RAG1 Deficiency May Present Clinically as Selective IgA Deficiency

详细信息    查看全文

• 作者：Tamaki Kato (1)
  Elena Crestani (2)
  Chikako Kamae (1)
  Kenichi Honma (1)
  Tomoko Yokosuka (3)
  Takeshi Ikegawa (4)
  Naonori Nishida (5)
  Hirokazu Kanegane (5) (6)
  Taizo Wada (7)
  Akihiro Yachie (7)
  Osamu Ohara (8) (9)
  Tomohiro Morio (6)
  Luigi D. Notarangelo (2)
  Kohsuke Imai (1) (6)
  Shigeaki Nonoyama (1)
  
  1. Department of Pediatrics ; National Defense Medical College ; Tokorozawa ; Saitama ; Japan
  2. Division of Immunology ; Children鈥檚 Hospital Boston ; Harvard Medical School ; Boston ; MA ; USA
  3. Department of Hemato-oncology/Regeneration Medicine ; Kanagawa Children鈥檚 Medical Center ; Yokohama ; Kanagawa ; Japan
  4. Department of Pediatrics ; Yokohama Rosai Hospital ; Yokohama ; Kanagawa ; Japan
  5. Department of Pediatrics ; University of Toyama ; Toyama ; Japan
  6. Department of Pediatrics ; Tokyo Medical and Dental University (TMDU) ; 1-5-45 ; Yushima ; Bunkyo-ku ; Tokyo ; 113-8519 ; Japan
  7. Department of Pediatrics ; Kanazawa University ; Kanazawa ; Ishikawa ; Japan
  8. Laboratory for Integrative Genomics ; RIKEN Center for Integrative Medical Sciences ; Yokohama ; Kanagawa ; Japan
  9. Department of Technology Development ; Kazusa DNA Research Institute ; Kisarazu ; Chiba ; Japan
  
