these cells.
Since then, the universe of mast cell biology has been ever extending and the deeper we explore the biology of these fascinating cells, the more functions we discover, including some that shatter long-held beliefs on their nature and limitations (Maurer et al., 2003; Maurer and Metz, 2005).
Initially, mast cells were primarily connected to the anaphylaxis reaction (Keller, 1962). Later they were given the role of “effector cells” in allergy (Williams and Galli, 2000) and for years the main focus of mast cell-related research was their histamine-containing metachromatic granules (Riley and West, 1952) and their high-affinity immunoglobulin (Ig) E receptor FcεRI (Metzger, 1992; Turner and Kinet, 1999). The resulting degranulation with release of histamine and inflammatory cytokines after crosslinking of FcεRI by IgE and antigen has been extensively correlated with the physiological role of mast cells, to the extent of mast cells being mainly referred to as effector cells in the allergic immune response.
More than a century passed before mast cells were attributed a crucial role in host defense and establishment of the innate immunity (Echtenacher et al., 1996; Malaviya et al., 1994, Malaviya et al., 1996a). Since then, the focus on mast cells has broadened towards the investigation of their phenotypical and functional characteristics that enable them to participate in the establishment of innate immunity. And, it has been only during the last two decades that a contribution of mast cells in the initiation of adaptive immune responses has been appreciated (Banovac et al., 1989a, Banovac et al., 1989b; Fox et al., 1994; Frandji et al., 1993; Grabbe et al., 1997).
Thus, nowadays, mast cells are recognized not only as “granular cells of the connective tissue” (Riley, 1954), whose activation exacerbates allergic immune responses, but also as key players in the establishment of innate immunity as well as modulators of adaptive immune responses.
During the first 100 years after Paul Ehrlich first mentioned them, mast cells were believed to be a component of the connective tissue. Only in the 1970s it was proved that they derive from hematopoietic stem cells (Kitamura et al., 1977; Nabel et al., 1981). Mast cell-committed precursors, defined by the phenotype Thy-1low c-kithigh FcεRIαlow and described in fetal murine liver, are able to generate functionally competent mast cells in vivo (Rodewald et al., 1996). Mast cell progenitors in the bone marrow of adult mice are phenotypically Lyn− c-kit+ Sca-1− Ly6c− FcεRIα− CD27− β7+ T1/ST2+ and derive directly from multipotent rather than from common myeloid progenitor cells (Chen et al., 2005). After homing into different tissues, mast cell progenitors differentiate into mature, long-lived, phenotypically diverse mucosal or connective tissue mast cells. Mast cell progenitors are either committed to a distinct subtype, and selectively recruited to the tissue, or get a tissue-specific character after epigenetic influence by environmental factors (Tsai et al., 2005).
c-kit plays a major role in mast cell differentiation and mast cell functions. Mice with c-kit loss of function mutations lack mast cells in contrast to mice deficient for interleukin (IL)-3, which exhibit only marked reduction of mast cell hyperplasia induced by parasites (Lantz et al., 1998). Two most frequently used mast cell-deficient mice strains are WBB6F1-KitW/KitW-v and KitW-sh/KitW-sh mice (C57BL/6 genetic background).
Double heterozygote mice WBB6F1-KitW/KitW-v bear two distinct mutations at the white spotting (W) locus. This locus on chromosome 5 encodes the stem cell factor (SCF) receptor c-kit (CD117). Point mutation resulting in threonine to methionine substitution on KitW-v allele and deletion mutation of 78 amino acids resulting in the absence of the transmembrane domain on the KitW allele, lead to an abnormal development and a decreased survival of mast cells. Therefore, WBB6F1-KitW/KitW-v mice are mast cell deficient and commonly used for studies of different immune reactions in the absence of mast cells (Galli and Kitamura, 1987; Tsai et al., 2005). However, this strain carries different additional abnormalities, caused by the lack of c-kit function, such as macrocytic anemia, lack of melanocytes, intestinal TCRγδ intraepithelial lymphocytes and interstitial cells of Cajal and sterility. Additionally, complex and long-lasting breeding strategies make this strain not very suitable for crossing with knockout mice to study the role of different cell surface molecules or cytokines in regulation of mast cell function in vivo.
