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The human model: a genetic dissection of immunity to infection in natural conditions

Nature Reviews Immunology volume 4, pages 55–66 (2004)Cite this article

Key Points

  • Infection and immunity in humans occur in natural conditions, as opposed to experimental conditions in animal models. In our view, this accounts for most of the advantages and disadvantages of human studies, when compared with animal studies.

  • Immunocompetence can be defined as the immune status that results in self-healing infection, with or without symptoms, but of favourable outcome without any specific treatment. After exposure to the microbial world, human immunocompetence (to all microorganisms) is rare and immunodeficiency (to at least one microorganism) is, therefore, the rule rather than the exception.

  • All clinical and biological phenotypes in the course of an infectious disease result from the complex interaction between environmental (microbial and non-microbial) and host (genetic and non-genetic) factors. A forward-genetic dissection of immunity to infection is therefore possible.

  • The human model is an indispensable complement to animal studies, as it provides insight into the ecologically relevant and evolutionary selected functions of cells and molecules that are involved in immunity to infection. The forward-genetic dissection of immunity to infection in humans benefits from being an observational study of host–environment interaction in a natural ecosystem.

  • In some cases, 'wild-type' individuals are vulnerable to common infection, whereas mutants with relatively common Mendelian mutations are fully resistant and otherwise healthy. Examples include resistance to Plasmodium vivax associated with recessive mutations in Duffy antigen receptor for chemokines (DARC), resistance to HIV-1 with recessive mutations in CC-chemokine receptor 5 (CCR5) and resistance to noroviruses with recessive mutations in fucosyltransferase 2 (FUT2).

  • Studies of human genetics of infectious diseases have challenged several immunological theories and, to a lesser extent, data obtained in mice. Examples include the lack of viral diseases in children with mutations that impair antigen presentation to, or recognition by, cytotoxic CD8+ T cells, and the narrow spectrum of infections in children with mutations in the interleukin-12 (IL-12)–interferon-γ pathway or IL-1 receptor-associated kinase 4 (IRAK4).

  • The study of Mendelian 'holes' in immunity to infection has indicated the existence of 'pathogen-specific' genes in natural conditions of infection. Examples include the group of genetic defects of the terminal components of complement, associated with Neisseria infections, and epidermodysplasia verruciformis, associated with a selective susceptibility to human papillomaviruses.

  • There is a continuous spectrum between rare Mendelian vulnerability to poorly virulent microorganisms and common complex predisposition to virulent microorganisms. The elucidation of the genetic basis of common infectious diseases also sheds light on immunological mechanisms. Mendelian susceptibility to tuberculosis and complex susceptibility to leprosy have indicated the function of important immunological pathways.

Abstract

Tremendous progress has been achieved in developmental, cellular and molecular immunology in the past 20 years, largely due to studies using the mouse as a model system and the arrival of molecular genetics. Immunology is now faced with a difficult challenge. What are the functions of the individual cells and molecules in achieving immunity to infection? Renewed interest in animal models of disease has provided considerable insight in this area, but such models of infection suffer from the inherent limitation of being experimental. In humans, the complex host–environment interaction occurs in natural, as opposed to experimental, conditions. The human model is therefore an indispensable complement to animal models, as it allows an observational genetic dissection of immunity to infection.

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Figure 1: A schematic showing the stages of the host–environment interaction in the course of infection.
Figure 2: A schematic showing the involvement of IRAK4, NEMO and IκBα, and the TIR and NF-κB signalling pathways downstream from TLR, IL-1R and TNFR superfamily members.
Figure 3: The IL-12/IL-23–IFN-γ loop and cooperation between macrophages/dendritic cells and natural killer cells/T cells.

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References

  1. Paul, W. E. Fundamental Imunology (Lippincott–Raven, Philadelphia, 1998).

    Google Scholar 

  2. Du Pasquier, L. The immune system of invertebrates and vertebrates. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 129, 1–15 (2001).

    CAS  PubMed  Google Scholar 

  3. Hoffmann, J. A. The immune response of Drosophila. Nature 426, 33–38 (2003).

    CAS  PubMed  Google Scholar 

  4. Tzou, P., De Gregorio, E. & Lemaitre, B. How Drosophila combats microbial infection: a model to study innate immunity and host–pathogen interactions. Curr. Opin. Microbiol. 5, 102–110 (2002).

    CAS  PubMed  Google Scholar 

  5. Fluhr, R. & Kaplan-Levy, R. N. Plant disease resistance: commonality and novelty in multicellular innate immunity. Curr. Top. Microbiol. Immunol. 270, 23–46 (2002).

