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The incidence in Europe of asthma and atopic (allergic) diseases in general is high and rising even more rapidly in children than adults. Even death from asthma is increasing, despite improved care.
Allergic diseases have multiple causes, influenced by both genetic and environmental factors. Predisposition to allergy is controlled by multiple genes, with disease then usually triggered by exposure to some allergen such as grass or dust. The result is an increase in IgE antibody production directed towards specific antigens, which are allergens in the case of atopic disease.
Current knowledge of the fine cellular and molecular mechanisms involved in the pathogenesis of allergy is still patchy. A coherent model for these mechanisms is desirable, but requires a concerted effort with integration between different scientific disciplines. However such an effort is possible in Europe because there is a longstanding tradition of excellence in laboratories within many EU countries. The ESF has already fostered steady and developing collaboration between research groups that have complementary expertise through its network "HLA and allergy".
On the genetic front, research is focusing on the HLA complex, which is the most polymorphic human genetic system of known function. Studies have already provided evidence that the allergic immune response is controlled at the level of the class II region. The HLA class II background of the host plays a key role in defining an allergen, and recent studies have indicated that IgE responsiveness to purified major allergens is closely linked to a TCR (T cell receptor), a major microsatellite defined polymorphism. In fact a gene controlling total serum IgE level and bronchial hyperactivity, which can lead to asthma, has been mapped at chromosome 5q31-33. There is also evidence that a gene involved in atopy and bronchial hyperactivity maps at chr11q13, close to the b chain of the high affinity IgE receptor (FCe-RIb) (8-10). Searches for other genes are underway and will be pursued further within the ESF programme.
At the cellular and molecular level, immune response is characterised by increased IgE synthesis by B cells and by the cytokine profile of allergen specific T cells. IgE antibodies bind to high affinity (type I) Fce receptors present on the surface of mast cells/basophils. Allergen induced FceRI crosslinking then triggers the release of vasoactive mediators, chemotactic factors, and cytokines, which are responsible for the allergic cascade.
However the mechanisms responsible for the joint development of allergen specific T cells, IgE producing B cells, mast cells/basophils and eosinophils in the pathogenesis of allergy have remained unclear until the identification of distinct subsets of CD4+ T helper (Th) cell subsets have been described in both mice and men: Th1 type cells that produce interleukin 2 (IL2) interferon gamma (IFNg) and tumor necrosis factor (TNF) b and Th2type of cells which produce IL4, IL5 and IL10.
For the allergens, detailed information is now available on the primary structure of a variety of allergens. With major allergens now available as recombinant proteins or purified molecules and their T and B cell epitopes as synthetic peptides, it has become possible to investigate the specificity and functional properties of allergen reactive T and B cell repertoires. One important question here is whether TCR gene segment usage in the response to allergens is restricted and whether HLA class II genotype controls TCR repertoire selection.
Such knowledge could potentially be used to develop experimental models of allergen mediated immunomodulation as a forerunner to the design of therapeutics for clinical use. Before this can be achieved it is necessary to determine the immunological changes needed to mediate non responsiveness and the underlying mechanisms.
Regulation of allergen specific immune response is after all the fundamental target of allergen specific immunotherapy. But to reach this goal, a detailed analysis of the mechanisms of hyposensitization of T cells is required. Experimental models have been developed both in vitro and in vivo to examine such mechanisms.
Coming onto the specifics of the programme, we note first that the heterogeneity both of Europes population and environment make it an ideal experimental laboratory for this kind of study. The point here is that genetic predisposition and environmental condition play an equal role in determining allergic response, and Europe provides sufficient diversity of both. A European database is clearly needed to store regional differences both of exposure to allergens, such as grass pollens, house dust mites and olive birch pollens, and of the prevalence of allergy related polymorphic genes.
The main scientific aims are to:
- better identify the cellular and molecular factors and processes that are responsible for directing the immune response towards allergy;
- identify the genes that control atopy;
- delineate the interplay between genotype, physiological and environmental factors.
Research activities then come under four headings:
. Identification of susceptibility genes as a step towards understanding and preventing allergy. Here, the main aims are to establish banks of clinical and genetic material of about 400 nuclear families; extend the study of HLA region polymorphism to new class II alleles, promoters, TAP and LMP; investigate TcR, Ig and chromosome 5 lymphokine gene cluster to establish the exact value of genetic markers and the functional impact of these loci in allergy; and study upcoming candidate genes.
. Allergens and allergen specific immune responses. Objectives are to identify dominant epitopes of major allergens in Europe; identify naturally processed peptides presented by the relevant HLA molecules - this means identification of specific regions of allergen molecules recognised by antibodies of different isotype; develop purified and/or recombinant allergens, and peptides with dominant epitopes or recombinant constructs, to test in vitro and for the ability to modulate the immune response; development of animal models to investigate molecules that are candidates as allergy vaccines and/or for inducing hyporesponsiveness.
. Identification of cellular and molecular mechanisms leading to Th2 associated cytokine profile. Aims are to identify transcription factors and other pathways able to activate Th2 associated chromosome 5 clustered cytokine gene promoters; and to identify mechanisms leading to Th2 response in atopy and its regulation in vitro and in vivo, with animal models.
. Analysis of T-B cell cooperation and B cell differentiation in atopy. Activities here are development of new in vitro models of specific immune response towards allergens in order to study T-B cell interaction under several conditions; functional analysis of allergen specific B cells; and development of in vivo models to study T-B cell cooperation and a B-switch programme to test molecules that can potentially interfere with these mechanisms.
A major aspect of the programme will be to recruit additional young scientists with new expertise to work on specific sections of the programme. A study workshop will give the young researchers an opportunity to meet with leading scientists in the fields of genetic, molecular and cellular regulation of atopy.
Activities
- Workshop (8-9 May 1998, Madrid, Spain)
- Travel grants and study visits
- Standardisation / Reagents / Special operations
- Steering Committee meetings (10 May 1998, Madrid, Spain - 6 May 1999, Berlin, Germany)
- Symposium on Immunogenetics and Allergy: Towards Prevention and Care (IGA), organised by Andreas Radbruch and Harad Renz: 7-9 May 1999, Berlin (Germany)
