Immunology Letters 138 (2011) 28–31                                                               Contents lists available...
E.F. Knol, M. Olszewski / Immunology Letters 138 (2011) 28–31                                        293. Basophilic granu...
30                                                           E.F. Knol, M. Olszewski / Immunology Letters 138 (2011) 28–31...
E.F. Knol, M. Olszewski / Immunology Letters 138 (2011) 28–31                                                       31hapt...
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1 basófilo e mastócitos - primeira apresentação

  1. 1. Immunology Letters 138 (2011) 28–31 Contents lists available at ScienceDirect Immunology Letters journal homepage: and mast cells: Underdog in immune regulation?Edward F. Knol ∗ , Maciej Olszewski 1Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht, The Netherlandsa r t i c l e i n f o a b s t r a c tArticle history: Mast cells and basophilic granulocytes have recently been recognized as potent immunomodulatoryAvailable online 17 February 2011 cells. Whereas these cells originally were described as potent cells that release their pro-inflammatory contents (i.e. histamine) unconstrained after activation, nowadays this process is considered to be muchKeywords: more subtle. Especially, via the release of pro- and anti-inflammatory cytokines basophils and mast cellsMast cells now can steer an immune response. Recently, it has become evident that at least in murine modelsBasophilic granulocytes basophils are crucial for the initial induction of a Th2 response in immunologically naive mouse.Basophils © 2011 Elsevier B.V. All rights reserved.TNFIgEIL-41. Introduction are specialized organelles, found primarily in granulocytes, which possess the unique capability of rapid release. Initial studies of Mast cells and basophilic granulocytes are most recognized for human mast cell granule composition by enzyme-affinity labellingtheir effector roles in the immune response towards parasites and and ultrastructural immunocytochemical techniques allowed forallergens. Both cells are rather unique in the immune system by identification of proteases chymase and tryptase a proinflam-sharing the expression of the high affinity Fc receptor for IgE (Fc␧RI). matory biogenic amine histamine and the proteoglycan heparin.Upon cross linking of IgE on the Fc␧RI by allergen these cells are acti- Subsequently, new techniques allowed for establishing granu-vated and release their inflammatory mediators via degranulation. lar localization of many more mediators, among them severalThe most well-known granule product is histamine. Recently, it has cytokines such as bFGF, SCF, VEGF, IL-4 and TNF [1]. The presence ofbeen demonstrated that both cell types are potent immunomodu- cytokines in granules adds a new dimension to a role of mast cellslating cells, not only via the release of stored and novel synthesized in cytokine biology. Perhaps the best example of novel mechanismscytokines and chemokines, but also via their antigen-presenting in cytokine biology is the role of mast cell granule-derived TNF. Thisproperties. In this review we will discuss in more detail the specific cytokine plays critical role in host defence against bacterial infec-properties of these separate lineage cell types particularly in the tions [2] and its lack results in drastically reduced neutrophil influxcontext of their immunomodulatory functions. and significantly increased mortality of experimental animals. Mast cells are considered the only cells storing preformed TNF. Remark- ably the selective granule targeting of TNF appears to be differently2. Mast cells and their granules regulated in mast cells from human and rat origin [3]. The unique capability of the fast release of a considerable amount of preformed Mast cells are tissue-dwelling cells that are predominantly cytokines might enable mast cells to influence the course of thelocated at the interfaces of the organism and the exterior, such as immune processes being initiated, directing it towards inflamma-skin, gut mucosal membranes and lung. They are evolutionarily old tory or allergic response, depending on the profile of cytokinescells that play multiple roles in many modes of immune response, released.including innate and antibody-dependent reactions. Mast cells Until recently it was unclear how mast cells released cytokinesderive their name from the original name given by Paul Ehrlich, can exert effects in draining lymph nodes. Kunder and cowork-Mastzellen (well-fed cells) reflecting the fact that a mature mast ers demonstrated that mast cell-released TNF is partly packedcell contains large number of cytoplasmic granules. These granules into submicrometer heparin-based particles [4]. Upon their release these stable particles enter the lymphatic vessels and end up in the draining lymph nodes. This is illustrating that in mast cells ∗ Corresponding author. a dedicated physiological drug delivery system facilitating com- E-mail address: (E.F. Knol). munication between peripheral sites of inflammation and remote 1 Current address: Department of Cell Biology, NHLBI, National Institute of Health,Bethesda, United States. secondary lymphoid tissues is active.0165-2478/$ – see front matter © 2011 Elsevier B.V. All rights reserved.doi:10.1016/j.imlet.2011.02.012