    CAS  PubMed  Google Scholar 

  6. Casanova, J. L., Schurr, E., Abel, L. & Skamene, E. Forward genetics of infectious diseases: immunological impact. Trends Immunol. 23, 469–472 (2002).

    CAS  PubMed  Google Scholar 

  7. Buer, J. & Balling, R. Mice, microbes and models of infection. Nature Rev. Genet. 4, 195–205 (2003).

    CAS  PubMed  Google Scholar 

  8. Kurz, C. L. & Ewbank, J. J. Caenorhabditis elegans: an emerging genetic model for the study of innate immunity. Nature Rev. Genet. 4, 380–390 (2003).

    CAS  PubMed  Google Scholar 

  9. Casanova, J. L. & Abel, L. Genetic dissection of immunity to mycobacteria: the human model. Annu. Rev. Immunol. 20, 581–620 (2002).

    CAS  PubMed  Google Scholar 

  10. Pasteur, L. Oeuvres complétes de Louis Pasteur, réunies par Pasteur Vallery-Radot (Masson et Cie, Paris, 1922–1939).

  11. Dubos, R. J. Louis Pasteur, Free Lance of Science (Little Brown, Boston, 1950).

    Google Scholar 

  12. Abel, L. & Dessein, A. J. Genetic epidemiology of infectious diseases in humans: design of population-based studies. Emerg. Infect. Dis. 4, 593–603 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kwiatkowski, D. Science, medicine, and the future: susceptibility to infection. BMJ 321, 1061–1065 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Burgner, D. & Levin, M. Genetic susceptibility to infectious diseases. Pediatr. Infect. Dis. J. 22, 1–6 (2003).

    PubMed  Google Scholar 

  15. Bruton, O. C. Agammaglobulinemia. Pediatrics 9, 722–728 (1952). This is the first clinical description of a Mendelian primary immunodeficiency. Children with X-linked recessive Bruton's aggamaglobulinaemia lack peripheral B cells and mostly suffer from severe pyogenic bacterial infections.

    CAS  PubMed  Google Scholar 

  16. Hitzig, W. H. The discovery of agammaglobulinaemia in 1952. Eur. J. Pediatr. 162, 289–304 (2003).

    PubMed  Google Scholar 

  17. WHO. Primary immunodeficiency diseases: an update. Clin. Exp. Immunol. 132, 9–15 (2003).

  18. Ochs, H., Smith C. I. E. & Puck, J. Primary Immunodeficiencies: a Molecular and Genetic Approach (Oxford Univ. Press, New York, 2003).

    Google Scholar 

  19. Fischer, A. Primary immunodeficiency diseases: an experimental model for molecular medicine. Lancet 357, 1863–1869 (2001).

    CAS  PubMed  Google Scholar 

  20. Allison, A. C. Protection afforded by sickle cell trait against subtertian malarian infection. BMJ 1, 290–294 (1954). This is the first evidence for a non-Mendelian contribution of human genes to the development of an infectious disease. The haemoglobin S trait (sickle-cell disease, drapanocytosis) confers protection from Plasmodium falciparum malaria, probably accounting for the increase of this trait in endemic regions.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Weatherall, D. J. Common genetic disorders of the red cell and the 'malaria hypothesis'. Ann. Trop. Med. Parasitol. 81, 539–548 (1987).

    CAS  PubMed  Google Scholar 

  22. Joliat, M. J. & Shultz, L. D. The molecular bases of spontaneous immunological mutations in the mouse and their homologous human diseases. Clin. Immunol. 101, 113–129 (2001).

    CAS  PubMed  Google Scholar 

  23. Kaufmann, S. H. Bacterial and protozoal infections in genetically disrupted mice. Curr. Opin. Immunol. 6, 518–525 (1994).

    CAS  PubMed  Google Scholar 

  24. van den Broek, M. F., Müller, U., Huang, S., Zinkernagel, R. M. & Aguet, M. Immune defence in mice lacking ype I and/or type II interferon receptors. Immunol. Rev. 148, 5–18 (1995).

    CAS  PubMed  Google Scholar 

  25. Yap, G. S. & Sher, A. The use of germ line-mutated mice in understanding host-pathogen interactions. Cell Microbiol. 4, 627–634 (2002).

    CAS  PubMed  Google Scholar 

  26. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    CAS  PubMed  Google Scholar 

  27. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    CAS  PubMed  Google Scholar 

  28. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    CAS  PubMed  Google Scholar 

  29. Sachidanandam, R. et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933 (2001).

    CAS  PubMed  Google Scholar 

  30. Nehls, M., Pfeifer, D., Schorpp, M., Hedrich, H. & Boehm, T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372, 103–107 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. Frank, J. et al. Exposing the human nude phenotype. Nature 398, 473–474 (1999).

