Genetics of Asthma: A Review: Asthma: HLA, TCR Genes, and Antigen-Specific IgE Responses

HLA, TCR Genes, and Antigen-Specific IgE Responses
Why is it that some people develop allergy to an antigen while others do not? In other words, what are the determinants of antigen-specific IgE responses? Clearly, timing, mode, and intensity of antigen exposure are important environmental determinants. Now there is evidence that human leukocyte antigen (HLA) and T-cell receptor (TCR) genes may be some of the genetic determinants of antigen-specific IgE responses. HLA class II molecules are expressed on monocytes and macrophages. They bind antigen-derived peptides and present them to T lymphocytes. T lymphocytes interact with the HLA-antigen complex via the TCR, and this interaction results in T-cell activation and initiation of immune response against that antigen. Both the HLA and TCR molecules are highly polymorphic, and this polymorphism determines which antigens they interact with, and influences the specificity of the immune response.

The HLA gene complex is located on chromosome 6p and consists of DR, DQ, and DP subregions, each of which includes one or more highly polymorphic A and B genes. One A and one B gene are expressed as the a and (3 chains of the HLA class II molecule. Initial studies used serologic methods to define the HLA system, whereas subsequent studies have used direct genotyping of the HLA genes. Numerous studies have demonstrated variable associations between particular HLA alleles (“susceptibility alleles”) and specific IgE responses. The most consistent association has been for IgE response to purified ragweed antigen Amb aV with the HLA DRB 1*1501 (DR-2) haplotype.Other associations that have been noted are sensitivity to rye grass antigens Lol p I, II and III with DRB1*03 and DRB1*11, mold antigen Alt a I sensitivity with DRB1*04 and 14, and cat antigen Fel d I sensitivity with DRBI*01.7578 Inconsistent associations between house dust mite antigen Der p I responsiveness and HLA have been reported. Analysis of HLA and house dust mite allergy is the primary aim of the 12th International Histocompatibility Workshop now underway. Some negative associations have also been reported, that is, some HLA alleles were more prevalent in those that did not have IgE response to a particular antigen (also called “protective alleles”). DR7 and DRw53 have a negative association with Lol p III responsiveness, and DR4 appears to be protective against mountain-cedar allergy.
Few studies have looked at the association of HLA alleles with asthma. HLA-DQw2 was more prevalent in Chinese children with asthma and house dust mite allergy,80 while HLA-DPB1*0401 was less prevalent in patients with mite-induced asthma in a Colombian population. In a group of patients with rhinitis and ragweed allergy, HLA-B7,SC31,DR2 was associated with presence of asthma, while HLA-B8,SC01,DR3 was associated with the absence of asthma. Association of HLA with nonatopic asthma has also been investigated. Isocyanates are one of the most common causes of occupational asthma; however, asthma develops in only 5% of those exposed to isocynates. Bignon et al looked at the influence of HLA on susceptibility to isocyanate-induced asthma. In a group of subjects all of whom had similar occupational exposure to isocyanate, HLA-DQB 1*0503 and DQB1*0201/0301 alleles were associated with isocyanate-induced asthma, while HLA-DQB1*0501 and DQA1*0101-DQB1*0501-DR1 appeared to be protective against the development of asthma.
TCR is composed of a and (5 chains in 95% of T cells. The a chain locus is on chromosome 14 and the (3 chain locus is on chromosome 7. The enormous variation in TCR arises from recombinations in the variable (V), diversity (D), and joining (J) segments. Moffat et al83 tested for linkage between specific IgE responses and the a and (3 chain loci in British and Australian subjects using affected-sib pair analysis. No linkage to the (3-chain locus was seen in either group. In both groups, there was linkage of the a-chain locus to the presence of IgE to Der p I (purified house dust mite antigen) and to Fel d I (purified cat antigen). Linkage of the a-chain locus to grass antigen was seen in the Australian but not in the British group.