  2. 2. E.F. Knol, M. Olszewski / Immunology Letters 138 (2011) 28–31 293. Basophilic granulocytes and their granules eral biologically and clinically important mechanisms of immune response such as allergy, inflammation and, as shown recently, also Basophilic granulocytes (basophils) reside, in contrast to mast immune tolerance [6]. Some of the more important mediators pre-cells, in blood. It was again Paul Ehrlich that first described these stored and synthesized by mast cells and basophils and their majorcells in 1879 as cells in blood that contained granules and stained pathophysiological effects are summarized in Table 2.metachromatically when exposed to basic dyes, naming this set ofgranulocytes basophilic granulocytes. Basophilic granulocytes rep- 5.2. Innate immunityresent only about 0.5% of the leukocyte population in human blood.Basophils are spheric cells with a diameter of about 10 ␮m and a Looking from a broader perspective of host defence especiallymultilobe nucleus. The most evident characteristics of basophils mast cells play several roles in innate and acquired immunity.are the round cytoplasmic granules with diameters up to 1.2 ␮m. Although there is some evidence of mast cells exhibiting directlyWithin the granules histamine is stored, at about 1–2 pg per cell. germicidal activity by phagocytosis or bactericidal peptide release,The characteristic metachromatic staining of basophils is due to several lines of evidence suggest that the most important way bythe presence of proteoglycans in the granule. Basophils release a which mast cells contribute to innate immune response is initia-variety of pre-stored and newly sensitized pro-inflammatory medi- tion and regulation of the magnitude of leukocyte infiltration intoators (e.g. Histamine and LTC4 ) and cytokines (e.g. IL-3, IL-4, IL-13 the site of inflammation. It has been demonstrated using mast-celland VEGF) which are involved in the pathogenesis of allergies. deficient mice that at least TNF and leukotrienes are important fac-The basophil population in blood represent a population that can tors in neutrophil recruitment towards sites of bacterial infectionrapidly migrate in tissues. At tissue sites of allergic inflammation a and mast cells deficiency correlates with much worse prognosismarked influx of basophils can be found. The influx of basophils is in experimentally infected mice. Experiments in other model sys-often accompanied by a simultaneous influx of eosinophilic gran- tems have shown that secretion of TNF and leukotrienes in the acuteulocytes and Th2 lymphocytes. Basophils enter tissue sites within phase of inflammatory processes may also promote influx of leuko-several hours after exposure to allergens. However, it is conceivable cytes other than neutrophils, such as T cells or macrophages whichthat by the time basophils enter these tissues the allergens may well are typical for chronic inflammatory state. Such leukocytes can thenhave been cleared. This evidently leads to the question as to what initiate and maintain features characteristic of the chronic inflam-else, other than allergen-mediated stimulation, can drive basophil matory state. Another function mast cell play in innate responsesactivation following extravasation into tissue sites affected by aller- is limiting the toxicity of certain substances generated by the hostgic inflammation. Recently, it was demonstrated that basophils can which have adverse effects when present in high activated by IL-18 and IL-33 to release large amounts of cytokines An example of such activity is degradation of endothelin-1, a pep-such as IL-4, IL-13, IL-6, IL-9, RANTES, GM-CSF, MIP-1a, MIP1b and tide that is involved in sepsis, by the proteases released from mastMCP-1, but not IL-17, IL-5 and IFN-␥ [5]. cell granules. Mast cells are also capable of releasing mediators influencing (positively or negatively) the transition from innate to acquired immunity. It has been reported that mast-cell derived TNF4. Relation between mast cells and basophils plays a role in draining lymph node hypertrophy and T cell recruit- ment to these nodes in a model of E. coli infection in mouse. This There is much confusion on the relation between basophils and indicates that while there is a mast cell-dependent component inmast cells. It is not uncommon that basophils are mistakenly con- the development of adaptive immune response, the mechanismssidered to be the blood-derived progenitor of tissue mast cells, are likely