    CAS  PubMed  Google Scholar 

  32. Shiflett, S. L., Kaplan, J. & Ward, D. M. Chediak-Higashi syndrome: a rare disorder of lysosomes and lysosome related organelles. Pigment Cell Res. 15, 251–257 (2002).

    CAS  PubMed  Google Scholar 

  33. Conley, M. E. & Howard, V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J. Pediatr. 141, 566–571 (2002).

    PubMed  Google Scholar 

  34. Gambineri, E., Torgerson, T. R. & Ochs, H. D. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr. Opin. Rheumatol. 15, 430–435 (2003).

    CAS  PubMed  Google Scholar 

  35. Lindenmann, J. Resistance of mice to mouse-adapted influenza A virus. Virology 16, 203–204 (1962).

    CAS  PubMed  Google Scholar 

  36. Horisberger, M. A., Stäheli, P. & Haller, O. Interferon induces a unique protein in mouse cells bearing a gene for resistance to influenza virus. Proc. Natl Acad. Sci. USA 80, 1910–1914 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Staeheli, P., Haller, O., Boll, W., Lindenmann, J. & Weissmann, C. Mx protein: constitutive expression in 3T3 cells transformed with cloned Mx cDNA confers selective resistance to influenza virus. Cell 44, 147–158 (1986).

    CAS  PubMed  Google Scholar 

  38. Haller, O. & Kochs, G. Interferon-induced Mx proteins: dynamin-like GTPases with antiviral activity. Traffic 3, 710–717 (2002).

    CAS  PubMed  Google Scholar 

  39. Gros, P., Skamene, E. & Forget, A. Genetic control of natural resistance to Mycobacterium bovis (BCG) in mice. J. Immunol. 127, 2417–2421 (1981).

    CAS  PubMed  Google Scholar 

  40. Vidal, S., Malo, D., Vogan, K., Skamene, E. & Gros, P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 73, 469–485 (1993).

    CAS  PubMed  Google Scholar 

  41. Buu, N., Sanchez, F. & Schurr, E. The Bcg host-resistance gene. Clin. Infect. Dis. 31 (Suppl. 3), S81–S85 (2000).

    CAS  PubMed  Google Scholar 

  42. Farrar, J. D. et al. Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2. Nature Immunol. 1, 65–69 (2000).

    CAS  Google Scholar 

  43. Wade, C. M. et al. The mosaic structure of variation in the laboratory mouse genome. Nature 420, 574–578 (2002).

    CAS  PubMed  Google Scholar 

  44. Guenet, J. L. & Bonhomme, F. Wild mice: an ever-increasing contribution to a popular mammalian model. Trends Genet. 19, 24–31 (2003).

    CAS  PubMed  Google Scholar 

  45. Appleby, M. W. & Ramsdell, F. A forward-genetic approach for analysis of the immune system. Nature Rev. Immunol. 3, 463–471 (2003).

    CAS  Google Scholar 

  46. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    CAS  PubMed  Google Scholar 

  47. Qureshi, S. T. et al. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J. Exp. Med. 189, 615–625 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Wright, E. K. et al. Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr. Biol. 13, 27–36 (2003).

    CAS  PubMed  Google Scholar 

  49. Diez, E. et al. Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nature Genet. 33, 55–60 (2003).

    CAS  PubMed  Google Scholar 

  50. Perelygin, A. A. et al. Positional cloning of the murine flavivirus resistance gene. Proc. Natl Acad. Sci. USA 99, 9322–9327 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Mashimo, T. et al. A nonsense mutation in the gene encoding 2′-5′-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice. Proc. Natl Acad. Sci. USA 99, 11311–11316 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Lee, S. H. et al. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nature Genet. 28, 42–45 (2001).

    CAS  PubMed  Google Scholar 

  53. Brown, M. G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001).

    CAS  PubMed  Google Scholar 

  54. Daniels, K. A. et al. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J. Exp. Med. 194, 29–44 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Holmes, K. V. & Dveksler, G. S. in Cellular Receptors for Animal Viruses (ed. Wimmer, E.) 403–443 (Cold Spring Harbor Laboratory Press, New York, 1994).

