Defects in memory B-cell and plasma cell subsets expressing different immunoglobulin-subclasses in patients with CVID and immunoglobulin subclass deficiencies - 05/09/19

Doi : 10.1016/j.jaci.2019.02.017

Elena Blanco, PhD ^a,^b,^{∗
These authors contributed equally to this work as first authors.}, Martín Pérez-Andrés, PhD ^a,^b,^{∗
These authors contributed equally to this work as first authors.}, Sonia Arriba-Méndez, MD, PhD ^c, Cristina Serrano, MD ^d, Ignacio Criado, PhD ^a,^b, Lucía Del Pino-Molina, PhD ^e, Susana Silva, MD, PhD ^f, Ignacio Madruga, MD ^g, Marina Bakardjieva, MSc ^h, Catarina Martins, PhD ⁱ, Ana Serra-Caetano, MSc ^f, Alfonso Romero, MD ^j, Teresa Contreras-Sanfeliciano, MD ^k, Carolien Bonroy, PhD ^l, Francisco Sala, MD ^m, Alejandro Martín, MD, PhD ^n,^o, José María Bastida, MD, PhD ^n,^o, Félix Lorente, MD, PhD ^c, Carlos Prieto, PhD ^p, Ignacio Dávila, MD, PhD ^q, Miguel Marcos, MD, PhD ^g, Tomas Kalina, MD, PhD ^h, Marcela Vlkova, PhD ^r, Zita Chovancova, MD, PhD ^r, Ana Isabel Cordeiro, MD ^s, Jan Philippé, MD, PhD ^l, Filomeen Haerynck, MD, PhD ^t, Eduardo López-Granados, MD, PhD ^e, Ana E. Sousa, PhD ^f, Mirjam van der Burg, PhD ^u,^v, Jacques J.M. van Dongen, MD, PhD ^w,^{‡
These authors contributed equally to this work as last authors.}, Alberto Orfao, MD, PhD ^a,^b,^⁎,^{‡
These authors contributed equally to this work as last authors.}
on behalf of the
EuroFlow PID group
^a 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
^b Biomedical Research Networking Centre Consortium of Oncology (CIBERONC), number CB16/12/00400, Instituto de Salud Carlos III, Madrid, Spain
^c Servicio de Pediatría, Hospital Universitario de Salamanca, Salamanca, Spain
^k Servicio de Bioquímica Clínica, Hospital Universitario de Salamanca, Salamanca, Spain
^d Servicio de Inmunología, Fundación Jiménez Díaz, Madrid, Spain
^e Clinical Immunology Department, University Hospital La Paz and Physiopathology of Lymphocytes in Immunodeficiencies Group, IdiPAZ Institute for Health Research, Madrid, Spain
^f Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
^g Servicio de Medicina Interna, Hospital Universitario de Salamanca, Institute for Biomedical Research of Salamanca, Department of Medicine, University of Salamanca, Salamanca, Spain
^h CLIP, Department of Haematology/Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
ⁱ NOVA Medical School/Faculdade de Ciências Médicas Universidade Nova de Lisboa, Lisbon, Portugal
^j Centro de Salud Miguel Armijo, Salamanca, Spain
^l Department of Laboratory Medicine, University Hospital Ghent, Ghent, Belgium
^t Department of Respiratory Diseases and Department of Pediatrics and Genetics, University Hospital Ghent, Ghent, Belgium
^m Servicio de Hematología, Hospital de Navarra, Pamplona, Spain
ⁿ Servicio de Hematología, Hospital Universitario de Salamanca, Institute for Biomedical Research of Salamanca, Salamanca, Spain
^o Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) number CB/16/12/00233, Instituto de salud Carlos III, Madrid, Spain
^p Bioinformatics service (NUCLEUS), University of Salamanca, Salamanca, Spain
^q Servicio de Alergia, Hospital Universitario de Salamanca, Institute for Biomedical Research of Salamanca, Biomedical and Diagnosis Science Department, University of Salamanca (USAL), Salamanca, Spain
^r Department of Clinical Immunology and Allergology, St Anne's University Hospital, and Faculty of Medicine, Masaryk University, Brno, Czech Republic
^s Hospital D. Estefânia, CHLC, Lisbon, Portugal
^u Department of Immunology, Erasmus MC, Rotterdam, The Netherlands
^v Department of Pediatrics, Laboratory for Immunology, Leiden University Medical Center, Leiden, The Netherlands
^w Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

^∗Corresponding author: Alberto Orfao, MD, PhD, Department of Medicine, Cancer Research Center, University of Salamanca, Paseo de la Universidad de Coimbra s/n, 37007 Salamanca, Spain.Department of MedicineCancer Research CenterUniversity of SalamancaPaseo de la Universidad de Coimbra s/nSalamanca37007Spain

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.

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Graphical abstract

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Key words : Immunodeficiency, primary antibody deficiency, selective IgA deficiency, common variable immunodeficiency, immunophenotyping, immunoglobulins, immunoglobulin subclasses, memory B cells, plasma cells, flow cytometry, diagnosis, classification

Abbreviations used : CVID, ESID, GC, HD, IgAdef, IgG/Adef, IgH, IUIS, LLN, MBC, NPV, PAD, PC, PPV, sm

Plan

Methods

Patients and control subjects

Flow cytometric identification of blood B cells and their subsets

Statistical analyses

Results

Blood B-cell and PC subset defects in patients with IgAdef

Blood B-cell and PC subset defects in patients with IgG/Adef

Blood B-cell and PC subset defects in patients with CVID

Classification of patients with PADs based on blood B-cell and PC subset immune profiles

Blood B-cell and PC immune profiles in patients with IgAdef

Blood B-cell and PC immune profiles in patients with CVID

Discussion

E.B. was supported by a grant from the Junta de Castilla y León (Fondo Social Europeo, ORDEN EDU/346/2013, Valladolid, Spain). This work was supported by the CB16/12/00400 and CB/16/12/00233 grants (CIBERONC, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain, and FONDOS FEDER), the FIS PI12/00905-FEDER grant (Fondo de Investigación Sanitaria of Instituto de Salud Carlos III, Madrid, Spain) and a grant from Fundación Mutua Madrileña (Madrid, Spain). The coordination and innovation processes of this study were supported by the EuroFlow Consortium.

Disclosure of potential conflict of interest: E. Blanco, M. Pérez-Andrés, T. Kalina, M. Vlkova, E. López-Granados, M. van der Burg, J. J. M. van Dongen, and A. Orfao each report being one of the inventors on the EuroFlow-owned patent PCT/NL 2015/050762 (Diagnosis of primary immunodeficiencies), which is licensed to Cytognos, a company that pays royalties to the EuroFlow Consortium. J. J. M. van Dongen and A. Orfao report an Educational Services Agreement from BD Biosciences. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 144 - N° 3

P. 809-824 - septembre 2019 Retour au numéro

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Defects in memory B-cell and plasma cell subsets expressing different immunoglobulin-subclasses in patients with CVID and immunoglobulin subclass deficiencies - 05/09/19

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