Hepatitis A virus, TIM-1 and allergy

  • Dale T. Umetsu
  • Rosemarie H. DeKruyff
Part of the Progress in Inflammation Research book series (PIR)


In 1989, Strachan first proposed the hygiene hypothesis to explain the rapid increase in the prevalence of allergy and asthma. While the significant rise in the prevalence of asthma and allergy remains unexplained, epidemiological data suggest that infection with the Hepatitis A virus (HAV) might protect against asthma and allergy, and genetic studies identifying the HAV receptor, TIM-1, as an important atopy susceptibility gene, support this idea. In this chapter, we review the genetics and immunobiology of TIM-1 and TIM gene family members, and the possibility that HAV and TIM-1 may regulate the development of asthma and allergy.


Atopic Dermatitis Food Allergy Allergy Clin Immunol Atopic Disease Hygiene Hypothesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Peden, D.B. 2005. The epidemiology and genetics of asthma risk associated with air pollution. J Allergy Clin Immunol 115: 213–219; quiz 220CrossRefPubMedGoogle Scholar
  2. 2.
    D’Amato, G., and L. Cecchi. 2008. Effects of climate change on environmental factors in respiratory allergic diseases. Clin Exp Allergy 38: 1264–1274CrossRefPubMedGoogle Scholar
  3. 3.
    Camargo, C.A., Jr., S.T. Weiss, S. Zhang, W.C. Willett, and F.E. Speizer. 1999. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 159: 2582–2588CrossRefPubMedGoogle Scholar
  4. 4.
    Beasley, R., T. Clayton, J. Crane, E. von Mutius, C.K. Lai, S. Montefort, and A. Stewart. 2008. Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme. Lancet 372: 1039–1048CrossRefPubMedGoogle Scholar
  5. 5.
    Camargo, C.A., Jr., S.L. Rifas-Shiman, A.A. Litonjua, J.W. Rich-Edwards, S.T. Weiss, D.R. Gold, K. Kleinman, and M.W. Gillman. 2007. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr 85: 788–795PubMedGoogle Scholar
  6. 6.
    Strachan, D.P. 1989. Hay fever, hygiene, and household size. BMJ 299: 1259–1260CrossRefPubMedGoogle Scholar
  7. 7.
    Bach, J. 2002. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347: 911–920CrossRefPubMedGoogle Scholar
  8. 8.
    Matricardi, P., F. Rosmini, S. Riondino, M. Fortini, L. Ferrigno, M. Rapicetta, and S. Bonini. 2000. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ 320: 412–417CrossRefPubMedGoogle Scholar
  9. 9.
    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. BMJ 314: 999–1003PubMedGoogle Scholar
  10. 10.
    Linneberg, A., C. Ostergaard, M. Tvede, L.P. Andersen, N.H. Nielsen, F. Madsen, L. Frolund, A. Dirksen, and T. Jorgensen. 2003. IgG antibodies against microorganisms and atopic disease in Danish adults: the Copenhagen Allergy Study. J Allergy Clin Immunol 111: 847–853CrossRefPubMedGoogle Scholar
  11. 11.
    Jarvis, D., C. Luczynska, S. Chinn, and P. Burney. 2004. The association of hepatitis A and Helicobacter pylori with sensitization to common allergens, asthma and hay fever in a population of young British adults. Allergy 59: 1063–1067CrossRefPubMedGoogle Scholar
  12. 12.
    Kosunen, T.U., J. Hook-Nikanne, A. Salomaa, S. Sarna, A. Aromaa, and T. Haahtela. 2002. Increase of allergen-specific immunoglobulin E antibodies from 1973 to 1994 in a Finnish population and a possible relationship to Helicobacter pylori infections. Clin Exp Allergy 32: 373–378CrossRefPubMedGoogle Scholar
  13. 13.
    Illi, S., E. von Mutius, S. Lau, R. Bergmann, B. Niggemann, C. Sommerfeld, and U. Wahn. 2001. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ 322: 390–395CrossRefPubMedGoogle Scholar
  14. 14.
    Shirakawa, T., T. Enomoto, S. Shimazu, and J.M. Hopkin. 1997. The inverse association between tuberculin responses and atopic disorder. Science 275: 77–79CrossRefPubMedGoogle Scholar
  15. 15.
    Haaheim, L., J. Pattison, and R. Whitley. 2002. A practical guide to clinical virology. John Wiley & Sons.Google Scholar
  16. 16.
    Ball, T.M., J.A. Castro-Rodriguez, K.A. Griffith, C.J. Holberg, F.D. Martinez, and A.L. Wright. 2000. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 343: 538–543CrossRefPubMedGoogle Scholar
  17. 17.
