PEDIATRICS Vol. 112 No. 2 August 2003, pp. 470
IDENTIFICATION OF Tapr (AN AIRWAY HYPERREACTIVITY REGULATORY LOCUS) AND THE LINKED Tim GENE FAMILY
Akaluck Thatayatikom, MD and
Andrew H. Liu, MD
Denver, CO
McIntire JJ, Umetsu SE, Akbari O, et al. Nature Immunol. 2001;2:1109–1116
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Purpose of the Study.
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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.
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Study Population.
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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.
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Methods.
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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.
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Results.
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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).
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Conclusions.
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Tim genes plays an important role in allergic T cell responses,
BHR, and asthma susceptibility.
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Reviewers’ Comments.
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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), ß-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).
PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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Purpose of the Study.
Study Population.