to be more redundant as compared to innate response.such as the link between monocytes and macrophages. Althoughmast cells and basophils share several unique properties, they are 5.3. IgE-associated adaptive responsesderived from distinct progenitors. Basophils differentiate in bonemarrow and are released in the blood as mature basophils, whereas Another aspect of mast cells and basophils contribution tomast cells progenitors are found in bone marrow and blood, but immune response is their involvement in adaptive immunity. Orig-differentiation of these cells does not occur before entering the inally, these activities were connected to antigen-specific IgE that,tissue. For the development of basophils IL-3 is crucial, whereas when bound to Fc␧RI and crosslinked by an antigen, activate mul-stem cell factor (c-kit ligand) is important for the differentiation tiple pathways in these cells. Recent findings demonstrate, that,of mast cells. The mast cell development in tissue is fine-tuned in mast cells, IgE at high concentrations has more than just a pas-by additional cytokines, such as TGF-␤, IL-4, IL-9 and matrix pro- sively sensitizing activity. Some antibodies are able to elicit fullteins, resulting in different phenotypes of mucosal tissue mast cells responses in the absence of antigen while other only upregulatecompared to connective tissue mast cells. In general it seems that Fc␧RI and enhance mast cells survival. This survival enhancementbasophils are much more related to eosinophils and mast cells are is mediated by autocrine IL-3 stimulation and activation of Bcl-much related to monocytes/macrophages. In Table 1, we provide a xL/Bcl-2. The extent of mast cell activation in absence of antigencomprehensive list of differences between mast cells and basophils. depends on a particular antibody, although the molecular determi- nants of this anti-apoptotic activities are not defined. Additionally,5. Mast cells and basophils in immune responses the increased survival after Fc␧RI stimulation differs between mast cell subpopulations [7].5.1. General remarks It has been widely accepted that mast cells contribute sig- nificantly to acute inflammatory reactions to antigens/allergens Mast cells and basophils are important elements of both innate against which the host bears antibodies of the IgE class. Mastand acquired immunity. They express numerous receptors that, cells are responsible for virtually all of the increased vascular per-when stimulated, may induce production of a plethora of medi- meability and tissue swelling early in the IgE-dependent passiveators. These receptors include IgE and IgG, complement, IL-1, TNF cutaneous anaphylactic response. If the stimulation is of moreand several Toll-like receptors, to name just a few most impor- persistent or more severe nature, acute response may undergo tran-tant. Upon stimulation they can degranulate, release and synthesize sition into late-phase reaction (LPR) which, except for the time scalehighly bioactive, proinflammatory, vasodilative, chemotactic, and ranging from few to several hours from initial antigen challenge, iscytotoxic substances. These cells are crucial for the function of sev- characterized by recruitment of leukocytes to the site of inflamma-
  3. 3. 30 E.F. Knol, M. Olszewski / Immunology Letters 138 (2011) 28–31Table 1Distinct properties of basophils and mast cells. Properties Basophils Mast cellsa Size 7–10 ␮m 14–20 ␮m Nucleus Multi-lobed Single-lobed Granules Fewer and larger than those of mast cells Smaller, more numerous than those of basophils Location Blood, can migrate into tissue Tissue Life span Days Weeks to months Development Maturation site Bone marrow Tissue, progenitors move from bone marrow via blood in tissue Differentiation factors IL-3 Stem cell factor (fine tuning with other local cytokines and tissue matrix Contents Histamine 1–2 pg/cell 1–15 pg/cell Major proteases – Tryptase Arachidonic acid metabolites LTC4 LTC4 , PGD2 , thromboxanes Granule contents Major basic protein, Charcot Leyden crystals No major basic protein or Charcot Leyden crystals Activation fMLP Activation No effect PMA/A23187 Activation by each separate agent Only activation when added together Compound 48/80 No effect Activation Substance P No effect Activation Morphine No effect Activation Pharmacological inhibition H2 agonists Inhibition No effect (also no H2 receptor) Steroids Inhibition No effects Indomethacin Enhances No effects a Within the mast cell population different cell types have been demonstrated. Therefore some of the characteristics given in this table do not account for all mast celltypes.tion. In this chronic response basophils can play an important role 5.4. IgE-independent responsesin the sustained nature of inflammation upon entering the affectedtissue, not only due to the release of stored and newly synthesized Apart from IgE-dependent responses, mast cells and