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Points of control in inflammation

Abstract

Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, if targeted destruction and assisted repair are not properly phased, inflammation can lead to persistent tissue damage by leukocytes, lymphocytes or collagen. Inflammation may be considered in terms of its checkpoints, where binary or higher-order signals drive each commitment to escalate, go signals trigger stop signals, and molecules responsible for mediating the inflammatory response also suppress it, depending on timing and context. The non-inflammatory state does not arise passively from an absence of inflammatory stimuli; rather, maintenance of health requires the positive actions of specific gene products to suppress reactions to potentially inflammatory stimuli that do not warrant a full response.

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Figure 1: Information flow in the early stages following mild trauma with infection.

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References

  1. Zweifach, B. W., Grant, L. & McCluskey, R. T. The Inflammatory Process (Academic, New York, 1965).

    Google Scholar 

  2. Bunting, M., Harris, E. S., McIntyre, T. M., Prescott, S. M. & Zimmerman, G. A. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving β2 integrins and selectin ligands. Curr. Opin. Hematol. 9, 30–35 (2002).

    PubMed  Google Scholar 

  3. Biesma, D. H. et al. A family with complement factor D deficiency. J. Clin. Invest. 108, 233–240 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Soiffer, R. et al. Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 95, 13141–13146 (1998).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Morales, A. Intravesical therapy of bladder cancer: an immunotherapy success story. Int. J. Urol. 3, 329–333 (1996).

    CAS  PubMed  Google Scholar 

  6. Riewald, M., Petrovan, R. J., Donner, A., Mueller, B. M. & Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296, 1880–1882 (2002).

    ADS  CAS  PubMed  Google Scholar 

  7. Steinhoff, M. et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nature Med. 6, 151–158 (2000).

    CAS  PubMed  Google Scholar 

  8. Basu, S. & Srivastava, P. K. Heat shock proteins: the fountainhead of innate and adaptive immune responses. Cell Stress Chaper. 5, 443–451 (2000).

    CAS  Google Scholar 

  9. Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).

    ADS  CAS  PubMed  Google Scholar 

  10. Carp, H. Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils. J. Exp. Med. 155, 264–275 (1982).

    CAS  PubMed  Google Scholar 

  11. Muller, W. A. Leukocyte-endothelial cell interactions in the inflammatory response. Lab. Invest. 82, 521–533 (2002).

    CAS  PubMed  Google Scholar 

  12. Lee, D. M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689–1692 (2002).

    ADS  CAS  PubMed  Google Scholar 

  13. van der Poll, T. Coagulation and inflammation. J. Endotoxin Res. 7, 301–304 (2001).

    CAS  PubMed  Google Scholar 

  14. Kaplan, A. P., Joseph, K. & Silverberg, M. Pathways for bradykinin formation and inflammatory disease. J. Allergy Clin. Immunol. 109, 195–209 (2002).

    CAS  PubMed  Google Scholar 

  15. Nathan, C., Xie, Q. W., Halbwachs-Mecarelli, L. & Jin, W. W. Albumin inhibits neutrophil spreading and hydrogen peroxide release by blocking the shedding of CD43 (sialophorin, leukosialin). J. Cell Biol. 122, 243–256 (1993).

    CAS  PubMed  Google Scholar 

  16. Nathan, C. F. Neutrophil activation on biological surfaces. Massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes. J. Clin. Invest. 80, 1550–1560 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Weiss, S. J. Tissue destruction by neutrophils. N. Engl. J. Med. 320, 365–376 (1989).

    CAS  PubMed  Google Scholar 

  18. Morgan, J. G., Pereira, H. A., Sukiennicki, T., Spitznagel, J. K. & Larrick, J. W. Human neutrophil granule cationic protein CAP37 is a specific macrophage chemotaxin that shares homology with inflammatory proteinases. Adv. Exp. Med. Biol. 305, 89–96 (1991).

    CAS  PubMed  Google Scholar 

  19. Yang, D. et al. β-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286, 525–528 (1999).

    CAS  PubMed  Google Scholar 

  20. Robbiani, D. F. et al. The leukotriene C4 transporter MRP1 regulates CCL19 (MIP-3β, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103, 757–768 (2000).

    CAS  PubMed  Google Scholar 

  21. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    ADS  CAS  PubMed  Google Scholar 

  22. Medzhitov, R. & Janeway, C. A. Jr Decoding the patterns of self and nonself by the innate immune system. Science 296, 298–300 (2002).

