Abstract
In vertebrates, generation of the T- and B-cell repertoire relies on genomic rearrangement of T-cell receptor and immunoglobulin gene coding segments. This process, known as V(D)J recombination, is initiated by the lymphoid specific proteins Rag1 and Rag2. Both in humans and in animal models, mutations that abrogate expression of either the Rag1 or Rag2 proteins result in severe combined immune deficiency with a complete lack of circulating T and B cells due to an early block in lymphoid development. We have recently shown that mutations that impair, but do not completely abolish the function of Rag1 and Rag2 in humans result in Omenn syndrome, an enigmatic form of combined immune deficiency characterized by oligoclonal, activated T lymphocytes with a skewed Th2 profile.
Similar content being viewed by others
REFERENCES
Agrawal A, Eastman Q, Schatz D: Transposition mediated by Rag1 and Rag2 and its implications for the evolution of the immune system. Nature 394:744–751, 1998
Hiom K, Melek M, Gellert M: Dna transposition by the Rag1 and Rag2 proteins: A possible source of oncogenic translocations. Cell 94:463–470, 1998
Tonegawa S: Somatic generation of antibody diversity. Nature 302:575–581, 1983
Lewis SM: The mechanism of V(D)J joining: Lessons from molecular, immunological and comparative analyses. Adv Immunol 56:27–150, 1994
Hesse JE, Lieber MR, Mizuuchi K, Gellert M: V(D)J recombination: A functional definition of the joining signals. Genes Dev 3:1053–1061, 1989
Ramsden DA, Baetz K, Wu GE: Conservation of sequence in recombination signal sequence spacers. Nucleic Acids Res 22:1785–1796, 1994
McBlane JF, van Gent DC, Ramsden DA, Romeo C, Cuomo CA, Gellert M, Oettinger MA: Cleavage at a V(D)J recombination signal requires only Rag1 and Rag2 proteins and occurs in two steps. Cell 83:387–395, 1995
van Gent DC, McBlane JF, Ramsden DA, Sadofsky MJ, Hesse JE, Gellert M: Initiation of V(D)J recombination in a cell-free system. Cell 81:925–934, 1995
Sawchuk DJ, Weis-Garcia F, Malik S, Besmer E, Bustin M, Nussenzweig MC, Cortes P: V(D)J recombination: modulation of Rag1 and Rag2 cleavage activity on 12/23 substrates by whole cell extract and DNA bending proteins. J Exp Med 185:2025–2032, 1997
van Gent D C, Hiom K, Paull TT, Gellert M: Stimulation of V(D)J cleavage by high mobility group proteins. EMBO J 16:2665–2670, 1997
Besmer E, Mansilla-Soto J, Cassard S, Sawchuck DJ, Brown G, Sadofsky M, Lewis SM, Nussenzweig MC, Cortes P: Hairpin coding end opening is mediated by the recombination activating genes Rag1 and Rag2. Mol Cell 2:817–828. 1998
Landau NR, Schatz DG, Rosa M, Baltimore D: Increased frequency of N-region insertion in a murine pre-B-cell line infected with a terminal deoxynucleotidyl transferase retroviral expression vector. Mol Cell Biol 7:3237–3243, 1987
Jackson SP, Jeggo PA: DNA double strand break repair and V(D)J recombination: Involvement of DNA-PK. Trends Biochem Sci 20:412–415, 1995
Bogue M, Roth DB: Mechanism of V(D)J recombination. Curr Opin Immunol 8:175–180, 1996
Agrawal A, Schatz DG: Rag1 and Rag2 form a stable postcleavage complex with DNA containing signal ends in V(D)J recombination. Cell 89:43–53, 1997
Zhu C, Bogue MA, Lim DS, Hasty P, Roth DB: Ku86–deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates. Cell 86:379–390, 1996
Bogue MA, Wang C, Zhu C, Roth DB: V(D)J recombination in Ku86–deficient mice: Distinct effects on coding, signal and hybrid joint formation. Immunity 7:37–47, 1997
