Editorial overview understanding the allergic response as a step towards its eradication

Atopic allergy and other hypersensitivities Editorial overview Understanding the allergic response as a step towards its eradication Raif S Geha Children’s

Hospital, Current

Harvard

Opinion

Medical

in Immunology

Allergic diseases, i.e. asthma, allergic rhinitis, atopic dermatitis, and food and drug allergy, affect 20?/ of the population and are an important cause of morbidity and mortality. The cost associated with the diagnosis and treatment of these diseases is simply staggering. It is estimated that the money spent on over the counter antihistamines exceeds by far the entire budget of the National Institute of Health in the USA. In the past five years we have gained a much better understanding of the pathogenesis of allergic diseases. The initial key players in allergy are IgE and the mast cell, which expresses high affinity receptors for IgE and is widely distributed in tissues, particularly in mucosae. Antigen entry results in crosslinking of receptor-bound IgE and mast-cell activation with the release of mediators that trigger an immediate (within 20 minutes) response as well as of chemotactic factors and cytokines that call in inflammatory cells (neutrophils, eosinophils, basophils and lymphocytes) to the site. This influx of inflammatory cells gives rise to the late phase (6-24 hours) of the allergic response and to the chronic inflammation seen in target tissues constantly exposed to allergen. The mechanisms of IgE antibody synthesis were reviewed in a recent issue of this series [ll. The reviews that follow focus on mast cells and their receptors and on the late phase of the allergic response. Atopic dermatitis is used to illustrate the complex factors that perpetuate chronic inflammation in atopic diseases and the potential of classic as well as peptide-based allergen immunotherapy in dampening the allergic response is discussed. Ishizaka et al. (pp 937-943) draw on three decades of experience in the study of mast cells to outline the factors that drive the differentiation of stem cells into mast cells or into basophils. In humans a CD34+ precursor differentiates under the influence of c-kit ligand into mast cells that contain only tryptase (MT), and thus are characteristic of mast cells normally present in lung and mucosae. A factor derived from fibroblasts acts in synergy with c-kit ligand to further drive mast-cell differentiation into more mature cells that contain both tryptase and chymotryptase (M&, which are similar to mast cells normally present in skin and submucosae. It is still a matter of debate whether MT and MTC are derived from a single precursor or from dif-

School, 1993,

Boston,

USA

5:935-936

ferent precursors. The importance of c-kit ligand in mast-cell differentiation in vivo is illustrated by the observation that administration of c-kit ligand causes an increase in the number of tissue mast cells and by the fact that the disease mastocytosis, which is characterized by increased numbers of mast cells infiltrating various tissues, is associated with increased expression of c-kit ligand. Basophils and mast cells are derived from different lineages. Unlike mast cells and their precursors, basophils and their precursors do not express c-kit. Interleukin (IL)-3 serves as a differentiation factor for basophils and its effects are enhanced by IL-4. In contrast, IL-3 does not cause mast-cell differentiation and IL-4 downregulates the effect of c-kit ligand on the differentiation of mast cells. Bonnefoy et al. (pp 944-949) discuss the role of IgE receptors in allergic diseases. The high affinity receptor for IgE, FceRI, expressed on mast cells, basophils and Langerhans cells, consists of a ligand-binding a-chain, a p-chain that spans the membrane four times and a disuffide-linked y-chain homodimer with homology to CD3& Given the presence of a Reth motif in Fc&RIy, it was not surprising to find that signaling pathways via FceRI and the T-cell receptor share many features, such as the involvement of Src-type kinases, and the activation of phospholipase Q and phosphoinositide turnover. The latter leads to the activation of protein kinase C and of a Ca2+ flux, which plays a critical role in degranulation, cytokine release and mast cell growth that follow crosslinking of receptor-binding IgE by allergen. A low affinity receptor for IgE, Fc&RII/CD23, is expressed constitutively on B cells and its expression is induced by IL-4 on monocytes and B cells. This induction is upregulated by CD40 engagement as well as by IL-13. The concerted effects of these agents in allergic patients probably underlie the presence of CD23 on skin macrophages and circulating monocytes in atopic dermatitis and on alveolar macrophages in allergic asthma. CD23 serves many functions. Crosslinking of CD23 by IgE and allergen results in release of IL-1 and tumor necrosis factor (TNF) by monocytes, enhances antigen presentation and modulates

Abbreviations APC-antigen-presenting

cell; IL-interleukin;

LPR-late-phase

reaction; TNF-tumor

0 Current Biology Ltd ISSN 0952-7915

necrosis factor.

