Biomedical subjects

Wendy-Anne Smith

Publications and source records attributed to Wendy-Anne Smith.

5 recordsLinked to original sources

PubMed2005

Structural biology of allergens.

Major allergens may have special aerobiological properties and allergenic structures. It would also be instructive to consider the properties of nonallergens and nonallergenic responses. In some cases, nonallergenic responses appear to result from a lack of antigenicity and in others from regulation. Proteolytic activity has been proposed as an adjuvant for allergenicity, but lipid binding is far more common and is found for more than 50% of the major allergens. Such structures can enhance allergenicity via Toll-like receptor (TLR) or CD1 pathways. TLR signaling can enhance both Th1 and Th2 responses and be induced by peptides as well as nonproteinaceous ligands.

Allergens↗

PubMed2005

Genetically engineered vaccines.

The application of recombinant DNA technology to allergen research has provided the sequence information and genetic material to produce new types of allergy vaccines. One general strategy has been to use the knowledge to produce synthetic peptides that represent selected T-cell or B-cell epitopes. The production of genetically engineered allergens provides an alternative strategy to construct hypoallergenic vaccines, which can provide a better and less selected representation of the epitopes. Many strategies have been used to produce such hypoallergens, and their ability to reduce allergenicity has been amply demonstrated by skin and nasal provocation tests. The retention of T cell-stimulating activity has also been demonstrated, and a consistent feature of the vaccines has been, despite the reduced immunoglobulin E (IgE)-binding reactivity, the ability to induce anti-allergen IgG antibody. The lead hypoallergens have been polypeptide fragments and trimeric constructs of the birch allergen Bet v 1. A clinical trial with these medicaments has shown the ability to modify IgE and IgG antibody production, skin test reactivity, and symptom scores. This is the first trial of a recombinant allergy vaccine, and it has set a benchmark for further studies. A new generation of hypoallergens is now being produced based on the detailed knowledge of the tertiary structures of the allergens and of the T-cell and B-cell epitopes. The modifications have been made to change the topography of the allergens while retaining a stable, folding structure. In the case of Bet v 1, tertiary structures of hypoallergens have been determined. Structurally modeled hypoallergens have been produced for pollen, venom, food, and latex allergens, with promising characteristics from preclinical studies.

Allergens↗

PubMed2004

Recombinant allergens for analysing T-cell responses.

T-cell responses constitute a central element of allergic disease and a model for studying Th1 and Th2 cytokine pathways. Most studies to date have used extracts of allergens which contain variable quantities of different allergens and non-allergenic antigens. Recombinant allergens provide the tools for studying the responses to allergens in a reproducible and dose-dependent manner and the different T-cell responses of allergic and non-allergic subjects provide a method for verifying the responses and their relationship to allergic sensitisation. Most allergies show dominant responses to one or a few major allergens. These allergens have been described for the common allergies and have been produced as recombinant allergens. A particular problem for allergens is that many are mixtures of proteins from multi-gene families or are highly polymorphic. Information now exists so the sequence variation can be represented. Purified recombinant allergens produced by standard expression systems stimulate the expected T-cell responses from the peripheral blood of allergic and non-allergics to allergen extracts. Although stimulation with recombinant allergens which are not produced with a natural IgE binding activity can provide a measure of allergenicity, the altered tertiary structure can reduce Th2 responses. The sequence information now available provides the means to use PCR to produce cDNA for the production of recombinant allergens from readily available sources. The production of the highly reactive recombinant Der p 2 allergen of house dust mite from natural sources is described.

Allergens↗

PubMed2004

The allergenic specificities of the house dust mite.

The most important house dust mites are Dermatophagoides pteronyssinus and in drier areas D. farinae. In subtropical and tropical regions the glycyphagid mite Blomia tropicalis is a major source of allergen, which co-exists with D. pteronyssinus. The group 1 and 2 allergens of Dermatophagoides mites are clearly major specificities and it is likely that these allergens could be the basis of new strategies of immunotherapy for many mite-allergic subjects. About 20% of patients, however, do not have IgE antibody to the group 1 and 2 allergens, and even though this is a minority, it constitutes a large population. There are also many other house dust mite allergens which have high IgE binding activity but these are present in low and variable concentrations in mite extracts, usually at less than 1% of the group 1 and 2 allergens. It must be appreciated that mite extracts are arbitrary preparations that do not accurately represent the relative concentrations of allergens in inhaled air. There is now the opportunity to produce more representative and more balanced formulations of allergens, possibly by mixtures of recombinant allergens. It is likely that the group 3, 5, 7 and 9 allergens will be important along with the high molecular weight group 11, 14, 15 and 18. The tropomyosin group 10 may be an important cross-reacting allergen. B. tropicalis is, because of its distribution in highly populated regions with increasing affluence, a very important allergen. It has low-grade cross-reactivity with Dermatophagoides but most allergens only have 30-40% sequence identity between the different families so they require different allergens for immunotherapy and new diagnostic measures are required to distinguish the sensitivity between the mite families. Studies on B. tropicalis allergens are required to identify the major allergens that do not appear to be the group land 2 specificities. Component resolved diagnosis is a newly developing procedure that uses allergen arrays to provide a diagnostic format to differentiate between cross-reacting allergens and to identify the optimal formulation of allergens for different patients.

Allergens↗

PubMed2002

Characterization and immunobiology of house dust mite allergens.

The examination of house dust mite extracts has indicated that over 30 different proteins can induce IgE antibody in patients allergic to the house dust mite. There are however dominant specificities especially the group 1 and 2 allergens which can account for much of the allergenicity of extracts. Of the 19 denominated allergens, the major IgE binding has been reported for the group 1, 2, 3, 9, 11, 14 and 15 allergens. The high-molecular-weight group 11, 14 and 15 allergens have only recently been described and although high IgE binding has been anticipated from immunoblotting, there is a need for considerable corroboration. Similarly, the study of the group 3 and 9 serine protease allergens has been incomplete. The group 4, 5, 7 and 8 allergens have shown intermediate IgE binding and the group 10 tropomyosins are of interest because of their potential cross-reactivity with allergen from disparate species. Although the progress with the production of recombinant group 1 allergens has been recent, many of the allergens can be produced as high IgE-binding polypeptides. The tertiary structure of the group 2 allergens has been determined from recombinant proteins and they are an excellent model for the investigation of modified allergens. An unexpected property of the group 1, 2 and 3 allergens has been the high degree of polymorphism found by cDNA analysis. It has however been possible to identify sequences to represent the variation in the natural allergens. The group 7 and 14 allergens show secondary modifications which vary in different extracts creating batch variation. While some estimate of the importance of allergens can be obtained from IgE binding, few analyses of T-cell responses have been made and these regulate both the development of, and the protection from sensitization.

Allergens↗