The role of Th2 cytokines in mast cell homeostasis

Summary: Homeostatic mechanisms regulating mast cell numbers and function in peripheral tissues have largely focused on cytokines, such as stem cell factor, interleukin (IL)-3, IL-4, and IL-10, which regulate mast cell maintenance and proliferation. Despite these advances, little attention has been paid to the mechanisms that mediate mature mast cell turnover, and control of mast cell hyperplasia generated during Th2-mediated responses. These are important issues, as mast cells are now known to be multi-functional effector cells, that have the capacity to mediate both innate and Th2-induced immune responses. Numerous secretagogues may elicit mast cells to release a large number of important mediators that can cause chronic inflammation. Therefore, how mast cell homeostasis is regulated may have significant effects on normal physiology, and contribute to the genesis of inflammatory disease. Our laboratory has characterized an in vitro model of mast cell homeostasis, by which long-term exposure of murine bone-marrow-derived mast cells to the Th2-derived cytokines IL-3, IL-4, and IL-10, will induce downregulation of critical mast cell effector proteins such as Kit and FcεRI, followed by mast cell apoptosis. These data offer a novel role for Th2 cytokines, acting to both initiate and resolve mast cell activation and proliferation. Loss of these signals may contribute to a multitude of diseases, such as mastocytosis and allergy.     

Manipulation of signaling to control allergic inflammation

PURPOSE OF REVIEW: Inflammatory mediators produced from activated mast cells and T helper type 2 cells drive allergic inflammation. The pathways required for mast and T helper type 2 cell activation and the effects of their products are being defined in order to identify new therapeutics. We focus on recent findings on the chief inducer of mast cell activation, the IgE receptor-signaling cascade, and the development of new inhibitors of this pathway. We also summarize work that examines the molecular mechanisms utilized by the interleukin IL-4/13 receptors and characterizes therapeutic compounds that target these pathways. RECENT FINDINGS: The tyrosine kinases Lyn, Fyn and Syk have complex roles in IgE receptor signaling. Biochemical analysis and gene expression profiling have shed light on both the positive and negative functions of these proteins and establish additional connections with downstream pathways. Syk inhibitors were identified that may prove useful as antiinflammatory agents. Progress has been made in characterizing how IL-4/13 interact with their cognate receptors that will aid in the design of inhibitors of these interactions. SUMMARY: Recent studies have advanced our understanding of how the IgE receptor and IL-4/13 receptors function. This new knowledge may lead to the development of novel and highly specific inhibitors of allergic inflammation.     

Development, migration, and survival of mast cells

Mast cells play a pivotal role in immediate hypersensitivity and chronic allergic reactions that can contribute to asthma, atopic dermatitis, and other allergic diseases. Because mast cell numbers are increased at sites of inflammation in allergic diseases, pharmacologic intervention into the proliferation, migration, and survival (or apoptosis) of mast cells could be a promising strategy for the management of allergic diseases. Mast cells differentiate from multipotent hematopoietic progenitors in the bone marrow. Stem cell factor (SCF) is a major chemotactic factor for mast cells and their progenitors. SCF also elicits cell-cell and cell-substratum adhesion, facilitates the proliferation, and sustains the survival, differentiation, and maturation, of mast cells. Therefore, many aspects of mast cell biology can be understood as interactions of mast cells and their precursors with SCF and factors that modulate their responses to SCF and its signaling pathways. Numerous factors known to have such a capacity include cytokines that are secreted from activated T cells and other immune cells including mast cells themselves. Recent studies also demonstrated that monomeric IgE binding to FcωRI can enhance mast-cell survival. In this review we discuss the factors that regulate mast cell development, migration, and survival.     

Role of IgE in Th2 cell-mediated allergic airway inflammation

Recent studies with gene knockout mice have demonstrated that T helper 2 (Th2) cell-derived cytokines, including IL-4, IL-5, and IL-13, play important roles in causing allergic airway inflammation. In addition to Th2 cytokines, IgE-dependent activation of mast cells has been suggested to play a role in allergic airway inflammation. In this review, we will discuss the role of IgE in Th2 cell-mediated allergic airway inflammation. We used IgE transgenic mice, which enabled us to investigate the role of IgE without the influence of activated T cells and other immunoglobulins. Whereas IgE cross-linking by antigens did not induce eosinophil recruitment into the airways or airway hyperreactivity, IgE cross-linking induced CD4+ T cell recruitment into the airways. In addition, when antigen-specific Th2 cells were transferred to IgE transgenic mice, IgE cross-linking significantly enhanced antigen-induced eosinophil recruitment into the airways. These findings suggest that IgE-dependent mast cell activation plays an important role in allergic airway inflammation by recruiting Th2 cells into the site of allergic inflammation.     

