We previously emphasized (1, 2) the usefulness of atopic allergy as a model for studying the genetics of human immune response. A particular advantage is that most allergies result from exposure to minute, immunogenically limiting doses of environmental antigens (allergens), usually <1 ptg/yr (3). Short ragweed pollen component Ra5 (5,000 tool wt) (4, 5) offers a particularly useful tool for studying specific immune response because of its relatively simple structure and low proportion in the pollen (3). In several studies (2, 6-8), immunoglobulin E (IgE)-mediated skin test response to Ra5 was significantly associated with HLA-B7 and the B7 cross-reacting group (Creg). x Further preliminary evidence suggested that the primary association might be with Dw2 (2).Analysis of the Ra5 preparations used in previous studies by crossed immunoelectrophoresis (CIE) indicated the presence of very low (but detectable) levels of impurities that might interfere with genetic analysis. Hence, further purification of Ra5 to -->99.9% purity was performed for the present studies, and highly sensitive assays for IgE and IgG antibodies (Ab) to Ra5 were developed.After studying responses to ultra-pure Ra5 in 447 Caucasians that were naturally exposed to ragweed pollen, we now find that Dw2 is almost a perfect marker for IgE and IgG responses to Ra5. The immune response association with HLA-B7 is secondary to Dw2 and presumably arises from the well-documented linkage disequilibrium between the alleles coding for these two specificities. Analysis of HLA-DR typing data in a portion of the study subjects suggests a weaker association between response to Ra5 with DR2 than with Dw2.

In the preceding paper (1), we reported a significant striking association between Dw2 and IgE and IgG antibody (Ab) 1 responses to Ra5 in ragweed-allergic Caucasian subjects as a result of natural exposure to ragweed pollen. The question arose as to whether this relationship might change after parenteral immunization with much higher dosages of ragweed antigens. Such treatment, known as immunotherapy or hyposensitization, is commonly administered to ragweed-allergic patients to alleviate their allergic symptoms (2). Effective treatment is normally accompanied by high levels of serum IgG Ab toward ragweed antigens, especially the principal component, antigen E (AGE) (3).Whereas the adult dosage of inhaled Ra5 is probably no more than 60 ng over the 8-wk period of ragweed pollination (4), cumulative annual immunotherapeutic dosages of Ra5 are usually at least one or two orders of magnitude higher. We will show that such immunotherapy induces good immunoglobulin G (IgG) Ab responses to Ra5 in all ragweed-allergic individuals who possess Dw2, whether or not they produced IgE and/or IgG Ab to Ra5 before therapy, whereas the prevalence and level of IgG Ab response in persons lacking Dw2 are both much lower. Despite an extreme degree of heterogeneity in the type of therapy and antigen dosage, the association between IgG Ab response to Ra5 and Dw2 becomes increasingly stronger and more significant over a 3-yr period of therapy. Materials and MethodsPatients. The study group was comprised of 61 highly ragweed-allergic patients, who were a subset of the 86 patients included in the "clinic group," in the preceding paper (1). As previously stated, there was a bias toward selecting Ra5 responders, and, therefore, the proportion of Ra5+ subjects (23%) was higher than the value of ~9% one might expect in a random sample of ragweed-allergic subjects (cf. data for Westinghouse study group in ref. 1).

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The relationship between HLA type and specific immune responsiveness toward ultrapure Ambrosia artemisiifolia (short ragweed) pollen allergen Amb a VI (Ra6) was explored in a genetic-epidemiologic study of groups of 116 and 81 Caucasoid subjects who were skin-test positive (ST+) toward common environmental allergens. Specific immune responsiveness to Amb a VI was assessed by measuring serum IgE and IgG antibodies (Abs) by double Ab radioimmunoassay in both ST+ groups. Significant associations were found between IgE Ab responsiveness to Amb a VI and the possession of HLA-DR5; P values for the two groups were, respectively, 7 X 10(-7) and 1 X 10(-3) by nonparametric analyses, and 4 X 10(-11) and 5 X 10(-8) by parametric analyses. The levels of significance for the associations between HLA-DR5 and IgG Ab responsiveness were highly dependent on the extent of ragweed immunotherapy (Rx) within the patient group; by parametric statistics, the associations were 10(-11) for the group that had received relatively little Rx and 2 X 10(-3) for the group that had received more intensive Rx. These results provide further striking evidence for the existence of specific HLA-linked human Ir genes involved in responsiveness toward inhaled allergens and illustrate the usefulness of the allergy model in studies of the genetic basis of human immune responsiveness. Extension of these studies to investigation of structure-function relationships involved in antigen recognition by Ia molecules and the T-cell receptor will lead to a better understanding of human susceptibility toward immunologic diseases.