Another mouse strain lacking mast cells, KitW-sh/KitW-sh mice, bear an inversion mutation in transcriptional regulatory elements upstream of the c-kit transcription start (Berrozpe et al., 1999) leading to tissue-type specific dysregulation of c-kit expression. Mice of this strain have white coat color and black eyes and almost complete lack of tissue mast cells. However, they are neither anemic nor sterile, they have normal numbers of TCR γδ IELs and do not exhibit a spontaneous pathology in the skin, stomach or duodenum (Grimbaldeston et al., 2005). This strain can be used to produce mast cell-deficient mice that additionally are deficient (knockout) or constitutively express particular genes (transgenic). After reconstitution with mast cells generated either from bone marrow or embryonic stem cells or isolated directly, e.g. from peritoneal cavity, mice are used to investigate how mast cells function in an environment with such deficiency or constitutive expression (Nakano et al., 1985).
The immune responses in contact hypersensitivity (CHS) and delayed type hypersensitivity (DTH) reactions, and production of ovalbumin (OVA)-specific IgE and IgG1 after sensitization and challenge with aerosolized OVA are comparable in WBB6F1-KitW/Kit W-v and WBB6F1-Kit+/+ mice (Ha et al., 1986; Ha and Reed, 1987; Kung et al., 1995; Mekori and Galli, 1985; Thomas and Schrader, 1983). However, results from functional comparisons of mast cell-mediated effects on multiple cellular players should be interpreted carefully at least for two reasons: first, due to the essential role of c-kit in lymphopoiesis (Agosti et al., 2004; Waskow et al., 2002), illustrated e.g. by reduction of percentage of CD25+ cells in thymus (Waskow et al., 2002) and second, because some inflammatory conditions could induce SCF-independent mast cell development (Galli et al., 1987; Gordon and Galli, 1990). Therefore, generation of new mouse strains exclusively deficient in mast cells will be an important task for future investigations.
Section snippets
Mast cells in host defense
Mast cells are commonly found at sites exposed to the external environment, namely the skin, the airways and the gastrointestinal tract (Galli et al., 1999; Marshall, 2004). At such places mast cells are capable of encountering antigens of the external environment, therefore playing an important role in the recognition and defense against invading microorganisms and the establishment of innate immunity. So far, mast cells are recognized mediators of host defenses against parasitic worms and
Toll-like receptors and mast cells
At the center of the detection mechanisms for invading microorganisms in vertebrates, lies the family of Toll-like receptors (TLRs). Similar to the Toll proteins of Drosophila and highly conserved during evolution, the TLR family has been extensively studied both in human and mouse (Gay and Keith, 1991; Medzhitov et al., 1997; Rock et al., 1998). TLRs are expressed by antigen-presenting cells, in order to enable them to recognize and initiate an adaptive immune response leading to the
Mast cells as modulators of T cell responses
Apart from their dominant contribution to the establishment of an innate immune response, mast cells are considered to be important participants also in the regulation of adaptive immunity (Galli et al., 2005). The recent shift in mast cell paradigms has transformed the role of mast cell from a pure protagonist in the effector phase of allergy to a main player in the interphase between innate and adaptive immunity. Further, mast cells control the phenotype and function of the adaptive immunity
Conclusions
In this review, we have summarized the available evidence that apart from their prominent and well-documented role as effector cells in allergy, mast cells play a significant role in the establishment of innate as well as adaptive immune responses. The expression of molecules, which have been correlated with the innate (TLRs) and with the adaptive (MHC class II and costimulatory molecules) immune signalling, suggests that mast cells are capable of acting as regulators of both innate and
Acknowledgments
The authors would like to thank Dr. Annalena Bollinger and Dr. Rene Rückert for critical reading of the manuscript.