Gu Y, Seidl KJ, Rathbun GA, Zhu C, Manis JP, van der Stoap N, Davidson L, Cheng HL, Sekiguchi JM, Frank K, Stanhope-Baker P, Schliesel M, Roth DB, Alt FW: Growth retardation and leaky SCID phenotype of Ku70–deficient mice. Immunity 7:853–865, 1997
Taccioli GE, Amatucci AG, Gell D, Xiang X, Arzayus T, Pristley A, Jackson SP, Rothstein AM, Jeggo PA, Herrera VLM: Targeted disruption of the catalytic subunit of the Dna-Pk gene in mice confers severe combined immunodeficiency and radiosensitivity. Immunity 9:355–366, 1998
Gao Y, Chaudhuri J, Zhu C, Davidson L, Weaver D, Alt FW: A targeted Dna-Pkes-null mutation reveals Dna-Pk-independent functions for Ku in V(D)J recombination. Immunity 9:367–376, 1998
Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M, Liebet MR: Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature 388:492–495, 1997
Schatz DG, Oettinger MA, Baltimore D: The V(D)J recombination activating gene Rag1. Cell 59:1035–1048, 1989
Oettinger MA, Schatz DG, Gorka C, Baltimore D: Rag1 and Rag2, adjacent genes that synergistically activate V(D)J recombination. Science 248:1517–1523, 1990
Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE: Rag1–deficient mice have no mature B and T lymphocytes. Cell 68:869–877, 1992
Shinkai Y, Rathbun G, Lam K-P, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM, Alt F: Rag2–deficient mice lack mature lymphocytes owing to inability to initiate V(D) rearrangement. Cell 68:855–867, 1992
Oettinger MA, Stanger B, Schatz DG, Glaser T, Call K, Housman D, Baltimore D: The recombination activating genes, Rag1 and Rag2, are on chromosome 11p in humans and chromosome 2p in mice. Immunogenetics 35:97–101, 1992
Bernstein RM, Schluter SF, Bernstein H, Marchalonis JJ: Primordial emergence of the recombination activating gene 1 (Rag1): Sequence of the complete shark gene indicates homology to microbial integrases. Proc. Natl. Acad. Sci. USA 93:9454–9459, 1996
Zarrin AA, Fong I, Malkin L, Marsden P, Berinstein NL: Cloning and characterization of the human recombination activating gene 1 (Rag1) and Rag2 promoter regions. J Immunol 159:4382–4394, 1997
Spanopoulou E, Cortes P, Huang E, Shih C, Silver D, Svec P, Baltimore D: Localization, interaction and RNA-binding properties of the V(D)J recombination activating proteins Rag1 and Rag2. Immunity 3:715–726, 1995
Mc Mahan CJ, Difilippantonio MJ, Rao N, Spanopoulou E, Schatz DG: A basic motif in the N-terminal region of Rag1 enhances V(D)J recombination activity. Mol Cell Biol 17:4544–4552, 1997
Roman CAJ, Cherry SR, Baltimore D: Complementation of V(D)J recombination deficiency in Rag1−/− B cells reveals a requirement for novel elements in the N-terminus of Rag1. Immunity 7:13–24, 1997
McMahan CJ, Sadofsky MJ, Schatz DG: Definition of a large region of Rag1 that is important for coimmunoprecipitation of Rag2. J Immunol 158:2202–2210, 1997
Cuomo CA, Kirch SA, Gyeris J, Brent R, Oettinger MA: Rch1, a protein that specifically interacts with the Rag1 recombination activating protein. Proc Natl Acad Sci USA 91:6156–6160, 1994
Sadofsky MJ, Hesse JE, McBlane JF, Gellert M: Expression and V(D)J recombination activity of mutated Rag1 proteins. Nucleic Acids Res 21:5644–5650, 1993
Spanopoulou E, Zaitseva F, Wang F-H, Santagata S, Baltimore D, Panayotou G: The homeodomain region of Rag1 reveals the parallel mechanisms of bacterial and V(D)J recombination. Cell 87:263–276, 1996
Difilippantonio M, McMahan CJ, Eastman QM, Spanopoulou E, Schatz DG: Rag-1 mediates signal sequence recognition and recruitment of Rag-2 in V(D)J recombination. Cell 87:253–262, 1996