  56. Taylor, G. M., Gao, Y. & Sanders, D. A. Fv-4: identification of the defect in Env and the mechanism of resistance to ecotropic murine leukemia virus. J. Virol. 75, 11244–11248 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Shaw, M. H. et al. A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10. Q/J mice to infection and autoimmunity. Proc. Natl Acad. Sci. USA 100, 11594–11599 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Lee, S. H. et al. Maneuvering for advantage: the genetics of mouse susceptibility to virus infection. Trends Genet. 19, 447–457 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Feigin, R. D. & Cherry, J. D. Textbook of Pediatric Infectious Diseases (W. B. Saunders Company, Philadelphia, USA, 1998).

    Google Scholar 

  60. Gorbach, S. L., Barlett, J. G. & Blacklow, N. R. Infectious Diseases (W. B. Saunders Company, Philadelphia, USA, 1998).

    Google Scholar 

  61. Lecuit, M. et al. A transgenic model for listeriosis: role of internalin in crossing the intestinal barrier. Science 292, 1722–1725 (2001).

    CAS  PubMed  Google Scholar 

  62. Favre, M., Ramoz, N. & Orth, G. Human papillomaviruses: general features. Clin. Dermatol. 15, 181–198 (1997).

    CAS  PubMed  Google Scholar 

  63. Breitburd, F., Salmon, J. & Orth, G. The rabbit viral skin papillomas and carcinomas: a model for the immunogenetics of HPV-associated carcinogenesis. Clin. Dermatol. 15, 237–247 (1997).

    CAS  PubMed  Google Scholar 

  64. Ramoz, N., Rueda, L. A., Bouadjar, B., Favre, M. & Orth, G. A susceptibility locus for epidermodysplasia verruciformis, an abnormal predisposition to infection with the oncogenic human papillomavirus type 5, maps to chromosome 17qter in a region containing a psoriasis locus. J. Invest. Dermatol. 112, 259–263 (1999).

    CAS  PubMed  Google Scholar 

  65. Ramoz, N. et al. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nature Genet. 32, 579–581 (2002). This is the first identification of a Mendelian genetic aetiology for the syndrome of epidermodysplasia verruciformis, which is characterized by a specific susceptibility to oncogenic cutaneous papillomaviruses. The positional cloning approach allowed the discovery of two new genes located in tandem, which opens a new field in skin immunity.

    CAS  PubMed  Google Scholar 

  66. Hernandez, P. A. et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nature Genet. 34, 70–74 (2003). Reports the genetic aetiology of the WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome, characterized by severe infections caused by human papillomaviruses and other microorganisms.

    CAS  PubMed  Google Scholar 

  67. Miller, L. H., Mason, S. J., Clyde, D. F. & McGinniss, M. H. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N. Engl. J. Med. 295, 302–304 (1976).

    CAS  PubMed  Google Scholar 

  68. Miller, L. H., Mason, S. J., Dvorak, J. A., McGinniss, M. H. & Rothman, I. K. Erythrocyte receptors for (Plasmodium knowlesi) malaria: Duffy blood group determinants. Science 189, 561–563 (1975). References 67 and 68 describe the first Mendelian resistance to common infectious diseases in humans. Individuals negative for the Duffy red-cell antigen were shown to be completely resistant to Plasmodium vivax , probably accounting for the increase of this genotype in endemic regions.

    CAS  PubMed  Google Scholar 

  69. Miller, L. H., Aikawa, M., Johnson, J. G. & Shiroishi, T. Interaction between cytochalasin B-treated malarial parasites and erythrocytes. Attachment and junction formation. J. Exp. Med. 149, 172–184 (1979).

    CAS  PubMed  Google Scholar 

  70. Tournamille, C., Colin, Y., Cartron, J. P. & Le Van Kim, C. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nature Genet. 10, 224–228 (1995). This paper elucidated the molecular basis of the lack of erythroid expression of Duffy in Plasmodium vivax -resistant individuals. Remarkably, a recessive regulatory single-nucleotide substitution accounts for the erythroid-specific lack of Duffy expression.

    CAS  PubMed  Google Scholar 

  71. Nickel, R. G. et al. Determination of Duffy genotypes in three populations of African descent using PCR and sequence-specific oligonucleotides. Hum. Immunol. 60, 738–742 (1999).

    CAS  PubMed  Google Scholar 

  72. Samson, M. et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR5 chemokine receptor gene. Nature 382, 722–725 (1996).

    CAS  PubMed  Google Scholar 

  73. Liu, R. et al. Homozygous defects in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).

    CAS  PubMed  Google Scholar 

  74. Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 273, 1856–1862 (1996). References 73 and 74 describe the first Mendelian resistance to HIV-1, caused by recessive mutations in CC-chemokine receptor 5 (I>CCR5).