935

936

Atopic allergy and other hypenensitivities

B-cell activation and IgE synthesis. In addition to its IgE dependent effects, CD23 functions as an adhesion molecule by virtue of the interaction of its lectin-binding domain with fucose-l-phosphate on CD21, thus potentially enhancing lymphoid-cell interactions. Furthermore, cleavage products of the extracellular domain of CD23 function as cytokines that drive prothymocyte maturation and myeloid cell precursor proliferation and inhibit macrophage migration. Another lectin-type protein, Mac-2, is expressed on mast cells, monocytes and neutrophils and has the potential to activate these cells upon IgE crosslinking. Zweiman (pp 950-955) emphasizes that the interaction between receptor-bound IgE and allergen plays a critical role in the late phase allergic response (LPR), the prelude to chronic allergic inflammation. This is underscored by the capacity of anti-IgE antibody to trigger the LPR. This reaction has been studied extensively in skin biopsies and in blister fluids, which were found to be rich in cytokine mediators and inflammatory cells. Cytokines present include IL-8, IL-~, TNF, IL-4 and IL-5. They induce expression of adhesion molecules on vascular endothelium [e.g. IL-4 induces vascular cell adhesion molecule (VCAM)-1 and TNF induces endothelial leukocyte adhesion molecule (ELAM)-1 and intercellular adhesion molecule (ICAM)-ll and are chemotactic for circulating cells (e.g. IL-8 attracts neutrophils and basophils and IL-5 attracts eosinophils) resulting in migration of inflammatory cells into the tissues at the site of allergen entry. Although the initial cells in the LPR are mainly neutrophils and eosinophils, T cells (predominantly T helper type 2 cells), infiltrate the site later on and through their cytokines cause renewed rounds of mast-cell degranulation, thus perpetuating the inflammatory response that underlies the chronicity of allergic diseases. The combination of neutrophil and eosinophil granule products (i.e. elastase, eosinophil major basic protein and eosinophil cationic protein) and of T-cell cytokines results in tissue injury and in heightened sensitivity to non-specific irritants, explaining the hyper-reactivity of the airways in asthma and of the skin in atopic dermatitis. Atopic dermatitis is discussed as a prototype of a chronic allergic disease by Leung (pp 956-962). There is no doubt that IgE antibody plays a critical role in triggering atopic dermatitis. It is now clear that both ingested and inhaled allergen are culprits, and that the lesion can be reproduced by patch application of the allergen. The resulting infiltrate resembles the LPR. In some patients the skin lesion was shown to contain T cells directed against mite allergens and that possess a T helper type 2 profile of cytokine release. Bacterial toxins released by staphylococci that heavily colonize the skin in atopic dermatitis appear to play a role in exacerbating the disease, not only by eliciting IgE antibody but perhaps more importantly by causing cytokine release locally from MHC class II+ macrophages and from T cells bearing the appropriate T-cell receptor VP chains. This illustrates how non-specific agents can aggravate allergic inflammation. Allergen immunotherapy has been used for more than half a century to treat allergic diseases. Nor-

man (pp 968-973) draws from his vast experience at Johns Hopkins University to summarize the effect of immunotherapy on the allergic response. In addition to preventing the seasonal rise in allergen-specific IgE and slowly decreasing serum IgE antibody levels, immunotherapy downregulates allergen-specific T-cell proliferation, and inhibits allergen-induced release of cytokines and of histamine-releasing factors by T cells. Immunotherapy dampens the LPR following allergen skin challenge. It particularly inhibits infiltration of CD4+ T cells and to a lesser extent infiltration of eosinophils. The mechanism of classic immunotherapy which uses intact allergen is not known. More recently, attempts to anergite allergen-specific T cells have been initiated using peptides derived from allergens. This experimental therapy is based on the oh servation that peptides, in the absence of antigen-presenting cells (APCs) in vitro or of an adjuvant in vivo, anergize T cells because the T-cell receptor is engaged in the absence of an appropriate co-stimulatory signal, such as the one normally provided by interaction of B7 on APCs with CD28 or cytotoxic T lymphocyte associated antigen (CTLA)4 on T cells. The results of ongoing immunotherapy trials with two dominant peptides derived from the Fe1 d 1 cat allergen are pending. There is no doubt that the next few years will witness the introductibn of novel therapeutic modalities in allergic diseases. A better understanding of mast-cell development may allow us to modulate their numbers in tissues. At the very least we should be able to interfere with IgE binding to its high affinity receptor on mast cells by using either soluble FceRIa or agents that interfere with IgE binding to FceRIa. The IgE response will be amenable to modulation in its inductive stage by IL-4 antagonists, including perhaps soluble forms of the IL-4 receptor and possibly by drugs that interfere with switch recombination. Comolyn and nedocromil, drugs currently used in the prevention of the allergic response, may belong in this category. Existing IgE responses can be targeted by non-immunogenic soluble FceRIa coupled to toxins. Anti-adhesion molecules may be useful in the prevention of the LPR. Finally, the induction of anergy in allergen-specific T cells by peptides or other means will have the advantage of specificity and, equally importantly, of interfering both with the inductive phase of the allergic response, by inactivating T helper cells necessary for IgE synthesis, and with the amplificatory phase of the allergic response, by inactivating allergenspecific T cells that participate in the LPR to give rise to chronic allergic inflammation.

References 1.

VEKxI.1.I D,

GEHA

KS:

Opitl Immrrnol182,

Regulation 41794-797.

of Isotype

Switching.

Ctrr

RS tieha, Division of Immunology. Children‘s Hospital. Hand Medical School. 300 Longwwd Avenue, Boston. Massachusetts 02115, USA.