In addition to environmental factors, asthma has a strong genetic component, and several chromosomal regions are linked with susceptibility to asthma and allergy. Pinpointing actual genes within these regions is no easy task. By taking advantage of the similarities between mouse and human genomes, Jennifer McIntire and co-workers, reporting in Nature Immunology, have identified a new family of candidate asthma-susceptibility genes.

Asthma is a chronic debilitating disease that is characterized by airway hyperreactivity and inflammation. Allergic asthma is the most common form of the disease and is thought to result from immune responses to normally harmless inhaled antigens. This leads to the accumulation of effector cells, such as mast cells and eosinophils, and the release of inflammatory mediators. T-helper type 2 (TH2) responses underpin the development of allergic responses. In this respect, it is intriguing that a region of human chromosome 5 associated with susceptibility to asthma (5q23–35) contains many genes that regulate TH2-cell development — including the interleukins IL4 , IL5 , IL13 , IL9 and IL12p40 — but none of these has yet been proven to be an asthma-susceptibility gene.

In this study, a classic genetic approach was used to investigate the effects of individual asthma-susceptibility loci in isolation from the influence of other traits. Allergen-induced airway hyperreactivity (AHR) in mice is an experimental model of asthma. Congenic mice strains were generated in which AHR-susceptible BALB/c mice carry small segments of chromosomes from resistant DBA/2 mice. The congenic mouse strains were then screened for reduced IL-4 production and resistance to AHR. This approach identified a susceptibility locus which is homologous with human 5q33, and has been named Tapr (T cell and airway phenotype regulator).

Fine mapping of the locus shows that Tapr is distinct from the IL4 gene cluster, IL12p40, and other candidate genes found in the syntenic region of human chromosome 5. Positional cloning of Tapr uncovered a new family of three genes that are named Tim. Tim1, Tim2 and Tim3 are transmembrane proteins with extracellular immunoglobulin-like and mucin-like domains, and an intracellular tail with tyrosine phosphorylation sites. The human homologue of Tim1 is the hepatitis A virus receptor (HAVR), which might explain the inverse relationship between HAV infection and allergic diseases.

Sequencing of Tim1 and Tim3 showed major polymorphisms between the susceptible and resistant mouse strains. But how might Tim variants influence TH2 development? The mechanism is not clear, but it seems that Tim expression by activated T cells early in activation might be crucial in controlling the polarization of T cells for TH2-cytokine secretion.