References (115)
- et al.
The W(sh), W(57), and Ph Kit expression mutations define tissue-specific control elements located between -23 and -154 kb upstream of Kit
Blood
(1999) - et al.
Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction
J. Biol. Chem.
(1999) - et al.
Rat peritoneal mast cells present antigen to a PPD-specific T cell line
Cell. Immunol.
(1994) - et al.
Presentation of soluble antigens by mast cells: upregulation by interleukin-4 and granulocyte/macrophage colony-stimulating factor and downregulation by interferon-γ
Cell. Immunol.
(1995) - et al.
Development of large numbers of mast cells at sites of idiopathic chronic dermatitis in genetically mast cell-deficient WBB6F1-W/Wv mice
Blood
(1987) - et al.
Mast cells as sentinels of innate immunity
Curr. Opin. Immunol.
(1999) - et al.
Expression, localization and regulation of NOS in human mast cell lines: effects on leukotrienes production
Blood
(2004) - et al.
Phorbol 12-myristate 13-acetate-induced development of functionally active mast cells in W/Wv but not Sl/Sld genetically mast cell-deficient mice
Blood
(1990) - et al.
Induction of MHC class II antigen expression on human HMC-1 mast cells
J. Dermatol. Sci.
(1997) - et al.
Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo
Am. J. Pathol.
(2005)
Altered function of murine mast cells in response to lipopolysaccharide and peptidoglycan
Immunol. Lett.
IL-6 in autoimmune disease and chronic inflammatory proliferative disease
Cytokine Growth Factor Rev.
The extracellular toll-like receptor 2 domain directly binds peptidoglycan derived from Staphylococcus aureus
J. Biol. Chem.
Toll-like receptor function and signalling
J. Allergy Clin. Immunol.
TNF pathophysiology in murine models of chronic inflammation and autoimmunity
Semin. Arthritis Rheum.
The mastocyte, the “other” inflammatory cell in immunopathogenesis
J. Allergy Clin. Immunol.
Mast cell–T cell interactions
J. Allergy Clin. Immunol.
The structure of normal skin and the morphology of atopic eczema
J. Invest. Dermatol.
Mucosal mast cells and the allergic response against nematode parasites
Vet. Immunol. Immunopathol.
Acetylsalicylic acid-induced release of HSP70 from mast cells results in cell activation through TLR pathway
Exp. Hematol.
TLR3-induced activation of mast cells modulates CD8+ T-cell recruitment
Blood
FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells
Blood
Critical role for Kit-mediated Src kinase but not PI 3-kinase signaling in pro T and pro B cell development
J. Exp. Med.
TLR4 mutations are associated with endotoxin hyperesponsiveness in humans
Nat. Genet.
The role of microorganisms in atopic dermatits
Clin. Exp. Immunol.
Intrathyroidal mast cells express major histocompatibility complex class-II antigens
Int. Arch. Allergy Appl. Immunol.
Are the mast cells antigen presenting cells?
Immunol. Invest.
Mast cells, histamine and the pathogenesis of intestinal damage in experimental Trypanosoma brucei brucei infections
Ann. Trop. Med. Parasitol.
Evidence for direct interaction between mast cells and Leishmania parasites
Parasite Immunol.
Potentiation of tumor necrosis factor-alpha-mediated cytotoxicity of mast cells by their production of nitric oxide
J. Immunol.
Animal models of sepsis: setting the stage
Nat. Rev. Drug Discov.
Histamine polarizes human dendritic cells into Th2 cell-promoting effector dendritic cells
J. Immunol.
Identification of mast cell progenitors in adult mice
Proc. Natl. Acad. Sci. USA
Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface
J. Immunol.
Mast cell-dependent down-regulation of antigen-specific immune response by mosquito bites
J. Immunol.
Cutting edge: mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide
J. Immunol.
Critical protective role of mast cells in a model of acute septic peritonitis
Nature
Prostaglandin D2 inhibits the production of interleukin-12 in murine dendritic cells through multiple signalling pathways
Eur. J. Immunol.
