Roles of mast cells and basophils in innate and acquired immunity

doi:10.1016/S0952-7915(00)00154-0

Current Opinion in Immunology

Volume 12, Issue 6, 1 December 2000, Pages 624-631

https://doi.org/10.1016/S0952-7915(00)00154-0 Get rights and content

Abstract

There have been several recent advances in knowledge about mast cells and basophils in immune responses, of which some are particularly important: a role has been found for heparin in the storage of certain proteases and other mediators in mast cell cytoplasmic granules; an important role for mast cells in the development of several chronic aspects of an asthma model in mice has been discovered; and a new approach has been developed, based on the generation of mast cells from embryonic stem cells in vitro, to investigate mast cell function in vitro or in vivo.

Introduction

Mast cells and basophils share a number of similarities but they also differ in many aspects of natural history and function. Both cell types express the αβγ₂ form of the high-affinity receptor for IgE (FcεRI) on their surface and both mast cells and basophils can be activated to secrete diverse preformed mediators and lipid mediators (the latter are synthesized de novo), as well as cytokines, after crosslinking of FcεRI-bound IgE with bivalent or multivalent antigen. However, recent work shows that mast cells can also play a critical role in innate immunity to bacterial infection and that mast cells and basophils can be activated by viral proteins. This review will discuss recent advances in our understanding of the effector and the potential immunoregulatory functions of mast cells and basophils during innate or acquired immune responses.

Mast cells and basophils not only are important effector cells in acute IgE-associated allergic reactions but also may contribute significantly to the expression of aspects of acquired immune responses that develop over hours (e.g. late-phase reactions [LPRs]) or days to weeks (e.g. chronic allergic inflammation) [1], [2], [3], [4], [5] (Fig. 1). Mast cells and basophils may also mediate immunoregulatory functions, both through their ability to produce certain cytokines and by other mechanisms [1], [2], [3], [4], [5], [6]. Before we discuss the potential roles of mast cells and basophils in acquired or innate immunity, we will provide some background on the biology of these two cell types.

Section snippets

Basic mast cell and basophil biology

Both mast cells and basophils are derived from CD34⁺ hematopoietic progenitor cells, such as those present in adult bone marrow; however, mast cells and basophils differ in natural history. Whereas basophils (like other granulocytes) typically mature in the bone marrow and then circulate in the peripheral blood, from where they can then be recruited into the tissues, mature mast cells typically do not circulate in the blood but complete their differentiation in vascularized tissues [1]. Under

Genetic approaches in studies of mast cell or basophil function

A particularly useful approach to study mast cell function in vivo is to employ genetically mast-cell-deficient WBB6F₁-Kit^W/Kit^W-v mice (W/W^v mice), which lack expression of a functional c-kit receptor due to spontaneous mutations in both copies of c-kit [9], [17]. The mast cell activity in these W/W^v mice can be selectively reconstituted by the adoptive transfer of genetically compatible, in-vitro-derived mast cells; such mast cells can be derived in at least two ways: firstly, from the bone

Mast cells and basophils in acquired immunity

The best-studied forms of acquired immunity involving mast cells and basophils are examples of IgE-associated immune responses. The aggregation of FcεRIs that are occupied by IgE (e.g. following binding of IgE to multivalent antigens) is sufficient for initiating downstream signaling pathways that activate the cells to degranulate and also induce the de novo synthesis and secretion of lipid mediators and cytokines [20], [21], [22].

In vitro and in vivo studies in both mice and humans have

IgE-associated immune responses

Studies in ‘mast cell knockin’ mice show that mast cells are essential for virtually all of the augmented vascular permeability and tissue swelling that are associated with IgE-dependent passive cutaneous anaphylaxis reactions [1]. Several findings indicate that mast cells are critical for the immediate phase of IgE-associated ‘Type I’ reactions in humans as well [1], [2], [3], [4], [5], [31]. However, in many allergic patients, the immediate reaction to cutaneous antigenic challenge is

Host defense against parasites

Parasite infections are often associated with increased levels of circulating basophils and eosinophils, markedly increased serum levels of IgE (and therefore enhanced expression of FcεRI on basophils and mast cells) and increased numbers of mast cells and/or basophils in the affected tissues [1], [2], [3], [4], [5].