Hiom K, Gellert M: A stable Rag1–Rag2–DNA complex that is active in V(D)J cleavage. Cell 88:65–72, 1997
Desiderio S, Lin WC, Li Z: The cell cycle and V(D)J recombination. Curr Top Microbiol Immunol 217:45–59, 1996
Hikida M, Mori M, Takai T, Tomochika K, Hamatani K, Ohmori H: Reexpression of Rag1 and Rag2 genes in activated mature mouse B cells. Science 274:2092–2094, 1996
Han S, Zheng B, Schatz DG, Spanopoulou E, Kelsoe G: Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells. Science 274:2094–2097, 1997
Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, Friedrich W, Seger RA, Hansen-Hagge TE, Desiderio S, Lieber MR, Bartram CR: Rag mutations in human B cell-negative SCID. Science 274:97–99, 1996
Nicolas N, Moshous D, Cavazzana-Calvo M, Papadopoulo D, de Chasseval R, Le Deist F, Fischer A, de Villartay J-P: A human severe combined immunodeficiency (SCID) condition with increased sensitivity to ionizing radiations and impaired V(D)J rearrangemen ts defines a new DNA recombination/repair deficiency. J Exp Med 188:627–634, 1998
Cavazzana-Calvo M, Le Deist F, de Saint Basile G, Papadopoulo D, De Villartay JP, Fisher A: Increased radiosensitivity of granulocyte macrophage colony-forming units and skin fibroblasts in human autosomal recessive severe combined immunodeficiency. J Clin Invest 91:1214–1218, 1993
Blunt T, Finnie NJ, Taccioli GE, Smith GC.M, Demengeot J, Gottlieb TM, Mizuta R, Varghese AJ, Alt FW, Jeggo PA, Jackson SP: Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the mur ine scid mutation. Cell 80:813–823, 1995
Blunt T, Gell D, Fox M, Taccioli GE, Lehmann AR, Jackson SP, Jeggo PA: Identification of nonsense mutation in the carboxyl-terminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse. Proc Natl Acad Sci USA 93:10285–10290, 1996
Danska JS, Holland DP, Mariathasa S, Williams, Guidos CJ: Biochemical and genetic defects in the DNA-dependent protein kinase in murine scid lymphocytes. Mol Cell Biol 16:5507–5517, 1996
Araki R, Fujimori A, Hamatani K, Mita K, Saito T, Mori M, Fukumura R, Morimyo M, Muto M, Itoh M, Tatsumi K, Abe M: Non-sense mutation at Tyr-4046 in the DNA-dependent protein kinase catalytic subunit of severe combined immune deficiency mice. Proc Natl Acad Sci USA 94:2438–2443, 1997
Omenn GS: Familial reticuloendotheliosis with eosinophilia. N Engl J Med 273:427–432, 1965
Le Deist F, Fischer, Durandy A, Arnaud-Battandier F, Nezelof C, Hamet M, De Prost Y, Griscelli C: Déficit immunitaire mixte et grave avec hyperéosinophilie. Arch Fr Pediatr 42:11–16, 1985
Pollack MS, Kirkpatrick D, Kapoor N, Dupont B, O'Reilly RJ: Identification by HLA typing of intrauterine-derived maternal T cells in four patients with severe combined immunodeficiency. N Engl J Med 307:662–666, 1982
Le Deist F, Raffoux C, Griscelli C, Fischer A: Graft vs graft reaction resulting in the elimination of maternal cells in a SCID patient with maternofetal GVHd after an HLA identical bone marrow transplantation. J Immunol 138:423–427, 1987
Ochs HD, Davis SD, Mickelson E, Lerner KG, Wedgwood RJ: Combined immunodeficiency and reticuloendothliosis with eosinophilia. J Pediatr 85:463–465, 1974
Brugnoni D, Airò P, Facchetti F, Blanzuoli L, Ugazio AG, Cattaneo R, Notarangelo LD: In vitro cell death of activated lymphocytes in Omenn's syndrome. Eur J Immunol 27:2765–2773, 1997
Martin JV, Willoughby PB, Giusti V, Price G, Cerezo L: The lymph node pathology of Omenn's syndrome. Am J Surg Pathol 19:1082–1087, 1995
