A second set of genes in this region of chromosome 5 belongs to the TIM family (for T cell, immunoglobulin domain, and mucin domain). The genes in this set encode three T-cell-surface proteins (Tim-1, -2, and -3) and one protein expressed primarily on antigen-presenting cells (Tim-4). In mice, Tim-3 protein is specifically expressed on TH1 cells and negatively regulates TH1 responses, whereas Tim-2 (and to a lesser extent Tim-1) is preferentially expressed in TH2 cells and negatively regulates them. Mouse strains that carry different variants of the Tim genes differ both in their susceptibility to allergic inflammation of the airways and in the production of IL-4 and IL-13 by their T cells. Although no homolog of the mouse Tim-2 gene has been found in humans, inherited variation in the three human TIM genes has been correlated with airway hyperreactivity or hyperresponsiveness. In this condition, contact not only with allergen but also with nonspecific irritants causes airway narrowing (bronchoconstriction), with wheezy breathlessness similar to that seen in asthma. The third candidate susceptibility gene in this part of the genome encodes p40, one of the two subunits of IL-12 and IL-23. These cytokines promote TH1 and TH17 responses, and genetic variation in p40 expression that could cause reduced production of IL-12 and IL-23 was found to be associated with more severe asthma. A fourth candidate susceptibility gene which encodes the β-adrenergic receptor is also located in this region. Variation in this receptor might be associated with alteration in smooth muscle responsiveness to endogenous and pharmacological ligands.
The detection of multiple potential susceptibility genes illustrates a common challenge in identifying the genetic basis of complex disease traits. Relatively small regions of the genome, identified as containing genes for altered disease susceptibility, may contain many good candidates, judging by their known physiological activities. Identifying the gene, or genes, that truly lead to expression of the disease may require studies of several very large populations of patients and controls. For chromosome 5q31–33, for example, it is still too early to know how important each of the different polymorphisms is in the complex genetics of atopy.
A second type of inherited variation in IgE responses is linked to the HLA class II region (the human MHC class II region), and it affects responses to specific allergens, rather than a general susceptibility to atopy. IgE production in response to particular allergens is associated with certain HLA class II alleles, implying that particular peptide:MHC combinations might favor a strong TH2 response; for example, IgE responses to several ragweed pollen allergens are associated with haplotypes containing the HLA class II allele DRB1*1501. Many people are therefore generally predisposed to make TH2 responses and are specifically predisposed to respond to some allergens more than others. Allergic responses to drugs such as penicillin were originally thought to show no association with HLA class II or with the presence or absence of atopy. Recent studies, however, have shown evidence that some drugs can interact with specific HLA alleles in a way that changes the structure of peptide antigens bound in the groove of the HLA molecule so that these altered peptides elicit an autoimmune-type reaction. An example of this is the binding of the seizure medication carbamazepine with HLA-B15:02 and peptide bound in this HLA-B allele. The immune response to this carbamazepine:peptide:HLA-B complex can lead to development of toxic epidermal necrolysis, a severe immune-mediated skin reaction in which widespread skin loss occurs due to necrosis, leaving the skin looking scalded.