    McIntire, J., S. Umetsu, C. Macaubas, E. Hoyte, C. Cinnioglu, L. Cavalli-Sforza, G. Barsh, J. Hallmayer, P. Underhill, N. Risch, G. Freeman, R. DeKruyff, and D. Umetsu. 2003. Immunology: hepatitis A virus link to atopic disease. Nature 425: 576CrossRefPubMedGoogle Scholar
  18. 18.
    McIntire, J.J., S.E. Umetsu, O. Akbari, M. Potter, V.K. Kuchroo, G.S. Barsh, G.J. Freeman, D.T. Umetsu, and R.H. DeKruyff. 2001. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2: 1109–1116CrossRefPubMedGoogle Scholar
  19. 19.
    Ruscetti, S., R. Matthai, and M. Potter. 1985. Susceptibility of BALB/c mice carrying various DBA/2 genes to development of Friend murine leukemia virus-induced erythroleukemia. J Exp Med 162: 1579–1587CrossRefPubMedGoogle Scholar
  20. 20.
    Marsh, D.G., J.D. Neely, D.R. Breazeale, B. Ghosh, L.R. Freidhoff, E. Ehrlich-Kautzky, C. Schou, G. Krishnaswamy, and T.H. Beaty. 1994. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 264: 1152–1156CrossRefPubMedGoogle Scholar
  21. 21.
    McIntire, J.J., D.T. Umetsu, and R.H. DeKruyff. 2004. TIM-1, a novel allergy and asthma susceptibility gene. Springer Semin Immunopathol 25: 335–348CrossRefPubMedGoogle Scholar
  22. 22.
    Santiago, C., A. Ballesteros, C. Tami, L. Martinez-Munoz, G.G. Kaplan, and J.M. Casasnovas. 2007. Structures of T Cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family. Immunity 26: 299–310CrossRefPubMedGoogle Scholar
  23. 23.
    Gao, P.S., R.A. Mathias, B. Plunkett, A. Togias, K.C. Barnes, T.H. Beaty, and S.K. Huang. 2005. Genetic variants of the T-cell immunoglobulin mucin 1 but not the T-cell immunoglobulin mucin 3 gene are associated with asthma in an African American population. J Allergy Clin Immunol 115: 982–988CrossRefPubMedGoogle Scholar
  24. 24.
    Graves, P.E., V. Siroux, S. Guerra, W.T. Klimecki, and F.D. Martinez. 2005. Association of atopy and eczema with polymorphisms in T-cell immunoglobulin domain and mucin domain-IL-2-inducible T-cell kinase gene cluster in chromosome 5 q 33. J Allergy Clin Immunol 116: 650–656CrossRefPubMedGoogle Scholar
  25. 25.
    Page, N.S., G. Jones, and G.J. Stewart. 2006. Genetic association studies between the T cell immunoglobulin mucin (TIM) gene locus and childhood atopic dermatitis. Int Arch Allergy Immunol 141: 331–336CrossRefPubMedGoogle Scholar
  26. 26.
    Chae, S., J. Song, Y. Lee, J. Kim, and H. Chung. 2003. The association of the exon 4 variations of Tim-1 gene with allergic diseases in a Korean population. Biochem Biophys Res Commun 12: 346–350CrossRefGoogle Scholar
  27. 27.
    Noguchi, E., J. Nakayama, M. Kamioka, K. Ichikawa, M. Shibasaki, and T. Arinami. 2003. Insertion/deletion coding polymorphisms in hHAVcr-1 are not associated with atopic asthma in the Japanese population. Genes Immun 4: 170–173CrossRefPubMedGoogle Scholar
  28. 28.
    Chae, S.C., Y.R. Park, J.H. Song, S.C. Shim, K.S. Yoon, and H.T. Chung. 2005. The polymorphisms of Tim-1 promoter region are associated with rheumatoid arthritis in a Korean population. Immunogenetics 56: 696–701CrossRefPubMedGoogle Scholar
  29. 29.
    Khademi, M., Z. Illes, A.W. Gielen, M. Marta, N. Takazawa, C. Baecher-Allan, L. Brundin, J. Hannerz, C. Martin, R.A. Harris, D.A. Hafler, V.K. Kuchroo, T. Olsson, F. Piehl, and E. Wallstrom. 2004. T Cell Ig-and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J Immunol 172: 7169–7176PubMedGoogle Scholar
  30. 30.
    Martinez, F.D. 2007. CD14, endotoxin, and asthma risk: actions and interactions. Proc Am Thorac Soc 4: 221–225CrossRefPubMedGoogle Scholar
  31. 31.
    Martinez, F.D. 2008. Gene-environment interaction in complex diseases: asthma as an illustrative case. Novartis Found Symp 293: 184–192; discussion 192–187CrossRefPubMedGoogle Scholar
  32. 32.