    CAS  PubMed  Google Scholar 

  75. Stephens, J. C. et al. Dating the origin of the CCR5-Δ32 AIDS-resistance allele by the coalescence of haplotypes. Am. J. Hum. Genet. 62, 1507–1515 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Lindesmith, L. et al. Human susceptibility and resistance to Norwalk virus infection. Nature Med. 9, 548–553 (2003). This is the third example of Mendelian resistance to common infections, as recessive mutations in fucosyltransferase 2 ( FUT2 ) are associated with resistance to gastroenteritis caused by noroviruses.

    CAS  PubMed  Google Scholar 

  77. Marionneau, S. et al. Norwalk virus binds to histo-blood group antigens present on gastroduodenal epithelial cells of secretor individuals. Gastroenterology 122, 1967–1977 (2002).

    CAS  PubMed  Google Scholar 

  78. Tsukada, S. et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72, 279–290 (1993).

    CAS  PubMed  Google Scholar 

  79. Zeidler, C. & Welte, K. Kostmann syndrome and severe congenital neutropenia. Semin. Hematol. 39, 82–88 (2002).

    CAS  PubMed  Google Scholar 

  80. Kostmann, R. Infantile genetic agranulocytosis: a review with presentation of ten new cases. Acta Pediatr. Scand. 64, 362–368 (1975).

    Google Scholar 

  81. Kostmann, R. Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria.. Acta Paediatr. Scand. 45, 1–78 (1956). The first description of a Mendelian disorder of myeloid cells, with an autosomal recessive lack of polymorphonuclear leukocytes in children with severe infections.

    CAS  Google Scholar 

  82. Dale, D. C. et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 96, 2317–2322 (2000).

    CAS  PubMed  Google Scholar 

  83. Person, R. E. et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nature Genet. 34, 308–312 (2003).

    CAS  PubMed  Google Scholar 

  84. DiGeorge, A. M. A new concept of the cellular basis of immunity. J. Pediatr. 67, 907–908 (1965). Following Bruton's agammaglobulinaemia and Kostmann's agranulocytosis, the third description of a genetically determined complete lack of a leukocyte subset: patients with Di George syndrome are heterozygous for a dominant 22q11 deletion and lack peripheral T cells due to impaired thymus formation. This disorder is not strictly Mendelian, as the causal dominant gene(s) is not known and the penetrance of the T-cell anomaly is very low.

    Google Scholar 

  85. Perez, E. & Sullivan, K. E. Chromosome 22q11.2 deletion syndrome (DiGeorge and velocardiofacial syndromes). Curr. Opin. Pediatr. 14, 678–683 (2002).

    PubMed  Google Scholar 

  86. Puel, A., Ziegler, S. F., Buckley, R. H. & Leonard, W. J. Defective IL7R expression in T−B+NK+ severe combined immunodeficiency. Nature Genet. 20, 394–397 (1998).

    CAS  PubMed  Google Scholar 

  87. de la Salle, H. et al. Homozygous human TAP peptide transporter mutation in HLA class I deficiency. Science 265, 237–241 (1994). The first report of human inherited deficiency of transporter for antigen processing (TAP), a condition associated with the deficiency of HLA class I molecule expression and low blood counts of cytotoxic CD8+ T cells, but surprisingly not with viral diseases. This paper illustrates the paradoxical insights that can be provided by human genetic studies.

    CAS  PubMed  Google Scholar 

  88. Gadola, S. D., Moins-Teisserenc, H. T., Trowsdale, J., Gross, W. L. & Cerundolo, V. TAP deficiency syndrome. Clin. Exp. Immunol. 121, 173–178 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Yabe, T. et al. A subject with a novel type I bare lymphocyte syndrome has tapasin deficiency due to deletion of 4 exons by Alu-mediated recombination. Blood 100, 1496–1498 (2002). The first report of inherited tapasin deficiency, also associated with HLA class I deficiency, but surprisingly not susceptibility to viral diseases.

    CAS  PubMed  Google Scholar 

  90. de la Calle-Martin, O. et al. Familial CD8 deficiency due to a mutation in the CD8α gene. J. Clin. Invest. 108, 117–123 (2001). The first report of CD8 deficiency, associated with a lack of cytotoxic CD8+ T cells, but not with viral diseases.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Barry, M. & Bleackley, R. C. Cytotoxic T lymphocytes: all roads lead to death. Nature Rev. Immunol. 2, 401–409 (2002).

