Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes

被引:57
作者
IJspeert, Hanna [1 ,2 ]
Driessen, Gertjan J. [1 ,2 ]
Moorhouse, Michael J. [3 ]
Hartwig, Nico G. [2 ]
Wolska-Kusnierz, Beata [4 ]
Kalwak, Krzysztof [5 ]
Pituch-Noworolska, Anna [6 ]
Kondratenko, Irina [7 ]
van Montfrans, Joris M. [8 ,9 ]
Mejstrikova, Ester [10 ,11 ]
Lankester, Arjan C. [12 ]
Langerak, Anton W. [1 ]
van Gent, Dik C. [13 ]
Stubbs, Andrew P. [14 ]
van Dongen, Jacques J. M. [1 ]
van der Burg, Mirjam [1 ]
机构
[1] Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands
[2] Univ Med Ctr Rotterdam, Erasmus MC, Dept Pediat, Rotterdam, Netherlands
[3] Stichting Sanquin Bloedvoorziening, Dept Blood Cell Res, Amsterdam, Netherlands
[4] Childrens Mem Hlth Inst, Dept Immunol, Warsaw, Poland
[5] Wroclaw Med Univ, Dept Pediat Hematol Oncol & Bone Marrow Transplan, Wroclaw, Poland
[6] Jagiellonian Univ, Coll Med, Dept Clin Immunol, Polish Amer Inst Pediat, Krakow, Poland
[7] Russian State Childrens Hosp, Dept Clin Immunol, Moscow, Russia
[8] Univ Med Ctr Utrecht, Dept Pediat Immunol & Infect Dis, Utrecht, Netherlands
[9] Wilhelmina Childrens Hosp, Utrecht, Netherlands
[10] Teaching Hosp Motol, Dept Pediat Hematol & Oncol, Prague, Czech Republic
[11] Charles Univ Prague, Sch Med 2, Prague, Czech Republic
[12] Leiden Univ, Dept Pediat, Med Ctr, NL-2300 RA Leiden, Netherlands
[13] Univ Med Ctr Rotterdam, Erasmus MC, Dept Cell Biol & Genet, Rotterdam, Netherlands
[14] Erasmus Univ, Dept Bioinformat, Med Ctr Rotterdam, NL-3000 DR Rotterdam, Netherlands
关键词
RAG deficiency; V(D)J recombination; B- and T-cell receptor repertoire; receptor editing; autoimmunity; next generation sequencing; immune repertoire analysis; T-CELL-RECEPTOR; SEVERE COMBINED IMMUNODEFICIENCY; IMMUNOGLOBULIN-SECRETING CELLS; OMENN-SYNDROME; SEQUENCE-ANALYSIS; SCID PATIENTS; DEFECTS; REARRANGEMENTS; DEFICIENCY; RETICULOENDOTHELIOSIS;
D O I
10.1016/j.jaci.2013.11.028
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: V(D)J recombination takes place during lymphocyte development to generate a large repertoire of T-and B-cell receptors. Mutations in recombination-activating gene 1 (RAG1) and RAG2 result in loss or reduction of V(D) J recombination. It is known that different mutations in RAG genes vary in residual recombinase activity and give rise to a broad spectrum of clinical phenotypes. Objective: We sought to study the immunologic mechanisms causing the clinical spectrum of RAG deficiency. Methods: We included 22 patients with similar RAG1 mutations (c.519delT or c.368_369delAA) resulting in N-terminal truncated RAG1 protein with residual recombination activity but presenting with different clinical phenotypes. We studied precursor B-cell development, immunoglobulin and T-cell receptor repertoire formation, receptor editing, and B-and T-cell numbers. Results: Clinically, patients were divided into 3 main categories: T-B- severe combined immunodeficiency, Omenn syndrome, and combined immunodeficiency. All patients showed a block in the precursor B-cell development, low B-and T-cell numbers, normal immunoglobulin gene use, limited B-and T-cell repertoires, and slightly impaired receptor editing. Conclusion: This study demonstrates that similar RAG mutations can result in similar immunobiological effects but different clinical phenotypes, indicating that the level of residual recombinase activity is not the only determinant for clinical outcome. We postulate a model in which the type and moment of antigenic pressure affect the clinical phenotypes of these patients.
引用
收藏
页码:1124 / +
页数:11
相关论文
共 47 条
[1]   XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining [J].
Ahnesorg, P ;
Smith, P ;
Jackson, SP .
CELL, 2006, 124 (02) :301-313
[2]  
Alamyar Eltaf, 2012, Methods Mol Biol, V882, P569, DOI 10.1007/978-1-61779-842-9_32
[3]  
[Anonymous], 2013, R LANG ENV STAT COMP
[4]  
Blankenberg Daniel, 2010, Curr Protoc Mol Biol, VChapter 19, DOI 10.1002/0471142727.mb1910s89
[5]   Fusion gene transcripts and Ig/TCR gene rearrangements are complementary but infrequent targets for PCR-based detection of minimal residual disease in acute myeloid leukemia [J].
Boeckx, N ;
Willemse, MJ ;
Szczepanski, T ;
van der Velden, VHJ ;
Langerak, AW ;
Vandekerckhove, P ;
van Dongen, JJM .
LEUKEMIA, 2002, 16 (03) :368-375
[6]  
Breit TM, 1997, J IMMUNOL, V159, P4341
[7]   Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly [J].
Buck, D ;
Malivert, L ;
de Chasseval, P ;
Barraud, A ;
Fondanèche, MC ;
Sanal, O ;
Plebani, A ;
Stéphan, JL ;
Hufnagel, M ;
le Deist, F ;
Fischer, A ;
Durandy, A ;
de Villartay, JP ;
Revy, P .
CELL, 2006, 124 (02) :287-299
[8]   Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome [J].
Cassani, Barbara ;
Poliani, Pietro Luigi ;
Marrella, Veronica ;
Schena, Francesca ;
Sauer, Aisha V. ;
Ravanini, Maria ;
Strina, Dario ;
Busse, Christian E. ;
Regenass, Stephan ;
Wardemann, Hedda ;
Martini, Alberto ;
Facchetti, Fabio ;
van der Burg, Mirjam ;
Rolink, Antonius G. ;
Vezzoni, Paolo ;
Grassi, Fabio ;
Traggiai, Elisabetta ;
Villa, Anna .
JOURNAL OF EXPERIMENTAL MEDICINE, 2010, 207 (07) :1525-1540
[9]   AIRE deficiency in thymus of 2 patients with Omenn syndrome [J].
Cavadini, P ;
Vermi, W ;
Facchetti, F ;
Fontana, S ;
Nagafuchi, S ;
Mazzolari, E ;
Sediva, A ;
Marrella, V ;
Villa, A ;
Fischer, A ;
Notarangelo, LD ;
Badolato, R .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (03) :728-732
[10]   A novel homozygous mutation in recombination activating gene 2 in 2 relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome [J].
Chou, Janet ;
Hanna-Wakim, Rima ;
Tirosh, Irit ;
Kane, Jennifer ;
Fraulino, David ;
Lee, Yu Nee ;
Ghanem, Soha ;
Mahfouz, Iman ;
Megarbane, Andre ;
Lefranc, Gerard ;
Inati, Adlette ;
Dbaibo, Ghassan ;
Giliani, Silvia ;
Notarangelo, Luigi D. ;
Geha, Raif S. ;
Massaad, Michel J. .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2012, 130 (06) :1414-1416