Antigen-dependent stimulation by bone marrow-derived mast cells of MHC-II-restricted T cell hybridoma
J. Immunol.
Exogenous and endogenous antigens are differentially presented by mast cells to CD4+ T lymphocytes
Eur. J. Immunol.
Genetically mast-cell-deficient W/Wv and Sl/Sld mice. Their value for the analysis of the roles of mast cells in biologic responses in vivo
Am. J. Pathol.
Mast cell cytokines in allergy and inflammation
Agents Actions Suppl.
Mast cells in the development of adaptive immune responses
Nat. Immunol.
Drosophila Toll and IL-1 receptor
Nature
Interleukin 10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia
J. Exp. Med.
The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models
Connect. Tissue Res.
Systemic anaphylaxis in mast-cell-deficient mice of W/Wv and Sl/Sld genotypes
Exp. Cell Biol.
Immune response potential of mast cell-deficient W/Wv mice
Int. Arch. Allergy Appl. Immunol.
Differential role of GATA-1 and GATA-2 in growth and differentiation of mast cells
Genes Cells
The importance of leukotrienes in mast cell-mediated Toxoplasma gondii cytotoxicity
J. Infect. Dis.
Cited by (68)
Mast cells, basophils and eosinophils: From allergy to cancer
2018, Seminars in ImmunologyCitation Excerpt :The principal effector function exerted by MCs and basophils relies on the activation of FcεRI as occurring in allergic diseases. Nevertheless, the role of these cells in the regulation of adaptive immunity through the release of their granule content is now well accepted [50]. In addition to the well-known expression of Ig receptors, MCs and basophils express molecules, such ad CD40L, involved in the regulation of other immune cell types such as B cells [51].
Mast cells, basophils and B cell connection network
2015, Molecular ImmunologyCitation Excerpt :Following IgE cross-linking by the antigen, these leukocytes are activated and release the content of their granules, including histamine, cytokines and lipid inflammatory mediators, responsible for anaphylactic and allergic reactions (Wedemeyer et al., 2000; Rivera and Gilfillan, 2006). In addition, it has now become clear that these two cell types play key roles also in the regulation of adaptive immunity (Galli et al., 2005; Stelekati et al., 2007). This could be mostly dependent on the ability of MCs and basophils to release a supplementary and diverse range of mediators, such as cytokines, chemokines and growth factors, which can modulate the proliferation, survival, recruitment and function of several immune cell types (Maurer et al., 2003; Henz et al., 2001).
Inhibitory effects of Quillaja saponin on IgE-mediated degranulation of rat basophilic leukemia RBL-2H3 Cells
2012, Journal of Functional FoodsCitation Excerpt :The enzyme β-hexosaminidase can be used in basophil release assays as a biomarker of basophil activation for antigen-induced degranulation in RBL-2H3 cell line (Ho, Choi, Yoo, Kim, & Ryu, 1998). Mast cells also play an important role in initiating and perpetuating the inflammatory response in allergic reactions by secreting abundant amounts of proinflammatory mediators such as IL-4, IL-5, IL-6, tumour necrosis factor (TNF)-α, and leukotrienes (Bradding et al., 1994; Stelekati, Orinska, & Bulfone-Paus, 2007). In particular, IL-4 has a prominent role in the initiation of an allergic reaction, and promotes the switch from naive T cells to the allergic type Th2 cells.
N-3 Long-chain PUFA reduce allergy-related mediator release by human mast cells in vitro via inhibition of reactive oxygen species
2013, British Journal of NutritionThe Response of Tissue Mast Cells to TLR3 Ligand Poly(I:C) Treatment
2020, Journal of Immunology Research