The Journal of Allergy and Clinical Immunology
Volume 122, Issue 6 , Pages 1082-1086 , December 2008

Omenn syndrome: Inflammation in leaky severe combined immunodeficiency

  • Anna Villa, MD

      Affiliations

    • Istituto Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy
    • ,
  • Luigi D. Notarangelo, MD

      Affiliations

    • Division of Immunology, Children's Hospital Boston, Harvard Medical School, Boston, Mass
    • ,
  • Chaim M. Roifman, MD, FRCPC

      Affiliations

    • Division of Immunology and Allergy, Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
    • Corresponding Author InformationReprint requests: Chaim M. Roifman MD, FRCPC, Division of Immunology/Allergy, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.

Received 3 September 2008 ,Accepted 10 September 2008.

References 

  1. Omenn GS. Familial reticulonendotheliosis with eosinophilia. N Engl J Med. 1965;273:427–432
  2. Barth RF, Vergara GE, Khurana SK, Lonman JT. Rapidly fatal familial histiocytosis associated with eosinophilia and primary immunological deficiency. Lancet. 1972;1:503–506
  3. 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. 1989;321:370–374
  4. Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 1998;93:885–896
  5. Roifman CM, Gu Y, Cohen A. Mutations in the RNA component of RNase mitochondrial RNA processing might cause Omenn syndrome. J Allergy Clin Immunol. 2006;117:897–903
  6. Ege M, Ma Y, Manfras B, Kalwak K, Lu H, Lieber MR, et al. Omenn syndrome due to Artemis mutations. Blood. 2005;105:4179–4186
  7. Shibata F, Toma T, Wada T, Inoue M, Tone Y, Ohta K, et al. Skin infiltration of CD56(bright) CD16(-) natural killer cells in a case of X-SCID with Omenn syndrome-like manifestations. Eur J Haematol. 2007;79:81–85
  8. Giliani S, Bonfim C, de Saint Basile G, Lanzi G, Brousse N, Koliski A, et al. Omenn syndrome in an infant with IL7RA gene mutation. J Pediatr. 2006;148:272–274
  9. Roifman CM, Zhang J, Atkinson A, Grunebaum E, Mandel K. Adenosine deaminase deficiency can present with features of Omenn syndrome. J Allergy Clin Immunol. 2008;121:1056–1058
  10. Pirovano S, Mazzolari E, Pasic S, Albertini A, Notarangelo LD, Imberti L. Impaired thymic output and restricted T cell repertoire in two infants with immunodeficiency and early-onset generalized dermatitis. Immunol Lett. 2003;86:93–97
  11. Gennery AR, Slatter MA, Rice J, Hoefsloot LH, Barge D, McLean-Tooke A, et al. Mutations in CHD7 in patients with CHARGE syndrome cause T−B+ natural killer cell + severe combined immune deficiency and may cause Omenn like syndrome. Clin Exp Immunol. 2008;153:75–80
  12. Grunebaum E, Bates A, Roifman CM. Omenn syndrome is associated with mutations in DNA ligase IV. J Allergy Clin Immunol. 2008; Oct 10;[epub ahead of print]
  13. Kavadas FD, Giliani S, Gu Y, Mazzolari E, Bates A, Peoiani E, et al. Variability of clinical and laboratory features among patients with RMRP gene mutations. J Allergy Clin Immunol. 2008;Sep 17 [epub ahead of print]
  14. McKusick VA, Eldridge R, Hostetler JA, Ruangwit U, Egeland JA. Dwarfism in the Amish, II: cartilage hair hypoplasia. Bull John Hopkins Hosp. 1965;116:231–272
  15. Roifman CM. Studies of patients' thymi aid in the discovery and characterization of immunodeficiency in humans. In:  Koretzky G,  Monroe J editor. Immunological reviews. Singapore: Blackwell Munksguard; 2005;p. 143–155
  16. Scheimberg I, Hoeger PH, Harper JI, Lake B, Malone M. Omenn's syndrome: differential diagnosis in infants with erythroderma and immunodeficiency. Pediatr Dev Pathol. 2001;4:237–245
