Molecular Genetics of Human Immune Responsiveness to Allergens

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Abstract
Specific immune responsiveness to certain highly purified allergens is significantly associated with particular HLA‐D types. In one striking example, IgE and IgG responsiveness to the ragweed Amb V (Ra5) allergens is strongly associated with HLA‐DR2/Dw2. We studied the HLA‐D gene sequences of 67 Caucasoid subjects. All Dw2+ (Dw2+− in one case) high responders to Amb a V, before or after high‐dose ragweed immunotherapy, possessed typical DRB1*2.2 and DRB3*2.2 (Dw2‐associated DRP) gene sequences. Their DQB1 genes all had typical Dw2‐associated DQB1* 1.2 sequences, with two exceptions (DQB1*1.21 and DQB1*1.18, that are usually associated with Dw21 and Dw18, respectively). The finding of these unusual sequence combinations in these Amb a V responders implicates a DRαβ12.2 or a DRαβIII2.2 molecule as the major Amb a V Ir gene product. This conclusion is supported by our finding of one non‐responder (after prolonged immunotherapy) who possessed the DQ1.2, but not the DR2.2, sequences. In ragweed‐allergic subjects further data suggest that a DR2.2 molecule is generally a necessary and almost always a sufficient requirement for high Amb a V responsiveness. An Amb a V‐specific T cell clone obtained from a Dw2+ subject was DR‐restricted according to inhibition studies using anti‐HLA‐D monoclonal antibodies. Also, antigen‐presenting cells that were DR2.2+ or DR2.12+, but not DR2.21+ or DR2.22+, were able to present antigen to the cloned T cells, implicating certain DR2 molecules as restriction elements. In similar studies using the rye grass allergen Lol p III we obtained preliminary data implicating the DRβ1, sequence E9YSTS13 (found in DR3, DR5 and DRw6 genotypes) in the recognition of a major Lol p III agretope. Since Lol p I and II are: homologous to Lol p III in one region of their amino acid sequences the EYSTS sequence may also be involved in the recognition of similar agretopes of these molecules. These and other studies demonstrate the power of the allergy model for genetic and molecular studies of the human immune response.