basophilsmediators, such as histamine and LTC4 , but also via the release of have been implicated in pathogenesis of several autoimmune dis-high amounts of the cytokines IL-4 and IL-13 [8]. eases, including multiple sclerosis and rheumatoid arthritis in In this view, a wide range of innate and IgE-associated immune humans and experimental autoimmune encephalomyelitis (EAE)responses appear to represent a situation in which mast cell activ- and IgG1 antibody-dependent autoimmune arthritis in mice.ity, depending on particular circumstances, may be either beneficial Moreover, under some experimental conditions mast cells are nec-or detrimental to the host. essary for complete elicitation of inflammation associated withTable 2Mast cell and basophil mediators. Mediator Major pathophysiologic effect Prestored Biogenic amines Histamine Vasodilation, angiogenesis, mitogenesis, suppressor T-cell activation 5-HT Leukocyte regulation, vasoconstriction, pain Chemokines (IL-8, MCP-1, MCP-3, MCP-4, RANTES) Chemoattraction and tissue infiltration of leukocytes Enzymes Chymase Tissue damage, pain, angiotensin II synthesis Tryptase Activation of PAR, inflammation, pain, tissue damage, degradation of antigens and peptides Kinogenases Synthesis of kinins, pain Nitric oxide synthase NO production Carboxypeptidase A Degrades enzymes Polypeptides CRH Inflammation, vasodilation, mast cell VEGF release Endothelin Sepsis Kinins Inflammation, pain, vasodilation, mast cell trigger Somatostatin (SRIF) Anti-inflammatory (?), mast cell trigger VEGF Neovascularization, vasodilation Proteoglycans Chondroitin sulfate Connective tissue component, anti-inflammatory, mast cell inhibitor Heparin Angiogenesis, NGF stabilization, mast cell inhibitor De novo synthesized Cytokines IL-1, -3, -4, -5, -6, -9, -10, -13, -16, IFN-␥, MIF, TNF Multiple roles Growth factors SCF, GM-CSF, GnRH-I ␤-FGF, NGF, VEGF Growth of a variety of cells, mast cell proliferation Phospholipid metabolites LTB4 Leukocyte chemotaxis LTC4 Vasoconstriction, pain PAF Platelet activation, vasodilation, inflammation PGD2 Bronchoconstriction, pain NO Vasodilation, neuromodulation
  4. 4. E.F. Knol, M. Olszewski / Immunology Letters 138 (2011) 28–31 31hapten-induced contact hypersensitivity (CHS) or asthma and were crucial for the Th2-response because depletion of peripheralinflammatory bowel disease. blood basophils with Mar-1 antibodies blocked the development of Th2 cells. Finally, further evidence for the important role of basophil-derived IL-4 in the induction of Th2-responses was pro-6. Mast cells do also limit inflammation vided by research from the group of Yoshimoto. This group studied the role of basophils in the induction of Th2 responses by infec- Although there is a solid body of evidence that mast cells exert tion with the nematode Strongyloides venezuelensis. In addition, thispredominantly proinflammatory activities, there are a few reports group demonstrated that activation of basophils did not depend onstating otherwise. Examination of biological activity of mast cell the presence of IgE antibodies on their membrane. This can be con-mediators, indicates that some of them, including TGF-␤, IL-4, IL-10 sidered an important finding because it indicates that basophilsand histamine have potentially anti-inflammatory activity. The first might be responsible for the initial induction of of such activity of mast cells in knockin mouse concerned Since the time that IL-4 has been demonstrated as mast cell andUV-induced suppression of contact hypersensitivity to DNFB that basophil products, now almost 20 years ago, it has been hypothe-was, at least partly, mediated by IL-10. It has also been demon- sized that these cells are important in the early induction of Th2strated, that mice that were bitten by a mosquito display lowered cells and the development of allergy. However, convincing stud-antigen-specific T cell responses in the model of delayed hypersen- ies were not yet published. In the three papers described abovesitivity to OVA and that this phenomenon requires mast cells at the clear indications are provided that basophilic granulocytes inducesite of the bite. The mechanism of this regulatory activity remains TH2 responses via the peptide presentation on MHC-II and simul-unknown. The results of yet another study show that mast cells taneous release of IL-4. Extrapolation of these results obtained inare necessary for peripheral tolerance to skin allografts. In toler- mouse models towards human is not clear yet. Expression of MHC-IIant mice considerable increase of mast cell-specific transcripts and on human basophils has not been convincingly demonstrated andnumber of mast cells was observed. This increase correlates with the mouse basophils appear to be morphologically distinct fromthe influx to the graft of IL-9-producing CD4+ Foxp3+ T cells. Mast the human basophils. It will probably be shortly before