    ADS  CAS  PubMed  Google Scholar 

  23. Kiechl, S. et al. Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med. 347, 185–192 (2002).

    CAS  PubMed  Google Scholar 

  24. Fink, M. P. Effect of critical illness on microbial translocation and gastrointestinal mucosa permeability. Semin. Respir. Infect. 9, 256–260 (1994).

    CAS  PubMed  Google Scholar 

  25. Levy, B. D., Clish, C. B., Schmidt, B., Gronert, K. & Serhan, C. N. Lipid mediator class switching during acute inflammation: signals in resolution. Nature Immunol. 2, 612–619 (2001).

    CAS  Google Scholar 

  26. Mizumoto, N. et al. CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nature Med. 8, 358–365 (2002).

    CAS  PubMed  Google Scholar 

  27. Ohta, A. & Sitkovsky, M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414, 916–920 (2001).

    ADS  CAS  PubMed  Google Scholar 

  28. Hoek, R. M. et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768–1771 (2000).

    ADS  CAS  PubMed  Google Scholar 

  29. Daheshia, M., Friend, D. S., Grusby, M. J., Austen, K. F. & Katz, H. R. Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J. Exp. Med. 194, 227–234 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Teder, P. et al. Resolution of lung inflammation by CD44. Science 296, 155–158 (2002).

    ADS  CAS  PubMed  Google Scholar 

  31. Ashcroft, G. S. et al. Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing. Nature Med. 6, 1147–1153 (2000).

    CAS  PubMed  Google Scholar 

  32. Marino, M. W. et al. Characterization of tumor necrosis factor-deficient mice. Proc. Natl Acad. Sci. USA 94, 8093–8098 (1997).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hodge-Dufour, J. et al. Inhibition of interferon γ induced interleukin 12 production: a potential mechanism for the anti-inflammatory activities of tumor necrosis factor. Proc. Natl Acad. Sci. USA 95, 13806–13811 (1998).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jin, F. Y., Nathan, C., Radzioch, D. & Ding, A. Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell 88, 417–426 (1997).

    CAS  PubMed  Google Scholar 

  35. Grobmyer, S. R. et al. Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia. Crit. Care Med. 28, 1276–1282 (2000).

    CAS  PubMed  Google Scholar 

  36. Zhu, J. et al. Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell (in the press).

  37. Segal, B. H., Leto, T. L., Gallin, J. I., Malech, H. L. & Holland, S. M. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore) 79, 170–200 (2000).

    CAS  Google Scholar 

  38. Morgenstern, D. E., Gifford, M. A., Li, L. L., Doerschuk, C. M. & Dinauer, M. C. Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus. J. Exp. Med. 185, 207–218 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Clark, R. A. & Klebanoff, S. J. Chemotactic factor inactivation by the myeloperoxidase-hydrogen peroxide-halide system. J. Clin. Invest. 64, 913–920 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Nathan, C. Inducible nitric oxide synthase: what difference does it make? J. Clin. Invest. 100, 2417–2423 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Bogdan, C. Nitric oxide and the immune response. Nature Immunol. 2, 907–916 (2001).

    CAS  Google Scholar 

  42. Schur, P. H. Genetics of complement deficiencies associated with lupus-like syndromes. Arthritis Rheum. 21, S153–S160 (1978).

    CAS  PubMed  Google Scholar 

  43. Walport, M. J., Davies, K. A., Morley, B. J. & Botto, M. Complement deficiency and autoimmunity. Ann. NY Acad. Sci. 815, 267–281 (1997).

    ADS  CAS  PubMed  Google Scholar 

  44. Wert, S. E. et al. Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc. Natl Acad. Sci. USA 97, 5972–5977 (2000).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ogura, Y. et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J. Biol. Chem. 276, 4812–4818 (2001).

    CAS  PubMed  Google Scholar 

  46. Kastner, D. L. & O'Shea, J. J. A fever gene comes in from the cold. Nature Genet. 29, 241–242 (2001).

    CAS  PubMed  Google Scholar 

  47. Liao, J. K. Isoprenoids as mediators of the biological effects of statins. J. Clin. Invest. 110, 285–288 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Levy, B. D. et al. Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A4 . Nature Med. 8, 1018–1023 (2002).

    CAS  PubMed  Google Scholar 

  49. Keane, J. et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N. Engl. J. Med. 345, 1098–1104 (2001).

    CAS  PubMed  Google Scholar 

  50. Vaishnaw, A. K. et al. The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans with CD95 (Fas/APO-1) mutations. Arthritis Rheum. 42, 1833–1842 (1999).