Although it has been difficult to prove that individual components of IgE-associated immune responses to parasites are truly essential for the expression of host immunity, W/W^v mice

Mast cells and basophils in innate immunity

‘Mast cell knockin’ mice were used to show that mast cells can represent a central component of innate host defense against certain bacterial infections, that the recruitment of circulating leukocytes with bactericidal properties is dependent on mast cells and that TNF-α is one important element of this response [10], [45], [46]. Whereas certain bacterial products—including lipopolysaccharide and at least one fimbrial adhesin [47 radical dot ]—can directly induce the release of some mast cell products,

Additional pathways for eliciting mast cell and/or basophil function during immune responses

Human basophils have been shown to respond to stimulation with immobilized secretory IgA (sIgA) by releasing both histamine and LTC₄; however, this only occurs if the cells had first been primed by pretreatment with IL-3, IL-5 or GM-CSF [49]. Since IgA is the most abundant immunoglobulin isotype in mucosal secretions, this finding suggests that sIgA may contribute to basophil activation during immune responses at mucosal sites [49].

Protein L of Pneumococcus magnus and Protein A of

Conclusions

It seems very likely that mast cells and basophils express complex—and partially overlapping—roles in acquired and innate immunity (Fig. 4); these roles include both effector cell and, potentially, immunoregulatory activities.

Studies in mast-cell-reconstituted, genetically mast-cell-deficient mice—and correlative analyses in humans—indicate that mast cells can contribute to leukocyte infiltration, tissue remodeling and long-term functional changes in the context of IgE-associated acquired

Acknowledgements

Some of the work reviewed herein was supported by United States Public Health Service grants CA 72074, AI 23990 and AI 41995 (project 1), by Deutsche Forschungsgemeinschaft grant WE 2300/1 and/or by AMGEN Inc. SJG consults for AMGEN Inc. under terms that are in accordance with Stanford University conflict-of-interest policies.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

of special interest
of outstanding interest

References (55)

CMM Williams et al.
The diverse potential effector and immunoregulatory roles of mast cells in allergic disease
J Allergy Clin Immunol
(2000)
S Mecheri et al.
Unravelling the mast cell dilemma: culprit or victim of its generosity?
Immunol Today
(1997)
P Valent et al.
Interleukin-3 is a differentiation factor for human basophils
Blood
(1989)
SJ Galli et al.
Mast cells as sentinels of innate immunity
Curr Opin Immunol
(1999)
MA Beaven et al.
Signal transduction by Fc receptors: the FcεRI case
Immunol Today
(1993)
DL Sylvestre et al.
A dominant role for mast cell Fc receptors in the Arthus reaction
Immunity
(1996)
BK Wershil et al.
Mast cell-dependent neutrophil and mononuclear cell recruitment in immunoglobulin E-induced gastric reactions in mice
Gastroenterology
(1996)
E Ruoslahti et al.
Proteoglycans as modulators of growth factor activities
Cell
(1991)
EB Steeves et al.
Basophils in skin reactions of mast cell-deficient mice infested with Dermacentor variabilis
Int J Parasitol
(1990)
BK Wershil et al.
Direct evidence of mast cell involvement in Clostridium difficile toxin A-induced enteritis in mice
Gastroenterology
(1998)

Galli SJ, Lantz CS: Allergy. In Fundamental Immunology, edn 4. Edited by Paul WE. Philadelphia: Lippincott-Raven Press;...

Schwartz LB, Huff TF: Biology of mast cells. In Allergy: Principles and Practice, edn 5. Edited by Middleton EJ, Reed...

DD Metcalfe et al.

Mast cells

Physiol Rev

(1997)

SJ Galli

Mast cells and basophils

Curr Opin Hematol

(2000)

CS Lantz et al.

Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites

Nature

(1998)

SJ Galli et al.

The kit ligand, stem cell factor

Adv Immunol

(1994)

T Brunner et al.

Human peripheral blood basophils primed by interleukin 3 (IL-3) produce IL-4 in response to immunoglobulin E receptor stimulation

J Exp Med

(1993)

D Jr MacGlashan et al.

Secretion of IL-4 from human basophils. The relationship between IL-4 mRNA and protein in resting and stimulated basophils

J Immunol

(1994)

H Li et al.

IL-13 released by and localized in human basophils

J Immunol

(1996)

DE Humphries et al.

Heparin is essential for the storage of specific granule proteases in mast cells

Nature

(1999)

E Forsberg et al.

Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme

Nature

(1999)

L Li et al.

Identification of basophilic cells that express mast cell granule proteases in the peripheral blood of asthma, allergy, and drug-reactive patients

J Immunol

(1998)

K Nocka et al.

Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W³⁷, W^v, W⁴¹ and W

EMBO J

(1990)

M Tsai et al.

In vivo immunological function of mast cells derived from embryonic stem cells: an approach for the rapid analysis of even embryonic lethal mutations in adult mice in vivo

Proc Natl Acad Sci USA

(2000)

M Maurer et al.

The c-kit ligand, stem cell factor, can enhance innate immunity through effects on mast cells

J Exp Med

(1998)

J-P Kinet

The high-affinity IgE receptor (FcεRI): from physiology to pathology

Annu Rev Immunol

(1999)

H Turner et al.

Signalling through the high-affinity IgE receptor FcεRI

Nature

(1999)

Cited by (292)

Ursodeoxycholic acid alleviates atopic dermatitis-associated inflammatory responses in HaCaT and RBL-2H3 cells and DNCB/DFE-treated mice
2024, Life Sciences
Ursodeoxycholic acid (UDCA) is a hydrophilic dihydroxy bile acid used for cholestatic liver disease and exhibits antioxidant, antitumor, and anti-inflammatory effects. However, its potential effects on atopic dermatitis (AD) have not been elucidated. This study aimed to evaluate the efficacy of UDCA in inhibiting the inflammatory response and alleviating lesions in AD-like mice.
To investigate the efficacy of UDCA in AD-like inflammatory responses, tumor necrosis factor-alpha (TNF-α)- and interferon-gamma (IFN-γ)-stimulated HaCaT cells and anti-dinitrophenyl immunoglobulin E (DNP-IgE)- and human serum albumin (HSA)-stimulated RBL-2H3 cells were used to investigate the levels of inflammatory factors and their mechanisms. AD-like lesions were induced by applying DNCB/DFE to mice. The effect of UDCA administration in AD-like mice was analyzed by assessing organ weight, serum IgE and inflammatory cytokine levels, and histopathological changes using immunohistochemical and immunofluorescent staining.
In HaCaT cells, UDCA significantly diminished TARC, MDC, MCP-1, and IL-6 expression by inhibiting the phosphorylation of nuclear NF-κB and cytoplasmic IκB, and also increased the levels of skin barrier protein. In RBL-2H3 cells, UDCA reduced β-hexosaminidase and IL-4 levels. In AD-like mice, UDCA suppressed organ hypertrophy, ear edema, SCORAD index, DFE-specific IgE levels, inflammatory cytokine levels, skin hypertrophy, mast cell invasion, skin barrier loss, and thymic stromal lymphopoietin-positive areas.
UDCA suppressed the expression of pro-inflammatory cytokines by keratinocytes and mast cells. It also alleviated atopy by suppressing symptoms without organ toxicity in AD-like mice. UDCA may be an effective and safe treatment for AD.
Mouse hygiene status–A tale of two environments for mast cells and allergy
2024, Allergology International
Animal models, including those employing the use of house mice (Mus musculus), are crucial in elucidating mechanisms in human pathophysiology. However, it is evident that the impreciseness of using laboratory mice maintained in super-hygienic barrier facilities to mirror relevant aspects of human physiology and pathology exists, which is a major limitation in translating mouse findings to inferring human medicine. Interestingly, free-living wild mice are found to be substantially different from laboratory-bred, specific pathogen-free mice with respect to various immune system compartments. Wild mice have an immune system that better reflects human immunity. In this review article, we discuss recent experimental findings that address the so-called “wild immunology”, which reveals the contrasting immune features between laboratory-raised mice and their wild companions as well as laboratory mice that have been exposed to a natural rodent habitat. A particular focus will be given to the development of pulmonary mast cells and its possible impact on the use of “naturalized” or “rewilded” laboratory mice as experimental asthma models.
The basophil: From control of immunity to control of leukemias
2022, Annales Pharmaceutiques Francaises
Les polynucléaires basophiles, décrits pour la première fois par Paul Ehlrich en 1879, sont des cellules circulantes rares, représentant environ 0,01 à 0,3 % des leucocytes sanguins. Jusqu’à récemment, ces cellules ont été négligées en raison de leur statut minoritaire parmi les cellules immunitaires et parce qu’elles présentent certaines similitudes avec les mastocytes résidant dans les tissus. Toutefois, les basophiles et les mastocytes sont maintenant reconnus comme des lignées cellulaires différentes et il apparaît que les basophiles exercent des fonctions importantes et non redondantes, distinctes de celles des mastocytes. D’une part, les basophiles contribuent de manière bénéfique à l’immunité protectrice, en particulier contre les infections parasitaires. D’autre part, les basophiles sont impliqués dans le développement de diverses pathologies bénignes ou malignes, allant de l’allergie à certaines leucémies. En effet, les basophiles interagissent avec d’autres cellules immunitaires normales ou avec des cellules néoplasiques par le biais de contacts directs ou de médiateurs solubles, tels que des cytokines et des protéases, contribuant ainsi à la régulation du système immunitaire mais aussi aux réponses allergiques et probablement aux processus de transformation néoplasique. Dans cette revue, nous développerons les connaissances récentes portant sur l’implication des basophiles dans la modulation de l’immunité innée et adaptative. Nous évoquerons ensuite les circonstances bénignes ou malignes dans lesquelles une élévation des basophiles circulants peut être constatée. Enfin, nous aborderons le rôle joué par ces cellules dans la physiopathologie de certaines leucémies, en particulier au cours de la leucémie myéloïde chronique.