    CAS  Google Scholar 

  92. Li, Q. & Verma, I. M. NF-κB regulation in the immune system. Nature Rev. Immunol. 2, 725–734 (2002).

    CAS  Google Scholar 

  93. Puel, A. et al. Inherited disorders of NF-κB-mediated immunity in man. Curr. Opin. Immunol. (in the press).

  94. Doffinger, R. et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nature Genet. 27, 277–285 (2001).

    CAS  PubMed  Google Scholar 

  95. Courtois, G. et al. A hypermorphic mutation of IkBα is associated with autosomal dominant anhydrotic ectodermal dysplasia and T cell immunodeficiency. J. Clin. Invest. 112, 1108–1115 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. O'Neill, L. A. Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr. Top. Microbiol. Immunol. 270, 47–61 (2002).

    CAS  PubMed  Google Scholar 

  97. Picard, C. et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076–2079 (2003). The first report of a human Mendelian defect that affects the common Toll-like receptor and interleukin-1 (IL-1)-receptor signalling (TIR) pathway. Surprisingly, patients with this condition suffer from a relatively narrow spectrum of infectious diseases, mostly limited to pyogenic bacteria.

    CAS  PubMed  Google Scholar 

  98. Medvedev, A. E. et al. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J. Exp. Med. 198, 521–531 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    CAS  PubMed  Google Scholar 

  100. Dinarello, C. A. The role of interleukin-1 in host responses to infectious diseases. Infect. Agents Dis. 1, 227–236 (1992).

    CAS  PubMed  Google Scholar 

  101. Dinarello, C. A. Interleukin-1. Cytokine Growth Factor Rev. 8, 253–265 (1997).

    CAS  PubMed  Google Scholar 

  102. Sieling, P. A. & Modlin, R. L. Toll-like receptors: mammalian 'taste receptors' for a smorgasbord of microbial invaders. Curr. Opin. Microbiol. 5, 70–75 (2002).

    CAS  PubMed  Google Scholar 

  103. Dinarello, C. A. & Fantuzzi, G. Interleukin-18 and host defense against infection. J. Infect. Dis. 187, S370–S384 (2003).

    CAS  PubMed  Google Scholar 

  104. Leddy, J. P., Frank, M. M., Gaither, T., Baum, J. & Klemperer, M. R. Hereditary deficiency of the sixth component of complement in man. I. Immunochemical, biologic, and family studies. J. Clin. Invest. 53, 544–553 (1974). The first description of a genetic defect of a component of the terminal phase of complement, associated with a selective susceptibility to Neisseria . It is also the first molecular elucidation of a Mendelian 'hole' in immunity to infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Wurzner, R. et al. Reference typing report for complement components C6, C7 and C9 including mutations leading to deficiencies. Exp. Clin. Immunogenet. 15, 268–285 (1998).

    CAS  PubMed  Google Scholar 

  106. Würzner, R., Orren, A. & Lachmann, P. J. Inherited deficiencies of the terminal components of human complement. Immunodef. Rev. 3, 123–147 (1992).

    PubMed  Google Scholar 

  107. Frank, M. M. Complement deficiencies. Pediatr. Clin. N. Am. 47, 1339–1354 (2000).

    CAS  Google Scholar 

  108. Newport, M. J. et al. A mutation in the interferon-γ-receptor gene and susceptibility to mycobacterial infection. N. Engl. J. Med. 335, 1941–1949 (1996).

    CAS  PubMed  Google Scholar 

  109. Jouanguy, E. et al. Interferon-γ-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N. Engl. J. Med. 335, 1956–1961 (1996). References 108 and 109 are the first descriptions of autosomal-recessive complete interferon-γ (IFN-γ)-receptor deficiency, in children with the syndrome of Mendelian susceptibility to mycobacterial diseases, which is characterized by a hole in immunity to infection and a narrow spectrum of infections, caused mostly by mycobacteria (and salmonella).

    CAS  PubMed  Google Scholar 

  110. Levin, M. et al. Familial disseminated atypical mycobacterial infection in childhood: a human mycobacterial susceptibility gene? Lancet 345, 79–83 (1995).

    CAS  PubMed  Google Scholar 

  111. Casanova, J. L. et al. Idiopathic disseminated bacillus Calmette-Guerin infection: a French national retrospective study. Pediatrics 98, 774–778 (1996).

    CAS  PubMed  Google Scholar 

  112. Dorman, S. E. et al. Viral infections in interferon-γ receptor deficiency. J. Pediatr. 135, 640–643 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Roesler, J. et al. Recurrent mycobacterial and listeria infections in a child with interferon-γ receptor deficiency: mutational analysis and evaluation of therapeutic options. Exp. Haematol. 27, 1368–1374 (1999).