    CAS  PubMed  Google Scholar 

  51. Fisher, G. H. et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81, 935–946 (1995).

    CAS  PubMed  Google Scholar 

  52. Sneller, M. C. et al. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J. Clin. Invest. 90, 334–341 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Cohen, P. L. & Eisenberg, R. A. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu. Rev. Immunol. 9, 243–269 (1991).

    CAS  PubMed  Google Scholar 

  54. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nature Genet. 19, 56–59 (1998).

    CAS  PubMed  Google Scholar 

  55. Lipsker, D. M. et al. Lupus erythematosus associated with genetically determined deficiency of the second component of the complement. Arch. Dermatol. 136, 1508–1514 (2000).

    CAS  PubMed  Google Scholar 

  56. Chen, Z., Koralov, S. B. & Kelsoe, G. Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J. Exp. Med. 192, 1339–1352 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sullivan, K. E. Complement deficiency and autoimmunity. Curr. Opin. Pediatr. 10, 600–606 (1998).

    CAS  PubMed  Google Scholar 

  58. Xu, C. et al. A critical role for murine complement regulator Crry in fetomaternal tolerance. Science 287, 498–501 (2000).

    ADS  CAS  PubMed  Google Scholar 

  59. Bickerstaff, M. C. et al. Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nature Med. 5, 694–697 (1999).

    CAS  PubMed  Google Scholar 

  60. Napirei, M. et al. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nature Genet. 25, 177–181 (2000).

    CAS  PubMed  Google Scholar 

  61. Bolland, S., Yim, Y. S., Tus, K., Wakeland, E. K. & Ravetch, J. V. Genetic modifiers of systemic lupus erythematosus in FcγRIIB−/− mice. J. Exp. Med. 195, 1167–1174 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Sullivan, K. E., Mullen, C. A., Blaese, R. M. & Winkelstein, J. A. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J. Pediatr. 125, 876–885 (1994).

    CAS  PubMed  Google Scholar 

  63. Leverrier, Y. et al. Cutting edge: the Wiskott-Aldrich syndrome protein is required for efficient phagocytosis of apoptotic cells. J. Immunol. 166, 4831–4834 (2001).

    CAS  PubMed  Google Scholar 

  64. Snapper, S. B. et al. Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9, 81–91 (1998).

    CAS  PubMed  Google Scholar 

  65. McDermott, M. F. et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133–144 (1999).

    CAS  PubMed  Google Scholar 

  66. Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kulkarni, A. B. et al. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl Acad. Sci. USA 90, 770–774 (1993).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  68. Willerford, D. M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995).

    CAS  PubMed  Google Scholar 

  69. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

    CAS  PubMed  Google Scholar 

  70. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    CAS  PubMed  Google Scholar 

  71. Dranoff, G. et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 264, 713–716 (1994).

    ADS  CAS  PubMed  Google Scholar 

  72. Nicklin, M. J., Hughes, D. E., Barton, J. L., Ure, J. M. & Duff, G. W. Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J. Exp. Med. 191, 303–312 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Horai, R. et al. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J. Exp. Med. 191, 313–320 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Mombaerts, P. et al. Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 75, 274–282 (1993).

    CAS  PubMed  Google Scholar 

  75. Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995).

    ADS  CAS  PubMed  Google Scholar 

  76. Tivol, E. A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995).

    CAS  PubMed  Google Scholar 

  77. Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).

    CAS  PubMed  Google Scholar 

  78. Sommers, C. L. et al. A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science 296, 2040–2043 (2002).

    ADS  CAS  PubMed  Google Scholar 

  79. Alexander, W. S. et al. SOCS1 is a critical inhibitor of interferon γ signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98, 597–608 (1999).

    CAS  PubMed  Google Scholar 

  80. Okkenhaug, K. et al. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297, 1031–1034 (2002).

    ADS  CAS  PubMed  Google Scholar 

  81. Di Cristofano, A. et al. Impaired Fas response and autoimmunity in Pten+/− mice. Science 285, 2122–2125 (1999).

    CAS  PubMed  Google Scholar 

  82. Hibbs, M. L. et al. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 83, 301–311 (1995).

    CAS  PubMed  Google Scholar 

  83. Nishizumi, H. et al. Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice. Immunity 3, 549–560 (1995).

    CAS  PubMed  Google Scholar 

  84. Bachmaier, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211–216 (2000).

    ADS  CAS  PubMed  Google Scholar 

  85. Rudolph, U. et al. Ulcerative colitis and adenocarcinoma of the colon in Gαi2-deficient mice. Nature Genet. 10, 143–150 (1995).