The basophils, first described by Paul Ehlrich in 1879, are rare circulating cells, representing approximately 0.01 to 0.3% of the blood leukocytes. Until recently, these cells have been neglected because of their minority status among immune cells and because they show some similarities to mast cells residing in tissues. However, basophils and mast cells are now recognized as distinct cell lines and it appears that basophils have important and non-redundant functions, distinct from those of mast cells. On the one hand, basophils have beneficial contribution to protective immunity, in particular against parasitic infections. On the other hand, basophils are involved in the development of various benign and malignant pathologies, ranging from allergy to certain leukemias. Basophils interact with other immune cells or neoplastic cells through direct contacts or soluble mediators, such as cytokines and proteases, thus contributing to the regulation of the immune system but also to allergic responses, and probably to the process of neoplastic transformation. In this review, we will develop recent knowledge on the involvement of basophils in the modulation of innate and adaptive immunity. We will then describe the benign or malignant circumstances in which an elevation of circulating basophils can be observed. Finally, we will discuss the role played by these cells in the pathophysiology of certain leukemias, particularly during chronic myeloid leukemia.
Pro-inflammatory response induced by the venom of Parachartergus fraternus wasp
2021, Toxicon
The sting of different wasp species triggers local and systemic reactions in victims that can lead to death. Parachartergus fraternus is responsible for frequent accidents in Latin America; however, few studies have been conducted on this insect and its venom. In this study, the inflammatory process induced by the venom of the P. fraternus wasp (Pfv; 100, 200, and 400 μg/kg) was characterized. Mice were used to assess paw edema, vascular permeability, mast cell degranulation, leukocyte influx, nitric oxide (NO) production, expression of inflammatory genes, and histopathological changes. Pfv triggered edema formation with a peak dose of 200 μg/kg at 10 min. There was an increase in permeability in all periods and doses evaluated, with no differences between them. The 200 μg/kg dose induced mast cell degranulation in all periods, with a peak at 15 min. This same dose induced leukocyte influx with a predominance of mononuclear cells and triggered a peak in NO production in the 12th hour. The increase in COX-2, iNOS, and IFN-γ mRNA expression occurred after 1 and 6 h, and there was an increase in IL-10 expression after 48 h. In addition, Pfv triggered edema and induced an influx of macrophages and mast cells into the injection site. Therefore, Pfv induces an inflammatory process from the first 5 min of inoculation that can persist for up to 48 h.
Leukotriene D<inf>4</inf> role in allergic asthma pathogenesis from cellular and therapeutic perspectives
2020, Life Sciences
Citation Excerpt :
c-KIT receptors belong to the tyrosine kinase receptor family that dimerize or oligomerize upon ligand binding leading to the cross phosphorylation of the intrinsic tyrosine domains and downstream activation of multiple signaling pathways [54]. MCs mediate their role in allergic diseases such as asthma through the activation of their surface-expressed high-affinity receptors for IgE (FcεRI) [55]. In asthma, MCs are sensitized by binding of IgE to the FcεR1.
Asthma is a chronic inflammatory and allergic disease that is mainly characterized by reversible airway obstruction and bronchial hyperresponsiveness. The incidence of asthma is increasing with more than 350 million people worldwide are affected. Up to now, there is no therapeutic option for asthma and most of the prescribed drugs aim to ameliorate the symptoms of the disease especially during the acute exacerbations after trigger exposure. Asthma is a heterogonous disease that involves interactions between inflammatory mediators and cellular components within the disease microenvironment including inflammatory and structural cells. Cysteinyl leukotrienes (cys-LTs) are inflammatory lipid mediators that have potent roles in asthma pathogenesis. CysLTs consisting of LTC₄, LTD₄, and LTE₄ are mainly secreted by leukocytes and act through three main G-protein coupled receptors (CysLT₁R, CysLT₂R, and CysLT₃R). LTD₄ is the most potent bronchoconstrictor which gives it the priority to be discussed in detail in this review. LTD₄ binds with high affinity to CysLT₁R and many studies showed that using CysLT₁R antagonists such as montelukast has a beneficial effect for asthmatics especially in corticosteroid refractory cases. Since asthma is a heterogeneous inflammatory disease of many cell types involved in the disease pathogenies and LTD₄ has a special role in inflammation and bronchoconstriction, this review highlights the role of LTD₄ on each cellular component in asthma and the benefits of using CysLT₁R antagonists in ameliorating LTD₄-induced effects.
Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice
2020, Blood Advances
The family of nuclear factor of activated T cells (NFAT) transcription factors plays a critical role in mediating immune responses. Our previous clinical pharmacogenetic studies suggested that NFATC2 is associated with the risk of hypersensitivity reactions to the chemotherapeutic agent L-asparaginase (ASNase) that worsen outcomes during the treatment of pediatric acute lymphoblastic leukemia. We therefore hypothesized that the genetic inhibition of NFATC2 would protect against the development of anti-ASNase antibodies and ASNase hypersensitivity. Our study demonstrates that ASNase-immunized NFATC2-deficient mice are protected against ASNase hypersensitivity and develop lower antigen-specific and total immunoglobulin E (IgE) levels compared with wild-type (WT) controls. Furthermore, ASNase-immunized NFATC2-deficient mice develop more CD4⁺ regulatory T cells, fewer CD4⁺ interleukin-4–positive (IL-4⁺) cells, higher IL-10/TGF-β1 levels, and lower IL-4/IL-13 levels relative to WT mice. Basophils and peritoneal mast cells from ASNase-immunized, but not naïve, NFATC2-deficient mice had lower FcεRI expression and decreased IgE-mediated mast cell activation than WT mice. Furthermore, ASNase-immunized, but not naïve, NFATC2-deficient mice developed less severe shock than WT mice after induction of passive anaphylaxis or direct histamine administration. Thus, inhibition of NFATC2 protects against ASNase hypersensitivity by impairing T helper 2 responses, which may provide a novel strategy for attenuating hypersensitivity and the development of antidrug antibodies, including to ASNase.