  17. Melamed I, Cohen A, Roifman CM. Expansion of CD3+ CD4− CD8− T cell population expressing high levels of IL-5 in Omenn's syndrome. Clin Exp Immunol. 1994;95:14–21
  18. de Said-Basile G, Le Deist F, De Villartay J-P, Cerf-Bensussan N, Jounet O, Brousse N, et al. Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). J Clin Invest. 1991;87:1352–1359
  19. Zhang J, Quintal L, Atkinson A, Williams B, Grunebaum E, Roifman CM. Novel Rag 1 mutation in a case of severe combined immunodeficiency. Pediatrics. 2005;116:e445–e449
  20. Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG, et al. V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood. 2001;97:81–88
  21. Businco L, Di Fazio A, Ziruolo MG, Boner AL, Valletta EA, Ruco LP, et al. Clinical and immunological findings in four infants with Omenn's syndrome: a form of severe combined immunodeficiency with phenotypically normal T cells, elevated IgE, and eosinophilia. Clin Immunol Immunopathol. 1987;44:123–133
  22. Signorini S, Imberti L, Pirovano S, Villa A, Facchetti F, Ungari M, et al. Intrathymic restriction and peripheral expansion of the T-cell repertoire in Omenn syndrome. Blood. 1999;94:3468–3478
  23. Larché M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol. 2006;6:761–771
  24. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol. 2007;119:780–791
  25. Hawrylowicz CM, O'Garra A. Potential role of interleukin-10 secreting regulatory T cells in allergy and asthma. Nat Rev Immunol. 2007;7:220–230
  26. Krupica T, Fry TJ, Mackall CL. Autoimmunity during lymphopenia: a two-hit model. Clin Immunol. 2006;120:121–128
  27. Cavadini P, Vermi W, Facchetti F, Fontana S, Nagafuchi S, Mazzolari E, et al. AIRE deficiency in thymus of 2 patients with Omenn syndrome. J Clin Invest. 2005;115:728–732
  28. Khiong K, Murakami M, Kitabayashi C, Ueda N, Sawa S, Sakamoto A, et al. Homeostatically proliferating CD4 T cells are involved in the pathogenesis of an Omenn syndrome murine model. J Clin Invest. 2007;117:1270–1281
  29. Marrella V, Poliani PL, Casati A, Rucci F, Frascoli L, Gougeon ML, et al. A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. J Clin Invest. 2007;117:1260–1269
  30. Marrella V, Poliani PL, Sobacchi C, Grassi F, Villa A. Of Omenn and mice. Trends Immunol. 2008;29:133–140
  31. Schandene L, Ferster A, Mascart-Lemone F, Crusiaux A, Gerard C, Marchant A, et al. T helper 2 like cells and therapeutic effects of interferon-γ in combine immunodeficiency with hypereosinophilia (Omenn's syndrome. Eur J Immunol. 1993;23:56–60
  32. Kay AB. Allergy and allergic diseases: first two parts. N Engl J Med. 2001;344:30–37
  33. Geha RS, Jabara HH, Brodeur SR. The regulation of immunoglobulin E class switch recombination. Nat Rev Immunol. 2003;3:721–732
  34. Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008;8:205–217
  35. Yazdanbakhsh M, Kremsner PG, van Ree R. Allergy, parasites and the hygiene hypothesis. Science. 2002;296:490–494
  36. Fallon PG, Mangan NE. Suppression of TH2 type allergic reactions by helminth infection. Nat Rev Immunol. 2007;7:220–230
  37. Corneo B, Moshous D, Güngör T, Wulffraat N, Philippet P, Le Deist FL, et al. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood. 2001;97:2772–2776
  38. Sobacchi C, Marrella V, Rucci F, Vezzoni P, Villa A. RAG-dependent primary immunodeficiencies. Hum Mutat. 2006;27:1174–1184
  39. Santagata S, Gomez CA, Sobacchi C, Bozzi F, Abinun M, Pasic S, et al. N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains. Proc Natl Acad Sci U S A. 2000;97:14572–14577