Suppression of mast cell activation by glucocorticoid

Mast cells play a critical role in allergic diseases. When mast cells are activated by cross-linking of their high affinity IgE receptors by the antigen and IgE antibodies, release of chemical mediators is followed by secretion of multiple cytokines. We report that IL-3-dependent mucosal-type mast cells undergo apoptosis when IL-3 is withdrawn. In addition, cross-linking of high affinity IgE receptors prevents apoptosis of mast cells by paracrine mechanisms, producing IL-3, IL-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF). However, the secretion of endogenous growth factors are not enough for cell survival, whereas IL-4 induces cell aggregation by expressing adhesion molecules such as leukocyte function-associated antigen 1 (LFA-1), and makes it reactive to endogenous growth factors by contact cell to cell interaction. On the other hand, dexamethazone down-regulates the expression of intracelluar adhesion molecule 1 (ICAM-1) and IL-4 in activated mast cells, by which the self-aggregation of mast cells is inhibited and apoptosis is induced. Thus, glucocorticoids suppress mast cell survival by inhibiting IL-4 production and expression of adhesion molecules.     

Autoreactive IgE in Chronic Spontaneous/Idiopathic Urticaria and Basophil/Mastocyte Priming Phenomenon,as a Feature of Autoimmune Nature of the Syndrome

Recent years of research have shed a new light on the role of IgE in immune reactions. It seems to be more than just a contribution to immediate type of allergic response. It appears that monomeric IgE may enhance mast cell activity without cross-linking of FcεRI by IgE specific allergen or autoreactive IgG anti-IgE antibodies. Monomeric IgE molecules are heterogeneous concerning their ability to induce survival and activation of mast cells only by binding the IgE to FcεRI, but not affecting degranulation of cells. It also turned out that IgE may react to autoantigens occurring in the blood not only in chronic spontaneous urticaria (CSU) but also in other autoimmune diseases. The aforementioned phenomena may promote the activity of mast cells/basophils in CSU that easily degranulate when influenced by various inner (autoreactive IgG against IgE and FcεRI, autoreactive IgE for self-antigens) and outer factors (cold, heat, pressure) or allergens. These findings forced the new approach to the role of autoimmunity, self-antigens and IgE autoantibodies in the pathology of CSU. CSU put in the scheme of autoreactive IgG and autoreactive IgE seems to be either a kind of an autoimmune disease or a clinical manifestation of some other defined autoimmune diseases or both.

     

Immunolocalization of cytokines to mast cells in normal and allergic conjunctiva

Background Recently, the potential role of mast cells in allergic reactions has been extended by the discovery that these cells synthesize, store and secrete multifunctional cytokines. Seasonal allergic conjunctivitis is characterized as an immediate hypersensitivity reaction, in which allergen binds to specitic IgE on mast cells, leading to release of preformed and newly synthesized inflammatory mediators. Objective In this study we aimed to localize the cytokines IL-4, IL-5, IL-6, IL-8 and TNFα to conjunctival mast cells and lo examine the relationship between mast cell-associated ctokines and allergic conjunctivitis. Methods Immunobistochemistry was perfonned on serial sections of conjunctival biopsies from patients with seasonal allergic conjunctivitis, in and out of tbe hay fever season, as well as from non-allergic volunteers. Results IL-4, IL-5, IL-6 and TNFα were localized to mast cells in normal and allergic conjunctiva. IL-8 was localized to mast cells in two patients with seasonal allergic conjunctivitis, one during and the other outside the pollen season. Using the monoclonal antibody 3H4, which identifies the secreted form of IL-4, biopsies frotn patients with active seasonal allergic conjunctivitis contained a significantly bigher proportion of mast cells positive for IL-4. than those from out-of-season patients (P= < 0.016). There was no difference between the two groups in the number of mast cells immunostained by the antibody 4D9 which identifies the stored form of IL-4. Conclusions These results suggest that conjunctival mast cells can store a range of multifunctional cytokines and release IL-4 during active disease, which may give them an important role in upregulating allergic inflamtnation in the conjunctiva.     

Human mast cell progenitors in peripheral blood from atopic subjects with high IgE levels.

