PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. New Genetic Insights into Asthma: the TIM Family Emerges by Paul D. Rennert Asthma is caused by inflammation in the lung. Such inflammation, triggered by allergens and influenced by underlying environmental and genetic factors, is responsible for the disease pathology. A compelling body of experimental evidence has shown that asthma is caused by disregulated T cell function. Activated CD4+ T cells provide the cellular framework supporting two distinct immunological responses termed TH1 or TH2 immunity. TH1 T cells control cytotoxic responses that combat bacterial and viral infections by producing pro-inflammatory cytokines including IFNg and TNF. TH2 T cells produce cytokines, including IL-4, IL-5, IL-6, and IL-13, that are important in the control of extracellular pathogens such as parasites. Importantly, TH1 and TH2 responses seem to counter-regulate each other, such that one or the other, but not both, predominate at any given time. As mentioned, activated T cells can also induce disease. Disregulation of TH1 cytokine production underlies chronic inflammation, such as occurs in rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Disregulation of TH2 cytokine production underlies the development of atopic disorders, including atopic dermatitis and asthma. In the asthma setting TH2 cytokines drive eosinophil activation, IgE production, IgE mediated mast cell activation and degranulation, and accumulation of mononuclear cells and granulocytes into the lung tissue. These cells continue to secrete TH2 cytokines, chemokines, and effector molecules, thereby fostering chronic lung inflammation, which leads to tissue damage and remodeling, causing airway restriction. Asthma and other atopic disorders are increasingly common diseases in developing countries. It has been suggested that the rise in asthma prevalence is linked to improved hygiene, and to a dramatic drop in exposure to viral and bacterial infections. This concept, termed the hygeine hypothesis, states that the recent increase in asthma is due to a disruption in the normal induction of TH1 immunity, leading to a pathogenic shift to predominant TH2 immunity, thereby causing atopic disease. Thus, improvements in living standards have reduced communicable diseases only to give rise to an increase in certain immunological diseases. Genetic linkage studies have also highlighted the association of TH2 cytokines with the development of asthma. Particular attention has focused on specific regions (loci) of chromosome 5 that contains a large number of cytokine pathway genes, including IL-9, the IL-12 receptor, IL-4, IL-5, and 1L-13, and many other relevant genes. A recent mouse study identified a new genetic locus on chromosome 5, adjacent to the cytokine loci, with significant linkage to asthma development. This locus, termed TAPR (T cell and airway phenotype regulator), cosegregated with IL-4 and IL-13 production by T cells and the development of airway hypersensitivity in different strains of mice. The locus contained a newly described gene family called the TIM (for T cell, Immunoglobulin domain and Mucin domain) family. More importantly, analysis of allelic variation in human atopic patients, including asthma patients, demonstrated that TIM-1 gene variability contributed to disease susceptibility in Hepatitis A virus (HAV) seropositive patients and in the general population. There are 2 major forms or alleles of TIM-1, a short form which confers protection from asthma and a long form which does not. As TIM-1 was previously identified as a HAV cellular receptor, this data suggested that the activity of the TIM-1 protein might explain the inverse correlation of HAV incidence and atopic disease described in epidemiological studies. How the allelic variants of human or primate TIM-1 affect binding of HAV is currently not known. It has been speculated that the longer form of TIM-1 allows more successful viral infection, thus driving a greater TH1 response, although there is no direct evidence for this yet. HAV is a member of the picornavirus family, most of which use Immunoglobulin (Ig)-superfamily proteins (like TIM-1) as cellular receptors. Binding of the virus to the Ig-domain may allow other domains of the cellular receptor to bind to the virus, and one or both of these events would then lead to viral instability, uncoating, and the release of viral genomic RNA. In the case of HAV, the Ig-domain of human TIM-1 is sufficient to bind to the viral particles, but does not induce uncoating, while an IgV-mucin-domain containing protein was shown to bind to HAV and disrupt the viral coat. This suggests that both domains are required for efficient HAV binding. It remains to be determined how the short and long forms of TIM-1 influence HAV binding to cells. Strangely, T cells do not appear to be susceptible to productive HAV infection. Instead, after oral ingestion of virus, virions are detected in the stomach and both small and large intestine, where gut epithelial cells are apparently productively infected. Virions then circulate systemically until reaching the liver, where they infect hepatocytes. In chronic infected patients, the disease can cause multiple symptoms, predominantly forms of hepatitis. It is not known yet if intestinal epithelial cells and hepatocytes are infected via TIM-1, or by some other protein. In summary, genetic analyses in mouse strains and in human patient populations have suggested that TIM-1 is an asthma susceptibility gene. Accumulating functional data support this genetic hypothesis. It has been recently shown that the TIM-1 pathway influences CD4+ T cell activity by controlling the expression of multiple TH2 cytokines, and thereby controls the extent of the immune response to antigen challenge in the context of lung inflammation. It is hoped that such work will yield a novel strategy for modulating TIM-1 activity to blunt the expression of TH2 cytokines and block lung inflammation. If this is indeed a pathway that can influence TH2 T cell responses and associated pathology, this suggests that TIM-1 itself will be a productive target for the development of therapeutics to treat asthma, atopic dermatitis, pulmonary fibrosis, and other TH2-driven diseases. References: 1) Woolcock, A.J., and J.K. Peat. 1997. Evidence for the increase in asthma worldwide. Ciba Found. Symp. 206:122-134 2) Matricardi, P.M., F. Rosmini, L. Ferrigno, R. Nisini, M. Rapicetta, P. Chionne,T. Stroffolini, P. Pasquini, and R. D'Amelio. 1997. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. Brit. J. Med. 314:999-1003. 3) Maddox, L., and D.A. Schwartz. 2002. The pathophysiology of asthma. Annu. Rev. Med. 53:477-498. 4) Meyers, J.H., C.A. Sabatos, S. Chakravarti, and V.K. Kuchroo. 2005. The TIM gene family regulates autoimmune and allergic diseases. Trends Mol Med.11:362-369. ### Paul D. Rennert Department of Immunology, Biogen Idec, Inc. 12 Cambridge Ctr, Cambridge, MA 02142 A Member of The Science Advisory Board Steering Commmittee ### << Previous Next >> [ View All Perspectives ] |
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