    CAS  Google Scholar 

  114. Dorman, S. E. & Holland, S. M. Interferon-γ and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev. 11, 321–333 (2000).

    CAS  PubMed  Google Scholar 

  115. Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A. & Coffman, R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).

    CAS  PubMed  Google Scholar 

  116. Döffinger, R. et al. Inheritable defects in IL-12- and IFNγ-mediated immunity and the TH1/TH2 paradigm in man. Allergy 54, 409–412 (1999).

    PubMed  Google Scholar 

  117. Allen, J. E. & Maizels, R. M. TH1–TH2: reliable paradigm or dangerous dogma? Immunol. Today 18, 387–392 (1997).

    CAS  PubMed  Google Scholar 

  118. Fieschi, C. & Casanova, J. L. The role of interleukin-12 in human infectious diseases: only a faint signature. Eur. J. Immunol. 33, 1461–1464 (2003).

    CAS  PubMed  Google Scholar 

  119. Fieschi, C. et al. Low penetrance, broad resistance, and favorable outcome of interleukin-12 receptor β1 deficiency: medical and immunological implications. J. Exp. Med. 197, 527–535 (2003). The first description of a low clinical penetrance (for the case-definition phenotype) among genetic aetiologies of the syndrome of Mendelian susceptibility to mycobacterial diseases, raising the possibility that other, related phenotypes, such as tuberculosis, might be associated with IL-12-receptor deficiency.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Caragol, I. et al. Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor β1 deficiency. Clin. Infect. Dis. 37, 302–306 (2003).

    CAS  PubMed  Google Scholar 

  121. Altare, F. et al. Interleukin-12 receptor β1 deficiency in a patient with abdominal tuberculosis. J. Infect. Dis. 184, 231–236 (2001).

    CAS  PubMed  Google Scholar 

  122. Jouanguy, E. et al. Partial interferon-γ receptor 1 deficiency in a child with tuberculoid bacillus Calmette–Guerin infection and a sibling with clinical tuberculosis. J. Clin. Invest. 100, 2658–2664 (1997). References 120–122 describe the first three families with a truly Mendelian tuberculosis: patients with a genetic defect of the IL-12–IFN-γ pathway developed clinical tuberculosis in the absence of any personal or even familial previous history of clinical disease caused by poorly virulent mycobacterial species.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Dupuis, S. et al. Human interferon-γ-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion. Immunol. Rev. 178, 129–137 (2000).

    CAS  PubMed  Google Scholar 

  124. Abel, L. & Casanova, J. L. Genetic predisposition to clinical tuberculosis: bridging the gap between simple and complex inheritance. Am. J. Hum. Genet. 67, 274–277 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Kwiatkowski, D. Genetic susceptibility to malaria getting complex. Curr. Opin. Genet. Dev. 10, 320–324 (2000).

    CAS  PubMed  Google Scholar 

  126. Abel, L. & Demenais, F. Detection of major genes for susceptibility to leprosy and its subtypes. Am. J. Hum. Genet. 42, 256–266 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Mira, M. T. et al. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nature Genet. 33, 412–415 (2003).

    CAS  PubMed  Google Scholar 

  128. Siddiqui, M. R. et al. A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nature Genet. 27, 439–441 (2001).

    CAS  PubMed  Google Scholar 

  129. Marquet, S. et al. Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33. Nature Genet. 14, 181–184 (1996). The first identification of a major susceptibility region to a common infectious disease (schistosomiasis) by a genome-wide scan approach.

    CAS  PubMed  Google Scholar 

  130. Dessein, A. J. et al. Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-γ receptor gene. Am. J. Hum. Genet. 65, 709–721 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Plancoulaine, S., Gessain, A., van Beveren, M., Tortevoye, P. & Abel, L. Evidence for a recessive major gene predisposing to human herpesvirus 8 (HHV-8) infection in a population in which HHV-8 is endemic. J. Infect. Dis. 187, 1944–1950 (2003).

    PubMed  Google Scholar 

  132. Plancoulaine, S. et al. Detection of a major gene predisposing to human T lymphotropic virus type I infection in children among an endemic population of African origin. J. Infect. Dis. 182, 405–412 (2000).

    CAS  PubMed  Google Scholar 

  133. Beutler, B. & Rietschel, E. T. Innate immune sensing and its roots: the story of endotoxin. Nature Rev. Immunol. 3, 169–176 (2003).

    CAS  Google Scholar 

  134. Isaacs, A. & Lindenmann, J. Virus interference. I. The interferon. Proc. R. Soc. London B 147, 258–267 (1957).

    CAS  Google Scholar 

  135. Dupuis, S. et al. Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency. Nature Genet. 33, 388–391 (2003).

    CAS  PubMed  Google Scholar 

  136. Nathan, C. F., Murray, H. W., Wiebe, M. E. & Rubin, B. Y. Identification of interferon-γ as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J. Exp. Med. 158, 670–689 (1983).

