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

• Published in: Journal of allergy and clinical immunology Vol. 144; no. 3; pp. 809 - 824
• Main Authors: Blanco, Elena, Pérez-Andrés, Martín, Arriba-Méndez, Sonia, Serrano, Cristina, Criado, Ignacio, Del Pino-Molina, Lucía, Silva, Susana, Madruga, Ignacio, Bakardjieva, Marina, Martins, Catarina, Serra-Caetano, Ana, Romero, Alfonso, Contreras-Sanfeliciano, Teresa, Bonroy, Carolien, Sala, Francisco, Martín, Alejandro, Bastida, José María, Lorente, Félix, Prieto, Carlos, Dávila, Ignacio, Marcos, Miguel, Kalina, Tomas, Vlkova, Marcela, Chovancova, Zita, Cordeiro, Ana Isabel, Philippé, Jan, Haerynck, Filomeen, López-Granados, Eduardo, Sousa, Ana E., van der Burg, Mirjam, van Dongen, Jacques J.M., Orfao, Alberto
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2019; Elsevier Limited
• Subjects: Age; Antigens; Autoimmunity; CD27 antigen; classification; Common variable immunodeficiency; Defects; diagnosis; Flow cytometry; Immunodeficiency; Immunoglobulin A; Immunoglobulin G; immunoglobulin subclasses; Immunoglobulins; Immunological memory; immunophenotyping; Lymphocytes B; Medical diagnosis; memory B cells; Memory cells; plasma cells; primary antibody deficiency; Primary immunodeficiencies; selective IgA deficiency; primary antibody deficiency; IgH; LLN; MBC; CVID; immunophenotyping; NPV; PPV; selective IgA deficiency; flow cytometry; sm; GC; IgG/Adef; Immunodeficiency; immunoglobulin subclasses; diagnosis; ESID; common variable immunodeficiency; immunoglobulins; memory B cells; plasma cells; classification; PAD; PC; IUIS; HD; IgAdef
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2019.02.017

Predominantly antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies, but their B-cell defects and underlying genetic alterations remain largely unknown. 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. 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. 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. Distinct PAD defective B-cell patterns were identified that are associated with unique clinical profiles. [Display omitted]