BACKGROUND: It remains unclear whether the number of circulating mast cell progenitors is increased in patients with atopic diseases. Distinct genotypes are reported to affect mast cell/basophil activation. OBJECTIVE: We compared the number and function of mast cell progenitors present in the peripheral blood from donors with normal IgE (IgE < 400 U/mL) and those with atopic dermatitis accompanied by high serum IgE (IgE > 5000 U/mL). METHODS: Purified peripheral blood cells were cultured in serum-free methylcellulose containing stem cell factor (SCF), IL-6 plus IL-3. Fresh methylcellulose containing the cytokines was layered over every 2 weeks. The cultured mast cells were retrieved from the methylcellulose and were functionally analysed. RESULTS: Mast cell colonies were distinguished at 6 weeks of culture as other colony types had been degenerated. The number of mast cell colony-forming cells varied depending on donors and was not significantly increased in peripheral blood from the hyper-IgE atopic patients. A significant inversed correlation was found between the number of mast cells per one colony and the ages of donors. The cultured mast cells derived from atopic patients and those from normal IgE donors equally expressed Fc epsilon RI and released histamine through Fc epsilon RI, although IL-4 priming in vitro markedly enhanced the function of mast cells regardless of donors. CONCLUSIONS: These results indicate that the number of circulating mast cell progenitors may be regulated by unknown individual factors unrelated to IgE levels. Mast cell function may be regulated largely by environmental factors, such as IL-4, but not determined by their progenitors' genotypes.     

Immunopathology of atopic dermatitis

Conclusions In summary, AD is a chronic inflammatory skin disease associated with increased IgE production, eosinophilia, increased mast cell number and increased expression of the CD23 low-affinity IgE receptor on mononuclear cells. The basis of these immunologic defects appear to be the result of increased numbers of IL-4-, IL-5-producing T_h2 cells. This results in an overstimulation of their IL-4-IL-4 receptor pathway that is accompanied by a relative deficiency of IFN- production.The acute manifestations of AD occur as the result of mast cell degranulation that can be triggered by a variety of stimuli including allergens, bacterial toxins or histamine-releasing factors secreted by activated T cells and macrophages. Mast cells release not only histamine which contributes to the acute sensation of pruritus but also cytokines and chemotactic factors which induce leukocyte adhesion molecules and attract inflammatory cells into the local tissue sites [3, 8, 26, 34].The chronic manifestations of AD are probably the result of sustained cellular activation. The cellular infiltrate in the chronic lesion of AD consists primarily of T cells and macrophages [29]. T lymphocytes play two important roles in allergic responses: First, as already discussed they play a critical role in the regulation of IgE responses. Second, there is increasing evidence that they may play an important role in the control of the inflammatory response. This is orchestrated through organization of the cellular composition of the inflammatory cell infiltrate by the release of various cytokines. The release of IL-3, IL-5, and GM-CSF have pronounced effects on the differentiation and activation of eosinophils [52]. IL-3 promotes the growth of mucosal mast cells and stimulates basophil and mast cell histamine release. IL-4 promotes the growth of murine mast cells [18] and induces the expression of CD23 on macrophages [71]. The release of cytokines may, thus, account for the observation of increased mast cell number in chronic eczematoid lesions.Taken together, these observations suggest that the AD skin lesion is characterized by the infiltration of inflammatory cells which differ from those infiltrating into a type IV contact-sensitivity reaction. The sustained immune activation, which results in chronic AD, may be the result of an underlying T cell defect, e.g., decreased IFN- production following the activation of lymphocytes with a variety of stimuli. Treatment of patients withh rIFN- down-regulates the IL-4-IL-4 receptor pathway which is overstimulated in this disease. It is important to note, however, that although many immunopathologic features of AD have recently been elucidated, the fundamental etiology of these abnormalities remains to be unraveled.     

The role of human mast cell-derived cytokines in eosinophil biology.