• 关键词：RAG1 deficiency ; IgA deficiency ; TRECs ; KRECs ; primary immunodeficiency ; V(D)J recombination
• 刊名：Journal of Clinical Immunology
• 出版年：2015
• 出版时间：April 2015
• 年：2015
• 卷：35
• 期：3
• 页码：280-288
• 全文大小：1,764 KB
• 参考文献：1. Hammarstrom, L, Vorechovsky, I, Webster, D (2000) Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 120: pp. 225-31 CrossRef
  2. Asai, E, Wada, T, Sakakibara, Y, Toga, A, Toma, T, Shimizu, T (2011) Analysis of mutations and recombination activity in RAG-deficient patients. Clin Immunol 138: pp. 172-7 CrossRef
  3. Corneo, B, Moshous, D, Gungor, T, Wulffraat, N, Philippet, P, Deist, FL (2001) 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 97: pp. 2772-6 CrossRef
  4. Villa, A, Santagata, S, Bozzi, F, Giliani, S, Frattini, A, Imberti, L (1998) Partial V(D)J recombination activity leads to Omenn syndrome. Cell 93: pp. 885-96 CrossRef
  5. Villa, A, Notarangelo, LD, Roifman, CM (2008) Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin Immunol 122: pp. 1082-6 CrossRef
  6. Ravin, SS, Cowen, EW, Zarember, KA, Whiting-Theobald, NL, Kuhns, DB, Sandler, NG (2010) Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood 116: pp. 1263-71 CrossRef
  7. Villartay, JP, Lim, A, Al-Mousa, H, Dupont, S, Dechanet-Merville, J, Coumau-Gatbois, E (2005) A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest 115: pp. 3291-9 CrossRef
  8. Ehl, S, Schwarz, K, Enders, A, Duffner, U, Pannicke, U, Kuhr, J (2005) A variant of SCID with specific immune responses and predominance of gamma delta T cells. J Clin Invest 115: pp. 3140-8 CrossRef
  9. Schuetz, C, Huck, K, Gudowius, S, Megahed, M, Feyen, O, Hubner, B (2008) An immunodeficiency disease with RAG mutations and granulomas. N Engl J Med 358: pp. 2030-8 CrossRef
  10. Ravin, SS, Cowen, EW, Zarember, KA, Whiting-Theobald, NL, Kuhns, DB, Sandler, NG (2010) Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood 116: pp. 1263-71 CrossRef
  11. Niehues, T, Perez-Becker, R, Schuetz, C (2010) More than just SCID鈥搕he phenotypic range of combined immunodeficiencies associated with mutations in therecombinase activating genes (RAG) 1 and 2. Clin Immunol 135: pp. 183-92 CrossRef
  12. Morinishi, Y, Imai, K, Nakagawa, N, Sato, H, Horiuchi, K, Ohtsuka, Y (2009) Identification of severe combined immunodeficiency by T-cell receptor excision circles quantification using neonatal guthrie cards. J Pediatr 155: pp. 829-33 CrossRef
  13. Nakagawa, N, Imai, K, Kanegane, H, Sato, H, Yamada, M, Kondoh, K (2011) Quantification of kappa-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects. J Allergy Clin Immunol 128: pp. 223-5 CrossRef
  14. Kamae, C, Nakagawa, N, Sato, H, Honma, K, Mitsuiki, N, Ohara, O (2013) Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin kappa-deleting recombination excision circles. J Allergy Clin Immunol 131: pp. 1437-40 CrossRef
  15. Lee, YN, Frugoni, F, Dobbs, K, Walter, JE, Giliani, S, Gennery, AR (2014) A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J Allergy Clin Immunol 133: pp. 1099-108 CrossRef
  16. Nomura, K, Kanegane, H, Karasuyama, H, Tsukada, S, Agematsu, K, Murakami, G (2000) Genetic defect in human X-linked agammaglobulinemia impedes a maturational evolution of pro-B cells into a later stage of pre-B cells in the B-cell differentiation pathway. Blood 96: pp. 610-7
  17. Currier JR, Robinson MA. Spectratype/immunoscope analysis of the expressed TCR repertoire. Curr Protoc Immunol. 2001; Chapter 10:Unit 10 28.
  18. Ng, PC, Henikoff, S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31: pp. 3812-4 CrossRef
  19. Villa, A, Sobacchi, C, Notarangelo, LD, Bozzi, F, Abinun, M, Abrahamsen, TG (2001) V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood 97: pp. 81-8 CrossRef
  20. Kumaki, S, Villa, A, Asada, H, Kawai, S, Ohashi, Y, Takahashi, M (2001) Identification of anti-herpes simplex virus antibody-producing B cells in a patient with an atypical RAG1 immunodeficiency. Blood 98: pp. 1464-8 CrossRef
  21. Kuijpers, TW, Ijspeert, H, Leeuwen, EM, Jansen, MH, Hazenberg, MD, Weijer, KC (2011) Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations. Blood 117: pp. 5892-6 CrossRef
  22. Henderson, LA, Frugoni, F, Hopkins, G, Boer, H, Pai, SY, Lee, YN (2014) Expanding the spectrum of recombination-activating gene 1 deficiency: a family with early-onset autoimmunity. J Allergy Clin Immunol 132: pp. 969-71 CrossRef
  23. Moshous, D, Callebaut, I, Chasseval, R, Corneo, B, Cavazzana-Calvo, M, Deist, F (2001) Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105: pp. 177-86 CrossRef
  24. Shiow, LR, Paris, K, Akana, MC, Cyster, JG, Sorensen, RU, Puck, JM (2009) Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion. Clin Immunol 131: pp. 24-30 CrossRef
  25. Sheehan, WJ, Delmonte, OM, Miller, DT, Roberts, AE, Bonilla, FA, Morra, M (2009) Novel presentation of Omenn syndrome in association with aniridia. J Allergy Clin Immunol 123: pp. 966-9 CrossRef
  26. Agematsu, K, Nagumo, H, Hokibara, S, Mori, T, Wada, T, Yachie, A (2001) Complete arrest from pro- to pre-B cells in a case of B cell-negative severe combined immunodeficiency (SCID) without recombinase activating gene (RAG) mutations. Clin Exp Immunol 124: pp. 461-4 CrossRef
  27. Noordzij, JG, Bruin-Versteeg, S, Verkaik, NS, Vossen, JM, Groot, R, Bernatowska, E (2002) The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins. Blood 100: pp. 2145-52
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Immunology
  Infectious Diseases
  Internal Medicine
  Medical Microbiology
  
• 出版者：Springer Netherlands
• ISSN：1573-2592

文摘

Background Recombination-activating gene (RAG) 1 and 2 deficiency is seen in patients with severe combined immunodeficiency (SCID) and Omenn syndrome. However, the spectrum of the disease has recently expanded to include a milder phenotype. Objective We analyzed a 4-year-old boy who was initially given the diagnosis of selective immunoglobulin A deficiency (SIgAD) based on immunoglobulin serum levels without any opportunistic infections, rashes, hepatosplenomegaly, autoimmunity or granulomas. The patient was found to be infected with varicella zoster; however, the clinical course was not serious. He produced antiviral antibodies. Methods We performed lymphocyte phenotyping, quantification of T cell receptor excision circles (TRECs) and kappa deleting recombination excision circles (KRECs), an analysis of target sequences of RAG1 and 2, a whole-genome SNP array, an in vitro V(D)J recombination assay, a spectratype analysis of the CDR3 region and a flow cytometric analysis of the bone marrow. Results Lymphocyte phenotyping demonstrated that the ratio of CD4+ to CD8+ T cells was inverted and the majority of CD4+T cells expressed CD45RO antigens in addition to the almost complete lack of B cells. Furthermore, both TRECs and KRECs were absent. Targeted DNA sequencing and SNP array revealed that the patient carried a deletion of RAG1 and RAG2 genes on the paternally-derived chromosome 11, and two maternally-derived novel RAG1 missense mutations (E455K, R764H). In vitro analysis of recombination activity showed that both RAG1 mutant proteins had low, but residual function. Conclusions The current case further expands the phenotypic spectrum of mild presentations of RAG deficiency, and suggests that TRECs and KRECs are useful markers for detecting hidden severe, as well as mild, cases.