View all citing articles on Scopus

View full text

ReviewRoles of mast cells and basophils in innate and acquired immunity

Abstract

Introduction

Section snippets

Basic mast cell and basophil biology

Genetic approaches in studies of mast cell or basophil function

Mast cells and basophils in acquired immunity

IgE-associated immune responses

Host defense against parasites

Mast cells and basophils in innate immunity

Additional pathways for eliciting mast cell and/or basophil function during immune responses

Conclusions

Acknowledgements

References and recommended reading

J Allergy Clin Immunol

Immunol Today

Blood

Curr Opin Immunol

Immunol Today

Immunity

Gastroenterology

Cell

Int J Parasitol

Gastroenterology

Mast cells

Physiol Rev

Mast cells and basophils

Curr Opin Hematol

Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites

Nature

The kit ligand, stem cell factor

Adv Immunol

Human peripheral blood basophils primed by interleukin 3 (IL-3) produce IL-4 in response to immunoglobulin E receptor stimulation

J Exp Med

Secretion of IL-4 from human basophils. The relationship between IL-4 mRNA and protein in resting and stimulated basophils

J Immunol

IL-13 released by and localized in human basophils

J Immunol

Heparin is essential for the storage of specific granule proteases in mast cells

Nature

Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme

Nature

Identification of basophilic cells that express mast cell granule proteases in the peripheral blood of asthma, allergy, and drug-reactive patients

J Immunol

Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W

EMBO J

In vivo immunological function of mast cells derived from embryonic stem cells: an approach for the rapid analysis of even embryonic lethal mutations in adult mice in vivo

Proc Natl Acad Sci USA

The c-kit ligand, stem cell factor, can enhance innate immunity through effects on mast cells

J Exp Med

The high-affinity IgE receptor (FcεRI): from physiology to pathology

Annu Rev Immunol

Signalling through the high-affinity IgE receptor FcεRI

Nature

Review
Roles of mast cells and basophils in innate and acquired immunity

Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W³⁷, W^v, W⁴¹ and W