Chilosi M, Pizzolo G, Facchetti F, Notarangelo LD, Romagnani S, Del Prete G, Almerigogna F, De Carli M: The pathology of Omenn's syndrome. Am J Surg Pathol 20:773–774, 1996
Schandené L, Ferster A, Mascart-Lemone F, Crusiaux A, Grard C, Marchant A, Lybin M, Velu T, Sariban E, Goldman M: T helper type 2–like cells and therapeutic effects of interferon-gamma in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). Eur J Immunol 23:56–60, 1993
Wirt DP, Brooks EG, Vaidya S, Klimpel GR, Waldmann TA, Goldblum RM: Novel T-lymphocyte population in combined immunodeficiency with features of graft-versus-host disease. N Engl J Med 321:370–374, 1989
Chilosi M, Facchetti F, Notarangelo LD, Romagnani S, Del Prete G, Almerigogna F, De Carli M, Pizzolo G: CD30 cell expression and abnormal soluble CD30 serum accumulation in Omenn's syndrome: evidence for a T helper 2–mediated acondition. Eur J Immunol 26:329–334, 1996
Harville TO, Adams DM, Howard TA, Ware RE: Oligoclonal expansion of CD45R0+ T lymphocytes in Omenn syndrome. J Clin Immunol 17:322–332, 1997
Rieux-Laucat F, Bahadoran P, Brousse N, Selz F, Fischer A, Le Deist F, dE Villartay JP: Highly restricted human T cell repertoire in peripheral blood and tissue-infiltrating lymphocytes in Omenn's syndrome. J. Clin Invest 102:312–321, 1998
Villa A, Santagata S, Bozzi F, Frattini A, Imberti L, Benerini Gatta L, Ochs HD, Schwarz K, Notarangelo LD, Vezzoni P, Spanopoulou E: Partial V(D)J recombination activity leads to Omenn syndrome. Cell 93:885–896, 1998
Gomez L, Le Deist F, Blanche S, Cavazzana-Calvo M, Griscelli C, Fischer A: Treatment of Omenn syndrome by bone marrow transplantation. J Pediatr 127:76–81, 1995
de Saint-Basile G, Le Deist F, de Villartay JP, Cerf-Bensussan N, Journet O, Brousse N, Griscelli C, Fischer A: Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). J Clin Invest 87:1352–1359, 1991
Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM: Development of TH1 CD4 + T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547–549, 1993
Hosken NA, Shibuya K, Heath AW, Murphy KM, O'Garra A: The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha and beta-transgenic model. J Exp Med 182:1579–1584, 1995
Kaplan MH, Sun Y-L, Hoey T, Grusby MJ: Impaired IL-12 responses and enhanced development of Th2 cells in Stat4–deficient mice. Nature 382:174–177, 1996
Magram J, Connaughton SE, Warrier RR, Carvajal DM, Wu CY, Ferrante J, Stewart C, Sarmiento U, Faherty DA, Gately MK: IL-12–deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity 5:471–481, 1996
Mattner F, Magram J, Ferrante J, Launois P, Di Padova K, Behin R, Gately MK, Louis JA, Alber G: Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response. Eur J Immunol 26:1553–1559, 1996
Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DAA, Doherty PC, Grosveld GC, Ihle JN: Requirement for Stat4 in interleukin-12–mediated responses of natural killer and T cells. Nature 382:171–174, 1996
Nadel B, Tang A, Escuro G, Lugo G, Feeney AJ: Sequence of the spacer in the recombination signal sequence affects V(D)J rearrangement frequency and correlates with nonrandom Vk usage in vivo. J Exp Med 187:1495–1503, 1998
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Villa, A., Santagata, S., Bozzi, F. et al. Omenn Syndrome: A Disorder of Rag1 and Rag2 Genes. J Clin Immunol 19, 87–97 (1999). https://doi.org/10.1023/A:1020550432126
Issue Date:
DOI: https://doi.org/10.1023/A:1020550432126