Eosinophil-mediated diseases, such as allergic asthma, eosinophilic fasciitis, and certain hypersensitivity pulmonary disorders, are characterized by eosinophil infiltration and tissue injury. Mast cells and T cells often colocalize to these areas. Recent data suggest that mast cells can contribute to eosinophil-mediated inflammatory responses. Activation of mast cells can occur by antigen and immunoglobulin E (IgE) via the high-affinity receptor (FcepsilonRI) for IgE. The liberation of proteases, leukotrienes, lipid mediators, and histamine can contribute to tissue inflammation and allow recruitment of eosinophils to tissue. In addition, the synthesis and expression of a plethora of cytokines and chemokines (such as granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin-1 [IL-1], IL-3, IL-5, tumor necrosis factor-alpha [TNF-alpha], and the chemokines IL-8, regulated upon activation normal T cell expressed and secreted [RANTES], monocyte chemotactic protein-1 [MCP-1], and eotaxin) by mast cells can influence eosinophil biology. Stem cell factor (SCF)-c-kit, cytokine-cytokine receptor, and chemokine-chemokine receptor (CCR3) interactions leading to nuclear factor kappaB (NF-kappaB), mitogen-activated protein kinase (MAPK) expression, and other signaling pathways can modulate eosinophil function. Eosinophil hematopoiesis, activation, survival, and elaboration of mediators can all be regulated thus by mast cells in tissue. Moreover, because eosinophils can secrete SCF, eosinophils can regulate mast cell function in a paracrine manner. This two-way interaction between eosinophils and mast cells can pave the way for chronic inflammatory responses in a variety of human diseases. This review summarizes this pivotal interaction between human mast cells and eosinophils.     

Recent advances in the cellular and molecular biology of mast cells

The mast cell is now considered to play a pivotal role not only in allergic reactions but also in a number of inflammatory disorders. After immunological activation via the IgE receptor, the mast cell releases a variety of cytokines, lipid-derived mediators, amines, proteases and proteoglycans--all of which can regulate adjacent cells and the metabolism of the extra-cellular matrix of connective tissues. While it had been known for some time that mast cells differ in a number of properties in varied tissue sites, it was not known why or how this heterogeneity occurred. The development of in-vitro techniques to culture mast cells and the reconstitution of mast-cell-deficient mice are two major approaches that have facilitated analyses of how the tissue microenvironment regulates the phenotype of mast cells. In this review by Richard L. Stevens and K. Frank Austen, some of the recent findings on the molecular biology of mast cell secretory granule proteins and proteoglycans, and the interaction of mast cells with fibroblasts in the presence and absence of interleukin 3(IL-3) are highlighted.     

Regulation of eosinophil-active cytokine production from human cord blood-derived mast cells.

Human mast cells are multifunctional tissue-dwelling cells that play a crucial role in eosinophil-dependent disorders, such as asthma and parasitic diseases, by the secretion of eosinophil-active mediators. Mast cell-derived cytokines, generated in response to cross-linking of the high-affinity IgE receptor, can regulate eosinophil activation, survival, and chemotaxis. In this study, mast cells generated from human cord blood progenitors (stem cells) were studied for eosinophil-active inflammatory cytokine expression. Cord blood-derived mast cells (CBDMC) expressed typical intracellular scroll granules and microvilli-like structures on their cell surfaces, demonstrated the presence of tryptase, and elaborated prostaglandin D2 (PGD2) after cross-linkage of the high-affinity receptor for IgE (FcepsilonRI). CBDMC expressed tumor necrosis factor-alpha (TNF-alpha) and the eosinophil-active growth factors, interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) after activation. (IL-1beta greatly enhanced IgE-dependent production of these cytokines in response to FcepsilonRI cross-linkage, suggesting a role for bystander/phagocytic cells in modulating mast cell function. In contrast, interferon-alpha (IFN-alpha) inhibited IL-5 and GM-CSF generation, and the glucocorticoid, dexamethasone (Dex), inhibited production of IL-5 and GM-CSF from CBDMC. A macrophage-mast cell-eosinophil axis may exist in vivo that may be susceptible to pharmacologic manipulation.     

Secreted Factors from Human Mast Cells Trigger Inflammatory Cytokine Production by Human Airway Smooth Muscle Cells

Background: A notable feature of allergic asthma is the infiltration of mast cells into smooth muscle in the human airway. Thus, mast cells and human airway smooth muscle (hASM) cells are likely to exhibit mutual functional modulation via direct cell-cell contact or through released factors. This study examined mast cell modulation of hASM cell cytokine release. Methods: The mast cell line HMCα was used to model mast cell function. hASM cells were either co-cultured directly with resting or IgE/antigen-stimulated HMCα cells or treated with HMCα-conditioned media to examine the impact on cytokine release. The activation pathways triggered in hASM cells by the mast cell-derived factors were examined through the use of selective inhibitors and by Western blotting. Results: HMCα cells, or their conditioned media, induced the expression of cytokines (IL-8 and IL-6) by hASM cells at both the mRNA and the protein level. Cytokine expression in hASM cells was greatly amplified when HMCα cells were IgE/antigen-activated. The effects of the conditioned media were not mediated by the chemokines MCP-1 and MIP-1α or by exosomes. While the mast cell-derived factor(s) increased p38(MAPK) phosphorylation in hASM cells, cytokine production was not inhibited by the p38(MAPK) inhibitor SB203580. hASM cell production of IL-8 induced by HMCα condition media but not IL-6 was, however, attenuated by the Src tyrosine kinase inhibitor PP2. Conclusions: Our study shows that the release of soluble mediators by activated mast cells can stimulate hASM cells to elicit production of proinflammatory cytokines that may then exacerbate airway inflammation in asthma.     

