McIntire JJ, Umetsu SE, Akbari O, et al. Nature Immunol. 2001;2:1109–1116
Purpose of the Study.
To identify a central asthma susceptibility gene in the large chromosome 5q23–35 region that has been linked to asthma and atopy, using mouse models of asthma.
Congenic inbred mouse strains: 1) selected for genetic variance in only the chromosomal region homologous to the human chromosome 5q region (mouse chromosome 11), and 2) in which fundamental features of atopic asthma (eg, TH-2-biased immune responses and enhanced bronchial hyperresponsiveness [BHR]) can be induced.
A positional cloning approach was taken to identify and map the genetic locus on mouse chromosome 11 that protected against the induction of TH-2 immune responsiveness and BHR. Using this information, the human homolog to the asthma susceptibility locus in mice was identified, as were genes in this region. The functional consequences of polymorphisms in these genes were then studied in the mouse models.
A single gene locus in mouse chromosome 11 was associated with both TH-2 immune responsiveness and BHR. Called Tapr (T cell and airway phenotype regulator), the human homolog to this region was mapped to human chromosome 5q33.2 and found to contain a Tim (T cell membrane glycoproteins with conserved immunoglobulin variable domain and mucin domains) family of genes. Both TIM-1 and TIM-3 gene expression were strongly associated TH-1-TH-2 differentiation and BHR. Additionally, the human homolog of TIM-1 is a cellular receptor for the hepatitis A virus (HAV).
Tim genes plays an important role in allergic T cell responses, BHR, and asthma susceptibility.
Genetic studies have discovered candidate genes for asthma susceptibility on chromosomes 5, 6, 11, 12, and 14. Chromosome 5q23–35 region has recently received the most attention because this region includes a large number of cytokine and control protein genes that have been associated with asthma, including the TH-2 cytokine cluster (interleukin [IL]-4, IL5, and IL-13), β-adrenergic receptor, IL-12p40 and IL-9. However, a single asthma susceptibility gene in this region has not yet been conclusively identified. This study identified a novel gene cluster of Tim genes in mouse and man, in which polymorphisms were associated with both TH-2 cytokine production and BHR in mouse asthma models. One particularly intriguing aspect of this finding is that human TIM-1 is the HAV receptor. Several recent studies in Italy and the United States by Matricardi and colleagues have associated serologic evidence of previous HAV infection with less allergen sensitization and asthma. The authors of this article postulate that an interaction of HAV with TIM-1 may reduce TH-2 differentiation and the subsequent risk of asthma and allergy. Studies of the immune-modulating effect of HAV via the TIM-1 gene in humans, and the influence of TIM-1 polymorphisms on this effect, are required to confirm this hypothesis. For more information, please see an editorial comment by Wills-Karp titled “Asthma Genetics: Not for the TIMid?” by on page 1095–1096 in the same issue of Nature Immunology, and a review article by Umetsu et al titled “Asthma: An Epidemic of Dysregulated Immunity” in Nature Immunology (2002;3:715–720).