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

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• 作者：Hanna IJspeert ; MSc^a ; ^b ; Gertjan J. Driessen ; MD ; PhD^a ; ^b ; Michael J. Moorhouse ; PhD^c ; Nico G. Hartwig ; MD ; PhD^b ; Beata Wolska-Kusnierz ; MD^d ; Krzysztof Kalwak ; MD^e ; Anna Pituch-Noworolska ; MD^f ; Irina Kondratenko ; MD^g ; Joris M. van Montfrans ; MD ; PhD^h ; Ester Mejstrikova ; MDⁱ ; Arjan C. Lankester ; MD ; PhD^j ; Anton W. Langerak ; PhD^a ; Dik C. van Gent ; PhD^k ; Andrew P. Stubbs ; PhD^l ; Jacques J.M. van Dongen ; MD ; PhD^a ; Mirjam van der Burg ; PhD^a ; ^{m.vanderburg@erasmusmc.nl" class="auth_mail}
• 关键词：RAG deficiency ; V(D)J recombination ; B- and T-cell receptor repertoire ; receptor editing ; autoimmunity ; next generation sequencing ; immune repertoire analysis
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：April, 2014
• 年：2014
• 卷：133
• 期：4
• 页码：1124-1133.e1
• 全文大小：1852 K

文摘

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Background

V(D)J recombination takes place during lymphocyte development to generate a large repertoire of T-聽and B-cell receptors. Mutations in recombination-activating gene 1 (RAG1) and RAG2 result in loss or reduction of V(D)J聽recombination. It is known that different mutations in RAG聽genes vary in residual recombinase activity and give rise to聽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^{鈭?/sup>B鈭?/sup> 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聽antigenic pressure affect the clinical phenotypes of these patients.