| Author |
IJspeert, Hanna Driessen, Gertjan J. Moorhouse, Michael J. Hartwig, Nico G. Wolska-Kusnierz, Beata Kalwak, Krzysztof Pituch-Noworolska, Anna Kondratenko, Irina Van Montfrans, Joris M. Mejstrikova, Ester Lankester, Arjan C. Langerak, Anton W. Van Gent, Dik C. Stubbs, Andrew P. Van Dongen, Jacques J. M. Van Der Burg, Mirjam |
| Description |
Country affiliation: Netherlands Author Affiliation: IJspeert H ( Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands); Driessen GJ ( Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands); Moorhouse MJ ( Department of Blood Cell Research, Stichting Sanquin Bloedvoorziening, Amsterdam, The Netherlands.); Hartwig NG ( Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.); Wolska-Kusnierz B ( Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland.); Kalwak K ( Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.); Pituch-Noworolska A ( Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.); Kondratenko I ( Department of Clinical Immunology, Russian State Children's Hospital, Moscow, Russia.); van Montfrans JM ( Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht and Wilhelmina Children's Hospital, Utrecht, The Netherlands.); Mejstrikova E ( Department of Pediatric Hematology and Oncology, Teaching Hospital Motol and 2nd Medical School, Charles University, Prague, Czech Republic.); Lankester AC ( Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.); Langerak AW ( Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.); van Gent DC ( Department of Cell Biology and Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.); Stubbs AP ( Department of Bioinformatics, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.); van Dongen JJ ( Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.); van der Burg M ( Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: m.vanderburg@erasmusmc.nl.) |
| Abstract |
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. |
