Elena Blanco1, Martín Pérez-Andrés1, Sonia Arriba-Méndez2, Cristina Serrano3, Ignacio Criado1, Lucía Del Pino-Molina4, Susana Silva5, Ignacio Madruga6, Marina Bakardjieva7, Catarina Martins8, Ana Serra-Caetano5, Alfonso Romero9, Teresa Contreras-Sanfeliciano10, Carolien Bonroy11, Francisco Sala12, Alejandro Martín13, José María Bastida13, Félix Lorente2, Carlos Prieto14, Ignacio Dávila15, Miguel Marcos6, Tomas Kalina7, Marcela Vlkova16, Zita Chovancova16, Ana Isabel Cordeiro17, Jan Philippé11, Filomeen Haerynck18, Eduardo López-Granados4, Ana E Sousa5, Mirjam van der Burg19, Jacques J M van Dongen20, Alberto Orfao21. 1. Department of Medicine, Cancer Research Centre (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS), University of Salamanca (USAL), Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Biomedical Research Networking Centre Consortium of Oncology (CIBERONC), number CB16/12/00400, Instituto de Salud Carlos III, Madrid, Spain. 2. Servicio de Pediatría, Hospital Universitario de Salamanca, Salamanca, Spain. 3. Servicio de Inmunología, Fundación Jiménez Díaz, Madrid, Spain. 4. Clinical Immunology Department, University Hospital La Paz and Physiopathology of Lymphocytes in Immunodeficiencies Group, IdiPAZ Institute for Health Research, Madrid, Spain. 5. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal. 6. Servicio de Medicina Interna, Hospital Universitario de Salamanca, Institute for Biomedical Research of Salamanca, Department of Medicine, University of Salamanca, Salamanca, Spain. 7. CLIP, Department of Haematology/Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. 8. NOVA Medical School/Faculdade de Ciências Médicas Universidade Nova de Lisboa, Lisbon, Portugal. 9. Centro de Salud Miguel Armijo, Salamanca, Spain. 10. Servicio de Bioquímica Clínica, Hospital Universitario de Salamanca, Salamanca, Spain. 11. Department of Laboratory Medicine, University Hospital Ghent, Ghent, Belgium. 12. Servicio de Hematología, Hospital de Navarra, Pamplona, Spain. 13. Servicio de Hematología, Hospital Universitario de Salamanca, Institute for Biomedical Research of Salamanca, Salamanca, Spain; Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) number CB/16/12/00233, Instituto de salud Carlos III, Madrid, Spain. 14. Bioinformatics service (NUCLEUS), University of Salamanca, Salamanca, Spain. 15. Servicio de Alergia, Hospital Universitario de Salamanca, Institute for Biomedical Research of Salamanca, Biomedical and Diagnosis Science Department, University of Salamanca (USAL), Salamanca, Spain. 16. Department of Clinical Immunology and Allergology, St Anne's University Hospital, and Faculty of Medicine, Masaryk University, Brno, Czech Republic. 17. Hospital D. Estefânia, CHLC, Lisbon, Portugal. 18. Department of Respiratory Diseases and Department of Pediatrics and Genetics, University Hospital Ghent, Ghent, Belgium. 19. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands; Department of Pediatrics, Laboratory for Immunology, Leiden University Medical Center, Leiden, The Netherlands. 20. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. 21. Department of Medicine, Cancer Research Centre (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS), University of Salamanca (USAL), Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Biomedical Research Networking Centre Consortium of Oncology (CIBERONC), number CB16/12/00400, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: orfao@usal.es.
Abstract
BACKGROUND: Predominantly antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies, but their B-cell defects and underlying genetic alterations remain largely unknown. OBJECTIVE: We investigated patients with PADs for the distribution of 41 blood B-cell and plasma cell (PC) subsets, including subsets defined by expression of distinct immunoglobulin heavy chain subclasses. METHODS: Blood samples from 139 patients with PADs, 61 patients with common variable immunodeficiency (CVID), 68 patients with selective IgA deficiency (IgAdef), 10 patients with IgG subclass deficiency with IgA deficiency, and 223 age-matched control subjects were studied by using flow cytometry with EuroFlow immunoglobulin isotype staining. Patients were classified according to their B-cell and PC immune profile, and the obtained patient clusters were correlated with clinical manifestations of PADs. RESULTS: Decreased counts of blood PCs, memory B cells (MBCs), or both expressing distinct IgA and IgG subclasses were identified in all patients with PADs. In patients with IgAdef, B-cell defects were mainly restricted to surface membrane (sm)IgA+ PCs and MBCs, with 2 clear subgroups showing strongly decreased numbers of smIgA+ PCs with mild versus severe smIgA+ MBC defects and higher frequencies of nonrespiratory tract infections, autoimmunity, and affected family members. Patients with IgG subclass deficiency with IgA deficiency and those with CVID showed defects in both smIgA+ and smIgG+ MBCs and PCs. Reduced numbers of switched PCs were systematically found in patients with CVID (absent in 98%), with 6 different defective MBC (and clinical) profiles: (1) profound decrease in MBC numbers; (2) defective CD27+ MBCs with almost normal IgG3+ MBCs; (3) absence of switched MBCs; and (4) presence of both unswitched and switched MBCs without and; (5) with IgG2+ MBCs; and (6) with IgA1+ MBCs. CONCLUSION: Distinct PAD defective B-cell patterns were identified that are associated with unique clinical profiles.
BACKGROUND:Predominantly antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies, but their B-cell defects and underlying genetic alterations remain largely unknown. OBJECTIVE: We investigated patients with PADs for the distribution of 41 blood B-cell and plasma cell (PC) subsets, including subsets defined by expression of distinct immunoglobulin heavy chain subclasses. METHODS: Blood samples from 139 patients with PADs, 61 patients with common variable immunodeficiency (CVID), 68 patients with selective IgA deficiency (IgAdef), 10 patients with IgG subclass deficiency with IgA deficiency, and 223 age-matched control subjects were studied by using flow cytometry with EuroFlow immunoglobulin isotype staining. Patients were classified according to their B-cell and PC immune profile, and the obtained patient clusters were correlated with clinical manifestations of PADs. RESULTS: Decreased counts of blood PCs, memory B cells (MBCs), or both expressing distinct IgA and IgG subclasses were identified in all patients with PADs. In patients with IgAdef, B-cell defects were mainly restricted to surface membrane (sm)IgA+ PCs and MBCs, with 2 clear subgroups showing strongly decreased numbers of smIgA+ PCs with mild versus severe smIgA+ MBC defects and higher frequencies of nonrespiratory tract infections, autoimmunity, and affected family members. Patients with IgG subclass deficiency with IgA deficiency and those with CVID showed defects in both smIgA+ and smIgG+ MBCs and PCs. Reduced numbers of switched PCs were systematically found in patients with CVID (absent in 98%), with 6 different defective MBC (and clinical) profiles: (1) profound decrease in MBC numbers; (2) defective CD27+ MBCs with almost normal IgG3+ MBCs; (3) absence of switched MBCs; and (4) presence of both unswitched and switched MBCs without and; (5) with IgG2+ MBCs; and (6) with IgA1+ MBCs. CONCLUSION: Distinct PAD defective B-cell patterns were identified that are associated with unique clinical profiles.
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