    CAS  PubMed  Google Scholar 

  86. Tsui, H. W., Siminovitch, K. A., de Souza, L. & Tsui, F. W. Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nature Genet. 4, 124–129 (1993).

    CAS  PubMed  Google Scholar 

  87. Shultz, L. D. et al. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73, 1445–1454 (1993).

    CAS  PubMed  Google Scholar 

  88. Helgason, C. D. et al. Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev. 12, 1610–1620 (1998).

    MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  89. Balomenos, D. et al. The cell cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus development. Nature Med. 6, 171–176 (2000).

    CAS  PubMed  Google Scholar 

  90. Taylor, G. A. et al. A pathogenetic role for TNFα in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity 4, 445–454 (1996).

    CAS  PubMed  Google Scholar 

  91. Ranger, A. M., Oukka, M., Rengarajan, J. & Glimcher, L. H. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity 9, 627–635 (1998).

    CAS  PubMed  Google Scholar 

  92. Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866 (2002).

    ADS  CAS  PubMed  Google Scholar 

  93. The International Incontinentia Pigmenti (IP) Consortium. Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti. Nature 405, 466–472 (2000).

  94. Schmidt-Supprian, M. et al. NEMO/IKKγ-deficient mice model incontinentia pigmenti. Mol. Cell 5, 981–992 (2000).

    CAS  PubMed  Google Scholar 

  95. Makris, C. et al. Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol. Cell 5, 969–979 (2000).

    CAS  PubMed  Google Scholar 

  96. Klement, J. F. et al. IκBα deficiency results in a sustained NF-κB response and severe widespread dermatitis in mice. Mol. Cell. Biol. 16, 2341–2349 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Perry, W. L. et al. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nature Genet. 18, 143–146 (1998).

    CAS  PubMed  Google Scholar 

  98. Weih, F. et al. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-κB/Rel family. Cell 80, 331–340 (1995).

    CAS  PubMed  Google Scholar 

  99. Burkly, L. et al. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 373, 531–536 (1995).

    ADS  CAS  PubMed  Google Scholar 

  100. Barton, D., HogenEsch, H. & Weih, F. Mice lacking the transcription factor RelB develop T cell-dependent skin lesions similar to human atopic dermatitis. Eur. J. Immunol. 30, 2323–2332 (2000).

    CAS  PubMed  Google Scholar 

  101. Ishikawa, H. et al. Chronic inflammation and susceptibility to bacterial infections in mice lacking the polypeptide (p)105 precursor (NF-κB1) but expressing p50. J. Exp. Med. 187, 985–996 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Finotto, S. et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295, 336–338 (2002).

    ADS  CAS  PubMed  Google Scholar 

  103. Salvador, J. M. et al. Mice lacking the p53-effector gene Gadd45a develop a lupus-like syndrome. Immunity 16, 499–508 (2002).

    CAS  PubMed  Google Scholar 

  104. Panwala, C. M., Jones, J. C. & Viney, J. L. A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. J. Immunol. 161, 5733–5744 (1998).

    CAS  PubMed  Google Scholar 

  105. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    ADS  CAS  PubMed  Google Scholar 

  106. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    ADS  CAS  PubMed  Google Scholar 

  107. Miceli-Richard, C. et al. CARD15 mutations in Blau syndrome. Nature Genet. 29, 19–20 (2001).

    CAS  PubMed  Google Scholar 

  108. International Mediterranean Fever Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90, 797–807 (1997).

    Google Scholar 

  109. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nature Genet. 17, 25–31 (1997).

  110. Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nature Genet. 29, 301–305 (2001).

    CAS  PubMed  Google Scholar 

  111. Houten, S. M. et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nature Genet. 22, 175–177 (1999).

    ADS  CAS  PubMed  Google Scholar 

  112. Drenth, J. P. et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nature Genet. 22, 178–181 (1999).

    CAS  PubMed  Google Scholar 

  113. Poss, K. D. & Tonegawa, S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc. Natl Acad. Sci. USA 94, 10919–10924 (1997).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank L. Grant for introducing me to the study of inflammation, K. F. Austen, P. Bernstein, A. Ding, M. Fuortes and L. Old for critique of the paper and S. Chen for help in the library. It is regretted that space precluded citing many relevant sources. Preparation of this article was supported by NIH. The Department of Microbiology and Immunology acknowledges the support of the William Randolph Hearst Foundation.

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Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002). https://doi.org/10.1038/nature01320

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