  40. West KL, Singha NC, De Ioannes P, Lacomis L, Erdjument-Bromage H, Tempst P, et al. A direct interaction between the RAG2 C terminus and the core histones is required for efficient V(D)J recombination. Immunity. 2005;23:203–212
  41. Liu Y, Subrahmanyam R, Chakraborty T, Sen R, Desiderio S. A plant homeodomain in RAG-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Immunity. 2007;27:561–571
  42. Matthews AG, Kuo AJ, Ramón-Maiques S, Han S, Champagne KS, Ivanov D, et al. RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature. 2007;450:1106–1110
  43. Ramón-Maiques S, Kuo AJ, Carney D, Matthews AG, Oettinger MA, Gozani O, et al. The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2. Proc Natl Acad Sci U S A. 2007;104:18993–18998
  44. Ridanpaa M, Sistonen P, Rockas S, Rimoin DL, Kakitie O, Kaitila I. Worldwide mutation spectrum in cartilage hair hypoplasia: ancient founder origin of the major 70A→G mutation of the untranslated. Eur J Hum Genet. 2002;10:439–447
  45. Ridanpaa M, Jain P, McKusick VA, Francomano CA, Daitila I. The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases. Am J Med Genet. 2003;121:81–83
  46. Nakashima E, Mabuchi A, Kashimada K, Onishi T, Zhang J, Obashi H, et al. RMRP mutations in Japanese patients with cartilage hair hypoplasia. Am J Med Genet. 2003;123:253–256
  47. Makitie O, Kaitila I, Savilahti E. Susceptibility to infections and in vitro immune functions in cartilage hair hypoplasia. Eur J Pediatr. 1998;157:816–820
  48. Makitie O, Kaitila I, Savilahti E. Deficiency of humoral immunity in cartilage hair hypoplasia. J Pediatr. 2000;137:487–492
  49. Berthet F, Siegrist CA, Ozsahin H, Tuchscmid P, Eich G, Superti-Furga A, et al. Bone marrow transplantation in cartilage hair hypoplasia: correction of the immunodeficiency but not of the chondrodysplasia. Eur J Pediatr. 1996;155:286–290
  50. Chang DD, Clayton DA. A mammalian mitochondrial RNA processing activity contains nucleus encoded. Science. 1987;235:1178–1184
  51. Clayton DA. A nuclear function for RNase MRP. Proc Natl Acad Sci U S A. 1994;91:4615–4617
  52. Li X, Zaman S, Langdon Y, Zengel JM, Lindah L. Identification of a functional core in the RNA component of RNase MRP of budding yeasts. Nucleic Acids Res. 2004;32:3703–3711
  53. Gill T, Cai T, Aulds J, Wierzbicki S, Schmitt ME. RNase MRP cleaves the CLB2 mRNA to promote cell cycle progression: novel method of mRNA degradation. Mol Cell Biol. 2004;24:945–953
  54. Cohen A, Hirschhorn R, Horowitz SD, Rubinstein A, Polmar SH, Hong R, et al. Deoxyadenosine triphosphates as a potentially toxic metabolite in adenosine deaminase deficiency. Proc Natl Acad Sci U S A. 1978;75:472–476
  55. Santisteban I, Arredondo-Vega FX, Kelly S, Mary A, Fischer A, Hummell DS, et al. Novel splicing, missense and deletion mutation in seven adenosine deaminase deficient patients with late/delayed onset of combined immunodeficiency disease. J Clin Invest. 1993;92:2291–2302
  56. Mazzolari E, Moshous D, Forino C, De Martiis D, Offer C, Lanfranchi A, et al. Hematopoietic stem cell transplantation in Omenn syndrome: a single-center experience. Bone Marrow Transplant. 2005;36:107–114
  57. Roifman CM, Somech R, Grunebaum E. Matched unrelated bone marrow transplant for T+ combined immunodeficiency. Bone Marrow Transplant. 2008;41:947–952
  58. Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, et al. Bone marrow transplantation for Severe combined immune deficiency. JAMA. 2006;295:508–518

 Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

PII: S0091-6749(08)01734-X

doi: 10.1016/j.jaci.2008.09.037

The Journal of Allergy and Clinical Immunology
Volume 122, Issue 6 , Pages 1082-1086 , December 2008

Article Tools