ReviewThe role of mast cells in allergy and autoimmunity
Introduction
There is a well-established paradigm of mast cell development and function. Mast cells are derived from CD34+ hematopoietic progenitor cells and initiate their differentiation in the bone marrow under the influence of c-kit ligand (stem cell factor) and IL-3 [1]. Similar to dendritic cells (DCs) and tissue macrophages, mast cells do not circulate in the blood. High affinity IgE receptor positive (FcεRI+), c-kit+ bone marrow-derived mast cell precursors migrate to vascularized regions of the body and exist as fixed cells where they complete their differentiation under the influence of a unique array of differentiation and growth factors present at each tissue site [2]. Mast cells are often associated with blood vessels and found within mucosal surfaces of the gastrointestinal and respiratory tracts, in the skin and in close proximity to peripheral nerves. Less appreciated is their prevalence in the central nervous system (CNS), where they are concentrated in the leptomeninges, hypothalamus, thalamus and habenula of the brain as well as in the spinal cord dura mater 3., 4.. There are well-defined differences in the array of mediators expressed by distinct mast cell populations found in connective tissue versus muscosal sites 2., 5..
It has long been recognized that mast cells play a direct and pathologic role in the inflammatory processes associated with allergic disease (for a review, see [6]). These include effects on acute local and systemic responses, such as allergic rhinitis and anaphylaxis, as well as on late phase responses and chronic asthma. These pathologic responses are dominated by Th2 cells and are dependent on the ability of antigen-specific IgE to bind to FcεRI expressed on mast cells. Cross-linkage of FcεRI results in activation of the mast cell and the initiation of a signal transduction cascade that leads to the release of two general classes of mediators upon subsequent antigen exposure. Hallmark mast cell molecules, such as TNF-α, IL-4, histamine, heparin, serotonin, kinins and proteases, are preformed and are released immediately upon activation of the mast cell. A second class of newly synthesized mediators includes the interleukins 1–8, TNF-α, IL-12, IL-13, IL-15 and IL-16, chemokines, and growth and angiogenesis factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), as well as prostaglandins and leukotrienes. Together these molecules have profound effects on inflammatory cell activation and recruitment (through effects on endothelium adhesion molecule expression, chemokine production or vascular permeability) as well as smooth muscle contraction associated with allergic disease.
Mast cells also provide immune protection in some settings. IgE-mediated mast cell responses are thought to have evolved as the major defense mechanism against parasites. Protective Th2-dominated immune responses which result in IgE production dominate in parasitic infections, a situation best characterized in the setting of Nippostrongylus brasiliensis infections [7]. In addition, TNF-α production by mast cells is essential for protective immunity to certain bacterial infections of the respiratory and gastrointestinal tracts 8., 9.. Th2 cytokine production by mast cells, notably IL-4, might downregulate the development or effector function of Th1 cells, thus playing an important immunoregulatory role.
Despite the well-characterized role of FcεRI-mediated mast cell activation, there are a variety of other agonists that lead to the activation of mast cells. Cross-linking of IgG can activate mast cells [10]. In addition, studies have shown that several Ig-independent activation pathways exist. Toll-like receptors (TLRs) that recognize specific molecular patterns associated with microbes are expressed on mast cells and activate pro-inflammatory cytokine production and migratory function 11••., 12••.. Helicobacter pylori, Staphylococcus aureus, lipopolysaccharide, Fim H ( a bacterial adhesion molecule; [13]) and Salmonella typhimurium (M Sherman, personal communication), are among the microbial products that stimulate mast cells; presumably through the TLRs. Mast cells are also activated by complement 14., 15., 16., neuropeptides [17] and components of the myelin sheath such as myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) (V Secor, personal communication; [18]). The identification of Ig-independent stimulators of mast cell activation is significant for at least two reasons: first, these data indicate that mast cells can act at the earliest stages of an immune response, before the development of adaptive immune responses that are necessary for B cell isotype switching and subsequent Fc receptor-mediated activation; second, mast cells are located at the interfaces of the host with its external environment, and they probably make a major contribution to the first line of host defense via their direct activation by pathogens.
Section snippets
Autoimmunity as an inflammatory disease
The term autoimmunity refers to a wide spectrum of diseases that vary in aetiology, target organ involvement and symptomology [19]. However, all of these diseases are characterized by the presence of clonally expanded populations of self-reactive lymphocytes; cells that have escaped negative selection during development. Self-reactive T and B cells are activated to express their effector function upon encounter with their target self-antigens only under fairly restricted conditions. Because
Mast cells: a role in autoimmune disease?
