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.

• Klíčová slova
• B- and T-cell receptor repertoire, RAG deficiency, V(D)J recombination, autoimmunity, immune repertoire analysis, next generation sequencing, receptor editing,
• MeSH
• B-lymfocyty imunologie   metabolismus   MeSH
• exprese genu MeSH
• fenotyp * MeSH
• genetické asociační studie * MeSH
• genotyp MeSH
• homeodoménové proteiny genetika   metabolismus   MeSH
• hypervariabilní oblasti genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mutace * MeSH
• novorozenec MeSH
• počet lymfocytů MeSH
• předškolní dítě MeSH
• T-lymfocyty imunologie   metabolismus   MeSH
• těžká kombinovaná imunodeficience diagnóza   genetika   imunologie   metabolismus   MeSH
• těžké řetězce imunoglobulinů genetika   MeSH
• V(D)J rekombinace MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• homeodoménové proteiny MeSH
• hypervariabilní oblasti MeSH
• RAG-1 protein MeSH Prohlížeč
• těžké řetězce imunoglobulinů MeSH

• MeSH
• cytokiny metabolismus   MeSH
• HLA antigeny genetika   metabolismus   MeSH
• lidé MeSH
• purinnukleosidfosforylasa metabolismus   MeSH
• receptory cytokinové metabolismus   MeSH
• těžká kombinovaná imunodeficience diagnóza   imunologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytokiny MeSH
• HLA antigeny MeSH
• purinnukleosidfosforylasa MeSH
• receptory cytokinové MeSH