New concepts of IgE regulation

B cell switch to IgE expression is mediated by IL-4 and is regarded as a T helper cell-related phenomenon. In this overview we describe that IgE switch can also be induced by mast cell/basophil like cells (from splenic non-B, non-T cells), activated by IgE receptor cross-linking and/or IL-3 which results in IL-4 production by these cells. Furthermore, activated mast cells produce their own growth factors, IL-3 and GM-CSF. Thus, activation of mast cells can provoke an ongoing local allergic reaction as long as antigen confrontation is maintained, a process which is sustained by further IgE production as well as renewal of mast cells. It is furthermore demonstrated that in certain established immune situations the IgE response may become independent of IL-4, namely in the spontaneous in vitro IgE expression of cells from atopic individuals as well as in an in vitro antigen-induced secondary IgE response of spleen cells derived from previously immunized mice. Thus, IgE-switched B cells may persist in vivo and may represent a pool of potentially IgE-producing cells. Finally, a selective inhibition of the IgE response is described in vitro and in vivo by the use of so-called non-anaphylactic monoclonal anti-IgE antibodies. Such antibodies bind to surface IgE+ B cells, but not to IgE-sensitized mast cells, and thereby inhibit IgE responses. Non-anaphylactic antibodies blocked the binding of allergen-specific IgE to mast cells by competing with the Fc epsilon on these cells. As a consequence they do not induce but rather prevent allergen-induced mediator release by mast cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mast cells express IL-13R alpha 1: IL-13 promotes human lung mast cell proliferation and Fc epsilon RI expression

BACKGROUND: The Th2 cytokine interleukin (IL)-13 is implicated in the development of various allergic diseases including asthma. The IL-13 receptor, IL-13Ralpha1, is expressed on most leukocytes, except T-cells. Evidence to support IL-13Ralpha1 expression on mast cells is limited. METHODS: We investigated: (i) IL-13Ralpha1 expression by human lung mast cells (HLMC); (ii) the number of IL-13Ralpha1+ bronchial submucosal mast cells in subjects with asthma and normal controls and (iii) the effect of IL-13 priming on HLMC expression of high-affinity IgE receptor (FcepsilonRI), stem cell factor receptor (CD117), histamine release, proliferation, and survival. RESULTS: Human lung mast cell expressed IL-13Ralpha1 mRNA. IL-13Ralpha1 was highly expressed on the surface HLMC (82+/-9%). Bronchial submucosal mast cell IL-13Ralpha1 expression was higher in asthmatics (86+/-2%) than normal controls (78+/-2%; P=0.015). IL-13 priming for 30 min did not increase HLMC histamine release, in the presence or absence of SCF or in response to IgE/anti-IgE activation. IL-13 priming for 5 days upregulated HLMC FcepsilonRI expression (22% increase in fluorescent intensity; P=0.003), increased histamine release following IgE/anti-IgE activation by 56% (P=0.03) and increased proliferation by 50% (P=0.003) without affecting cell survival or CD117 expression. The IL-13 specific neutralizing antibody CAT-354 inhibited all IL-13 mediated effects. CONCLUSION: Human lung mast cell express IL-13Ralpha1 and activation by IL-13 for 5 days increased FcepsilonRI expression and proliferation. Histamine release was not affected by short-term priming with IL-13, but was upregulated by priming for 5 days suggesting that this effect was mediated by the increased FcepsilonRI expression. These data support the view that targeting IL-13 may be beneficial in the treatment of asthma.     