    Umetsu, D.T., S.E. Umetsu, G.J. Freeman, and R.H. DeKruyff. 2008. TIM gene family and their role in atopic diseases. Curr Top Microbiol Immunol 321: 201–215CrossRefPubMedGoogle Scholar
  33. 33.
    Kuchroo, V.K., V. Dardalhon, S. Xiao, and A.C. Anderson. 2008. New roles for TIM family members in immune regulation. Nat Rev Immunol 8: 577–580CrossRefPubMedGoogle Scholar
  34. 34.
    Umetsu, S., W. Lee, J. McIntire, L. Downey, B. Sanjanwala, O. Akbari, G. Berry, H. Nagumo, G. Freeman, D. Umetsu, and R. DeKruyff. 2005. TIM-1 induces T cell activation and inhibits the development of peripheral tolerance. Nature Immunol 6: 447–454CrossRefGoogle Scholar
  35. 35.
    Akbari, O., G.J. Freeman, E.H. Meyer, E.A. Greenfield, T.T. Chang, A.H. Sharpe, G. Berry, R.H. DeKruyff, and D.T. Umetsu. 2002. Antigen-specific regulatory T cells develop via the ICOS-ICOS-Ligand pathway and inhibit allergen-induced airway hyper-reactivity. Nat Med 8: 1024–1032CrossRefPubMedGoogle Scholar
  36. 36.
    Stock, P., O. Akbari, G. Berry, G. Freeman, R. DeKruyff, and D.T. Umetsu. 2004. Induction of TH1-like regulatory cells that express Foxp3 and protect against airway hyperreactivity. Nature Immunol 5: 1149–1156CrossRefGoogle Scholar
  37. 37.
    Degauque, N., C. Mariat, J. Kenny, D. Zhang, W. Gao, M.D. Vu, S. Alexopoulos, M. Oukka, D.T. Umetsu, R.H. DeKruyff, V. Kuchroo, X.X. Zheng, and T.B. Strom. 2008. Immunostimulatory Tim-1-specific antibody deprograms Tregs and prevents transplant tolerance in mice. J Clin Invest 118: 735–741CrossRefPubMedGoogle Scholar
  38. 38.
    Sizing, I.D., V. Bailly, P. McCoon, W. Chang, S. Rao, L. Pablo, R. Rennard, M. Walsh, Z. Li, M. Zafari, M. Dobles, L. Tarilonte, S. Miklasz, G. Majeau, K. Godbout, M.L. Scott, and P.D. Rennert. 2007. Epitope-dependent effect of anti-murine TIM-1 monoclonal antibodies on T cell activity and lung immune responses. J Immunol 178: 2249–2261PubMedGoogle Scholar
  39. 39.
    Xiao, S., N. Najafian, J. Reddy, M. Albin, C. Zhu, E. Jensen, J. Imitola, T. Korn, A.C. Anderson, Z. Zhang et al. 2007. Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function. J Exp Med 204: 1691–1702CrossRefPubMedGoogle Scholar
  40. 40.
    de Souza, A.J., T.B. Oriss, J. O’Malley K, A. Ray, and L.P. Kane. 2005. T cell Ig and mucin 1 (TIM-1) is expressed on in vivo-activated T cells and provides a costimulatory signal for T cell activation. Proc Natl Acad Sci USA 102: 17113–17118CrossRefPubMedGoogle Scholar
  41. 41.
    Binne, L.L., M.L. Scott, and P.D. Rennert. 2007. Human TIM-1 associates with the TCR complex and up-regulates T cell activation signals. J Immunol 178: 4342–4350PubMedGoogle Scholar
  42. 42.
    Tami, C., E. Silberstein, M. Manangeeswaran, G.J. Freeman, S.E. Umetsu, R.H. DeKruyff, D.T. Umetsu, and G.G. Kaplan 2007. Immunoglobulin A (IgA) is a natural ligand of hepatitis A virus cellular receptor 1 (HAVCR1), and the association of IgA with HAVCR1 enhances virus-receptor interactions. J Virol 81: 3437–3446CrossRefPubMedGoogle Scholar
  43. 43.
    Kobayashi, N., P. Karisola, V. Pena-Cruz, D.M. Dorfman, M. Jinushi, S.E. Umetsu, M.J. Butte, H. Nagumo, I. Chernova, B. Zhu et al. 2007. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27: 927–940CrossRefPubMedGoogle Scholar
  44. 44.
