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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

IJspeert, Hanna^1,2  Driessen, Gertjan J.^1,2  Moorhouse, Michael J.³  Hartwig, Nico G.²  Wolska-Kusnierz, Beata⁴  Kalwak, Krzysztof⁵  Pituch-Noworolska, Anna⁶  Kondratenko, Irina⁷  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, Mirjam¹ 

[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;   

DOI  :  10.1016/j.jaci.2013.11.028

来源: Elsevier

【 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.

【 授权许可】

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