IgE,Mast Cells,and Eosinophils in Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease with specific immune and inflammatory mechanisms. Atopy is among the major features of the diagnosis criteria for AD but is not an essential feature. Thus, patients diagnosed with AD can be atopic or non-atopic. This review focuses on the role of IgE, mast cells, and eosinophils in the pathogenesis of AD. The known functions of IgE in allergic inflammation suggest that IgE and IgE-mediated mast cell and eosinophil activation contribute to AD, but direct evidence supporting this is scarce. The level of IgE (thus the degree of allergic sensitization) is associated with severity of AD and contributed by abnormality of skin barrier, a key feature of AD. The function of IgE in development of AD is supported by the beneficial effect of anti-IgE therapy in a number of clinical studies. The role of mast cells in AD is suggested by the increase in the mast cell number and mast cell activation in AD lesions and the association between mast cell activation and AD. It is further suggested by their role in mouse models of AD as well as by the effect of therapeutic agents for AD that can affect mast cells. The role of eosinophils in AD is suggested by the presence of eosinophilia in AD patients and eosinophil infiltrates in AD lesions. It is further supported by information that links AD to cytokines and chemokines associated with production, recruitment, and activation of eosinophils.     

Histamine-Releasing Factor and Immunoglobulins in Asthma and Allergy

Factors that can induce the release of histamine from basophils have been studied for more than 30 years. A protein termed histamine-releasing factor (HRF) was purified and molecularly cloned in 1995. HRF can stimulate histamine release and IL-4 and IL-13 production from IgE-sensitized basophils and mast cells. HRF-like activities were found in bodily fluids during the late phase of allergic reactions, implicating HRF in allergic diseases. However, definitive evidence for the role of HRF in allergic diseases has remained elusive. On the other hand, we found effects of monomeric IgE on the survival and activation of mast cells without the involvement of a specific antigen, as well as heterogeneity of IgEs in their ability to cause such effects. The latter property of IgE molecules seemed to be similar to the heterogeneity of IgEs in their ability to prime basophils in response to HRF. This similarity led to our recent finding that ~30% of IgE molecules can bind to HRF via their Fab interactions with two binding sites within the HRF molecule. The use of peptide inhibitors that block HRF-IgE interactions revealed an essential role of HRF to promote skin hypersensitivity and airway inflammation. This review summarizes this and more recent findings and provides a perspective on how they impact our understanding of allergy pathogenesis and potentially change the treatment of allergic diseases.     

Interleukins in immunologic and allergic diseases

Figure 1 depicts some of the potential interactions of the interleukins. Among the substances discussed here, only IL-2 has been used to any large degree in a clinical series. Other cytokines not discussed including some of the colony stimulating factors, tumor necrosis factor and the interferons have also been used in clinical trials. Undoubtedly as we learn more about interleukins IL-1 through IL-7, clinical applications will become apparent. For the allergist/immunologist there are two areas of greatest potential interest. The first of these is in treating immunodeficiency states. Preliminary studies of the use of IL-2 in patients with T cell dysfunction suggest that this substance may be useful in treating selective T cell disorders. IL-4, 5, and 6 all have some influence on B cell function. It is likely that in the near future one or more of these agents will be used clinically. It is also clear that the interleukins have the potential to influence basic mechanisms known to be important in allergic disease. IL-3 is the major factor influencing mast cell growth. IL-4 among other things, promotes B cells to switch to IgE synthesis as well as to induce Fc epsilon RII receptors on B cells. IL-5 is important in the differentiation and growth of eosinophils. Finally, IL-6 is the terminal differentiation factor that causes B cells to become plasma cells. The next few years should result in an even better understanding of the role of each of these interleukins. It is likely that such information will greatly expand the horizons for understanding the pathogenesis of many immunologically mediated diseases and will provide the basis for new modalities of treatment.     

The diverse potential effector and immunoregulatory roles of mast cells in allergic disease

Mast cells are of hematopoietic origin but typically complete their maturation in peripheral connective tissues, especially those near epithelial surfaces. Mast cells express receptors that bind IgE antibodies with high affinity (FcepsilonRI), and aggregation of these FcepsilonRI by the reaction of cell-bound IgE with specific antigens induces mast cells to secrete a broad spectrum of biologically active preformed or lipid mediators, as well as many cytokines. Mast cells are widely thought to be essential for the expression of acute allergic reactions, but the importance of mast cells in late-phase reactions and chronic allergic inflammation has remained controversial. Although it is clear that many cell types may be involved in the expression of late-phase reactions and chronic allergic inflammation, studies in genetically mast cell-deficient and congenic normal mice indicate that mast cells may be critical for the full expression of certain features of late-phase reactions and may also contribute importantly to clinically relevant aspects of chronic allergic inflammation. Moreover, the pattern of cytokines that can be produced by mast cell populations, and the enhancement of such cytokine production in mast cells that have undergone IgE-dependent up-regulation of their surface expression of FcepsilonRI, suggests that mast cells may contribute to allergic diseases (and host defense) by acting as immunoregulatory cells, as well as by providing effector cell function.