follow-upcell-deficient mice cannot be tolerized and experience rapid graft papers will address the potency of human basophils.rejection, which can be prevented by local skin reconstitution withmast cells. IL-9 released by Tregs is the major mediator of mast cells 8. Final conclusionrecruitment and activation in the dermis of these tolerant grafts.Mast cells may then act by limiting the influx of inflammatory T Mast cells and basophils have long been considered to be smallcells or cooperating with dermal Tregs. Unexpected as it sounds, bags filled with potent inflammatory mediators that were releasedmast cells do contain TGF-␤ that is a major Tregs inducing factor. after a specific stimulation. Especially in the context of allergicEven in the response to cobra venom and bee venom it was found inflammation these cells are thought to be crucial in the initi-in mice that the presence of mast cells was an important factor in ation and maintenance of the inflammatory reactions. Recently,limiting the pathologic effects. Most likely this limitation was due much more subtle roles of these cells have been demonstrated, notto release of carboxypeptidase A and possibly other proteases by only via the large numbers of cytokines and chemokines that thesethe mast cells. cells can produce, but also via their pro- and anti-inflammatory In conclusion, mast cell activators may yield pro- or functions. In addition, most pronounced for the basophils, there isanti-inflammatory responses [9]; most probably are the pro- a potent antigen-presenting cell activity described that togetherinflammatory effect most pronounced in the earlier phase of the with the release of IL-4 might be important for the very earlyresponse and is the anti-inflammatory effects more pronounced at Th2 skewing of the immune response towards allergens and para-the later phase of the response to limit ongoing inflammation. sites.7. Basophils are important cells in the induction of an Referencesallergic immune response via their Th2-skewing, antigenpresenting functional capacity [1] Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M. Mast cells as “tunable” effector and immunoregu- latory cells: recent advances. Annu Rev Immunol 2005;23:749– In the summer of 2009 in Nature Immunology a rather unique 86.three-fold back-to-back set of papers has been published, all [2] Malaviya R, Ikeda T, Ross E, Abraham SN. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha. Naturedescribing a breakthrough in the important role of basophils in the 1996;381:77–80.induction of allergic immune responses. The take home message of [3] Olszewski MB, Groot AJ, Dastych J, Knol EF. TNF trafficking to humanthese papers is that basophilic granulocytes not only have the abil- mast cell granules: mature chain-dependent endocytosis. J Immunolity to function as antigen presenting cells, but they also promote 2007;178(9):5701–9. [4] Kunder CA, St John AL, Li G, Leong KW, Berwin B, Staats HF, et al. Mast cell-Th2-responses [10]. Sokol and colleagues studied the strong Th2 derived particles deliver peripheral signals to remote lymph nodes. J Exp Medresponse induced by papain in mice. In their setup papain mim- 2009;206(11):2455–67.icked the protease activity of allergens and parasites. Remarkably [5] Knol EF, Gibbs BF. Basophil survival and immunomodulatory function are uniquely regulated by a novel MyD88-dependent pathway. J Leukoc Biolwas that removal of classic antigen presenting cells did not affect 2009;86(4):753–5.the Th2 response but diminished the induction of both Th1 and [6] Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, et al.Th17 responses. The presence of basophils turned out to be crucial Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 2006;442(7106):997–1002.for the induction of the Th2 responses. The authors demonstrated [7] Kawakami T, Kitaura J. Mast cell survival and activation by IgE in the absence ofthat basophils not only expressed MHC-II molecules, they also con- antigen: a consideration of the biologic mechanisms and relevance. J Immunoltained the machinery to take up, process and present antigens to T 2005;175(7):4167–73. [8] Falcone FH, Haas H, Gibbs BF. The human basophil: a new appreciation of itscells on MHC-II molecules. In addition, Perrigoue et al. studied Th2 role in immune responses. Blood 2000;96(13):4028–38.responses that were induced via infection with the gastrointesti- [9] Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: negative, asnal nematode parasite Trichuris muris. They also demonstrated that well as positive, regulators of immunity. Nat Rev Immunol 2008;8(6):478–86. [10] Wynn TA. Basophils trump dendritic cells as APCs for T(H)2 responses. Natbasophils present the antigenic peptides of the parasite on MHC-II Immunol 2009;10(7):679–81.molecules to naïve T cells. Via the simultaneous release of IL-4 thebasophils skewed the T cells towards the Th2 phenotype. Basophils