The existing evidence that mast cells play a role in autoimmune diseases is largely indirect and relatively scant. Mast cell infiltrates have been found in the salivary glands of patients with Sjogren's syndrome [27]. A variety of studies have documented the presence of mast cells or mast cell mediators in the synovial fluid of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) 28., 29., 30., 31., 32.. The best correlative evidence comes from studies of mast cells
Mast cells as modulators of inflammation associated with autoimmunity
The widespread distribution of mast cells and the recent appreciation of the myriad of immunologically important molecules expressed by these cells strongly suggest the potential for mast cells to exert both parallel and unique effects in the inflammatory processes that accompany autoimmune diseases when compared to DCs and other cells of the innate immune system (see Fig. 1). At early stages in the generation of an infection-associated autoreactive response, mast cells may be directly
Autoimmunity, an ‘allergic’ disease?
Many autoimmune diseases including MS, RA and diabetes are defined by a pathogenic CD4+ Th1 type response and a protective immune deviation towards a Th2 response. However, it is becoming increasingly apparent that we can no longer consider the destructive phase of these diseases to be strictly Th1 mediated, as there is an emerging role for Th2 cytokines in disease pathogenesis. Recent clinical trials focused on treating MS with an altered peptide ligand regime aimed at skewing the Th cell
Conclusions
Although mast cells have been well characterized in the context of Th2-type allergic responses, it is important to consider the often-overlooked impact that mast cells may play in autoimmune diseases. The variety of potent pro-inflammatory mediators expressed by mast cells and the widespread tissue distribution of these cells make them excellent candidates for modulating autoimmune responses, especially those that are associated with infection and modulated by inflammation. We propose that mast
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 (52)
- et al.
Mast cells in the brain: evidence and functional significance
Trends Neurosci
(1996) - et al.
The diverse potential effector and immunoregulatory roles of mast cells in allergic disease
J Allergy Clin Immunol
(2000) - et al.
Activating and inhibitory signaling in mast cells: new opportunities for therapeutic intervention
J Allergy Clin Immunol
(2000) - et al.
Complement peptides C3a- and C5a-induced mediator release from dissociated human skin mast cells
J Invest Derm
(1994) - et al.
Mast cells in experimental allergic encephalomyelitis: characterization, distribution in the CNS and in vitro activation by myelin basic protein and neuropeptides
J Neurosci
(1994) Molecular mimicry and autoimmune disease
Cell
(1987)- et al.
Molecular mimicry in T cell mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein
Cell
(1995) - et al.
The mast cells of the multiple sclerosis brain
J Neuroimmunol
(1996) - et al.
The role of mast cells in demyelination. 1. Myelin proteins are degraded by mast cell proteases and myelin basic protein and P2 can stimulate mast cell degranulation
Brain Res
(1988) - et al.
Mast cell proteases liberate stable encephalitogenic fragments from intact myelin
Cell Immunol
(1991)
Treatment of experimental allergic neuritis with nedocromil sodium, an anti-inflammatory drug with mast cell stabilizing properties
J Neuroimmunol
Identification of a committed precursor for the mast cell lineage
Science
Mast cell and basophil development
Curr Opin Hematol
Interactions of mast cells with the nervous system-recent advances
Neurochem Res
Heterogeneity of mast cells and phenotypic changes between subpopulations
Annu Rev Immunol
Infection with Nippostrongylus brasiliensis or injection of anti-IgD antibodies markedly enhances Fc-receptor-mediated interleukin 4 production by non-B, non-T cells
J Exp Med
Critical protective role of mast cells in a model of acute septic peritonitis
Nature
Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha
Nature
Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity
J Clin Invest
Cutting Edge: VacA, a vacuolating cytotoxin of Helicobacter pylori, directly activates mast cells for migration and production of proinflammatory cytokines
J Immunol
Mast cell degranulation induced by type 1 fimbriated Escherichia coli in mice
J Clin Invest
C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils
Blood
Differential expression of complement receptors on human basophils and mast cells
J Immunol
Substance P selectively activates TNF-α gene expression in murine mast cells
J Immunol
Autoimmune disease: why and where it occurs
Nat Med
Autoimmunity through infection or immunization?
Nat Immunol
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