The principal long-term aim of this work is to determine the genetic factors which control human immune responsiveness in inhaled allergens. Since the dosages of most inhaled allergens are immunogenically limiting, allergy provides a particularly good model for this study. We hypothesize that two principal immunogenetic factors control allergic response: HLA-linked loci which control specific antibody responses and a non-HLA-linked locus which regulates overall IgE responsiveness. The genetics of specific response will be studied using ultra-pure allergens, especially those of low molecular weight, where the structural simplicity facilities elucidation of the genetic controls. The relationship between levels of allergen-specific antibodies (measured using highly sensitive radioimmunoassays) and HLA type and total IgE level will be determined using both parametric and nonparametric statistical analyses. In this way, we will define the interrelationship between HLA and IgE phenotypes and the person's """"""""immune response fingerprint"""""""" toward a wide variety of allergens of different molecular structure. In order to study cellular mechanisms of immune response, human T-cell and B-cell hybridomas specific for various ultra-pure grass and ragweed allergens will be produced, and soluble effector and suppresor molecules derived from these cells will be studied. Epidemiologic and genetic factors controlling the expression of allergy, especially genetic regulation of basal total IgE level, will be investigated in a large, well-defined industrial population, including 43 large families. Analysis of the genetics of IgE will involve complex segregation analysis and linkage of the hypothesized IgE-regulating gene to a large array of polymorphic chromosomal markers. Segregation and linkage analysis of specific responses toward ultra-pure allergens wll also be studied in these families.
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