    CAS  PubMed  Google Scholar 

  137. Kobayashi, M. et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 170, 827–845 (1989).

    CAS  PubMed  Google Scholar 

  138. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Rev. Immunol. 3, 133–146 (2003).

    CAS  Google Scholar 

  139. Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998).

    CAS  PubMed  Google Scholar 

  140. Coffey, A. J. et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nature Genet. 20, 129–135 (1998).

    CAS  PubMed  Google Scholar 

  141. Nichols, K. E. et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc. Natl Acad. Sci. USA 95, 13765–13770 (1998). References 139–141 were the first to identify the molecular basis of an X-linked-specific susceptibility to Epstein–Barr virus, another hole in immunity to infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Conley, M. E., Rohrer, J., Rapalus, L., Boylin, E. C. & Minegishi, Y. Defects in early B-cell development: comparing the consequences of abnormalities in pre-BCR signaling in the human and the mouse. Immunol. Rev. 178, 75–90 (2000).

    CAS  PubMed  Google Scholar 

  143. Kung, C. et al. Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nature Med. 6, 343–345 (2000).

    CAS  PubMed  Google Scholar 

  144. Dadi, H. K., Simon, A. J. & Roifman, C. M. Effect of CD3δ deficiency on maturation of αβ and γδ T-cell lineages in severe combined immunodeficiency. N. Engl. J. Med. 349, 1821–1828 (2003).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank P. Kourilsky, P. Sansonetti and J.-C. Weill for critical reading; O. Haller, F. Novelli and R. Würzner for helpful discussions; and present and past members of the Laboratory of Human Genetics of Infectious Diseases for critical reading, helpful discussions and enthusiastic hard work. Our laboratory is supported by grants from the University of Paris René Descartes, INSERM, the European Union, the BNP-Paribas Foundation and the Schlumberger Foundation.

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Authors and Affiliations

  1. Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-INSERM U550, Necker Medical School, 156 Rue de Vaugirard, Paris, 75015, EU, France

    Jean-Laurent Casanova

  2. Pediatric Hematology–Immunology Unit, Necker Hospital, Paris, 75015, EU, France

    Jean-Laurent Casanova & Laurent Abel

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  1. Jean-Laurent Casanova
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Correspondence to Jean-Laurent Casanova.

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DATABASES

LocusLink

Beige

Ceacam1

CXCR4

DARC

ELA2

EVER1

EVER2

FUT2

GFI1

IFN-α/β

IFN-γ

IL-12

IL-1R

IL-23

IRAK4

Ly49h

Mx1

Naip5

Nramp1

Nude

Oas1.1

Scurfy

TAP1

TAP2

tapasin

Tlr4

Tyk2

Xid

FURTHER INFORMATION

World Health Organization

Glossary

SEGREGATION STUDIES

Statistical analyses of the familial distribution of a disease (or any phenotype) displaying some degree of intra-familial aggregation (clustering within families). The main goal of a segregation study is to test whether or not the observed familial distributions can be explained by the segregation of a major gene (that is, a gene with a marked effect on the heredity of the disease).

MICROSATELLITE MARKERS

A microsatellite consists of a specific sequence of genomic DNA that contains mono-, di-, tri- or tetranucleotide repeats. Alleles at a specific location (locus) differ in the number of repeats. Microsatellites are inherited in a Mendelian manner, and are, therefore, used as multiallelic (highly polymorphic) genetic markers.

SINGLE-NUCLEOTIDE POLYMORPHISMS

(SNPs). Positions in the genome at which at least two alternative nucleotides occur at appreciable frequencies (usually >1%) in the population. Similar to microsatellites, SNPs display Mendelian inheritance, and are used as genetic markers.

GENOME-WIDE LINKAGE STUDY

Random search over the whole genome of chromosomal regions that are shared in excess by relatives showing a given phenotypic resemblance (for example, affected siblings). In practice, genome scans are done by genotyping 300–400 microsatellite markers that cover all chromosomes (average spacing ∼10 centimorgans) in a relevant sample (for example, 100–200 affected sibling pairs). These data are then analysed by an appropriate linkage method (see Box 1).

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Casanova, JL., Abel, L. The human model: a genetic dissection of immunity to infection in natural conditions. Nat Rev Immunol 4, 55–66 (2004). https://doi.org/10.1038/nri1264

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