    Meyers, J., S. Chakravarti, D. Schlesinger, D. Illes, H. Waldner, S. Umetsu, J. Kenny, X. Zheng, D. Umetsu, R. DeKruyff, T. Strom, and V. Kuchroo. 2005. Tim-4 is the ligand for Tim-1, and the Tim-1-Tim-4 interaction regulates T cell expansion. Nature Immunol 6: 455–464CrossRefGoogle Scholar
  45. 45.
    Wilker, P.R., J.R. Sedy, V. Grigura, T.L. Murphy, and K.M. Murphy. 2007. Evidence for carbohydrate recognition and homotypic and heterotypic binding by the TIM family. Int Immunol 19: 763–773CrossRefPubMedGoogle Scholar
  46. 46.
    Shakhov, A.N., S. Rybtsov, A.V. Tumanov, S. Shulenin, M. Dean, D.V. Kuprash, and S.A. Nedospasov. 2004. SMUCKLER/TIM4 is a distinct member of TIM family expressed by stromal cells of secondary lymphoid tissues and associated with lymphotoxin signaling. Eur J Immunol 34: 494–503.CrossRefPubMedGoogle Scholar
  47. 47.
    Thery, C., L. Zitvogel, and S. Amigorena. 2002. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2: 569–579PubMedGoogle Scholar
  48. 48.
    Santiago, C., A. Ballesteros, L. Martinez-Munoz, M. Mellado, G.G. Kaplan, G.J. Freeman, and J.M. Casasnovas. 2007. Structures of T cell immunoglobulin mucin protein 4 show a metal-ion-dependent ligand binding site where phosphatidylserine binds. Immunity 27: 941–951CrossRefPubMedGoogle Scholar
  49. 49.
    Miyanishi, M., K. Tada, M. Koike, Y. Uchiyama, T. Kitamura, and S. Nagata. 2007. Identification of Tim4 as a phosphatidylserine receptor. Nature 450: 435–439CrossRefPubMedGoogle Scholar
  50. 50.
    Nagata, S. 1997. Apoptosis by death factor. Cell 88: 355–365CrossRefPubMedGoogle Scholar
  51. 51.
    Vaux, D.L., and S.J. Korsmeyer. 1999. Cell death in development. Cell 96: 245–254CrossRefPubMedGoogle Scholar
  52. 52.
    Savill, J., I. Dransfield, C. Gregory, and C. Haslett. 2002. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2: 965–975CrossRefPubMedGoogle Scholar
  53. 53.
    Savill, J., and V. Fadok 2000. Corpse clearance defines the meaning of cell death. Nature 407: 784–788CrossRefPubMedGoogle Scholar
  54. 54.
    Botto, M., C. Dell’Agnola, A.E. Bygrave, E.M. Thompson, H.T. Cook, F. Petry, M. Loos, P.P. Pandolfi, and M.J. Walport. 1998. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 19: 56–59CrossRefPubMedGoogle Scholar
  55. 55.
    Taylor, P.R., A. Carugati, V.A. Fadok, H.T. Cook, M. Andrews, M.C. Carroll, J.S. Savill, P.M. Henson, M. Botto, and M.J. Walport. 2000. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 192: 359–366CrossRefPubMedGoogle Scholar
  56. 56.
    Hanayama, R., M. Tanaka, K. Miyasaka, K. Aozasa, M. Koike, Y. Uchiyama, and S. Nagata. 2004. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304: 1147–1150CrossRefPubMedGoogle Scholar
  57. 57.
    Albert, M.L., B. Sauter, and N. Bhardwaj 1998. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392: 86–89CrossRefPubMedGoogle Scholar
  58. 58.
    Scott, R.S., E.J. McMahon, S.M. Pop, E.A. Reap, R. Caricchio, P.L. Cohen, H.S. Earp, and G.K. Matsushima. 2001. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411: 207–211CrossRefPubMedGoogle Scholar
  59. 59.
    Hanayama, R., M. Tanaka, K. Miwa, A. Shinohara, A. Iwamatsu, and S. Nagata. 2002. Identification of a factor that links apoptotic cells to phagocytes. Nature 417: 182–187CrossRefPubMedGoogle Scholar
  60. 60.
    Liu, G., C. Wu, Y. Wu, and Y. Zhao. 2006. Phagocytosis of apoptotic cells and immune regulation. Scand J Immunol 64: 1–9CrossRefPubMedGoogle Scholar
  61. 61.
    Nagata, K., K. Ohashi, T. Nakano, H. Arita, C. Zong, H. Hanafusa, and K. Mizuno. 1996. Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J Biol Chem 271: 30022–30027CrossRefPubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2009

Authors and Affiliations

  • Dale T. Umetsu
    • 1
  • Rosemarie H. DeKruyff
    • 1
  1. 1.Harvard Medical SchoolChildren’s Hospital BostonBostonUSA

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