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Genetic variation in Toll-like receptors and disease susceptibility

Nature Immunology volume 13, pages 535–542 (2012)Cite this article

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Abstract

Toll-like receptors (TLRs) are key initiators of the innate immune response and promote adaptive immunity. Much has been learned about the role of TLRs in human immunity from studies linking TLR genetic variation with disease. First, monogenic disorders associated with complete deficiency in certain TLR pathways, such as MyD88-IRAK4 or TLR3-Unc93b-TRIF-TRAF3, have demonstrated the specific roles of these pathways in host defense against pyogenic bacteria and herpesviruses, respectively. Second, common polymorphisms in genes encoding several TLRs and associated genes have been associated with both infectious and autoimmune diseases. The study of genetic variation in TLRs in various populations combined with information on infection has demonstrated complex interaction between genetic variation in TLRs and environmental factors. This interaction explains the differences in the effect of TLR polymorphisms on susceptibility to infection and autoimmune disease in various populations.

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Figure 1: TLRs, their main ligands and the intracellular pathways that lead to the stimulation of proinflammatory cytokines.
Figure 2: The structure of the Myddosome and Mal provide information on the molecular basis of why variants in MyD88 and Mal are associated with disease.
Figure 3: The major routes of migration of modern humans after the movement out of Africa 100,000 years ago, and the worldwide geographical distribution of haplotypes of TLR4 and TIRAP (which encodes Mal).
Figure 4: Adaptive evolution caused by infections, combined with nonadaptive evolution caused by genetic drift, population bottlenecks and migration routes, all contribute to PRR polymorphisms in various populations.

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Acknowledgements

Supported by the Netherlands Organization for Scientific Research (M.G.N. and C.W.), Science Foundation Ireland (L.A.J.O.) and the European Research Council (L.A.J.O.).

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Authors and Affiliations

  1. Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Mihai G Netea

  2. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Cisca Wijmenga

  3. Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, The University of Dublin, Dublin, Ireland

    Luke A J O'Neill

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Netea, M., Wijmenga, C. & O'Neill, L. Genetic variation in Toll-like receptors and disease susceptibility. Nat Immunol 13, 535–542 (2012). https://doi.org/10.1038/ni.2284

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