Defective B-cell proliferation and maintenance of long-term memory in patients with chronic granulomatous disease

• Published in: Journal of allergy and clinical immunology Vol. 135; no. 3; pp. 753 - 761.e2
• Main Authors: Cotugno, Nicola, Finocchi, Andrea, Cagigi, Alberto, Di Matteo, Gigliola, Chiriaco, Maria, Di Cesare, Silvia, Rossi, Paolo, Aiuti, Alessandro, Palma, Paolo, Douagi, Iyadh
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2015; Elsevier Limited
• Subjects: Adolescent; Age; Allergy and Immunology; Antigens, CD - genetics; Antigens, CD - immunology; B cell; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Case-Control Studies; Cell growth; Cell Proliferation - drug effects; Child, Preschool; Chronic granulomatous disease; Data analysis; Disease; Female; Flow cytometry; Gene Expression; Granulomatous Disease, Chronic - genetics; Granulomatous Disease, Chronic - immunology; Granulomatous Disease, Chronic - pathology; Humans; Immune system; Immunologic Memory - drug effects; Immunophenotyping; Infant; long-term memory; Male; Measles; Measles - immunology; Measles - prevention & control; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; memory B-cell compartment; NADPH Oxidase 2; NADPH Oxidases - genetics; NADPH Oxidases - immunology; Phenotype; Pokeweed Mitogens - pharmacology; Primary Cell Culture; proliferation; Proteins; Reactive Oxygen Species - immunology; Reactive Oxygen Species - metabolism; reactive oxygen species deficiency; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - immunology; Software; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology; Vaccination; Viral Vaccines - administration & dosage; Young Adult; NADPH; CGD; Chronic granulomatous disease; proliferation; PMA; memory B-cell compartment; PWM; long-term memory; BCR; B cell; reactive oxygen species deficiency; ASC; Anti-Ig; ROS; HC; TLR; measles; Reactive oxygen species; B-cell receptor; Pokeweed mitogen; Healthy control subject; Toll-like receptor; F(ab′) 2 fragment goat anti-human IgA+IgG+IgM; Nicotinamide adenine dinucleotide phosphate; Antibody-secreting cell; Phorbol 12-myristate 13-acetate
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.07.012

Chronic granulomatous disease (CGD) is a primary immune deficiency characterized by a defect in reactive oxygen species production. Although the effect of CGD mainly reflects on the phagocytic compartment, B-cell responses are also impaired in patients with CGD. We sought to investigate how defective gp91phox expression in patients with CGD and CGD carriers might affect the B-cell compartment and maintenance of long-term memory. We studied the B-cell compartment of patients with CGD in terms of phenotype and ability to produce reactive oxygen species and proliferate on stimuli differently directed to the B-cell receptor and Toll-like receptor 9. We further studied their capacity to maintain long-term memory by measuring cellular and serologic responses to measles. We show that the memory B-cell compartment is impaired among patients with CGD, as indicated by reduced total (CD19+CD27+) and resting (CD19+CD27+CD21+) memory B cells in parallel to increased naive (CD19+CD27−IgD+) B-cell frequencies. Data on CGD carriers reveal that such alterations are related to gp91phox expression. Moreover, proliferative capabilities of B cells on selective in vitro stimulation of B-cell receptor or Toll-like receptor 9 pathways were reduced in patients with CGD compared with those seen in age-matched healthy control subjects. Significantly lower measles-specific antibody levels and antibody-secreting cell numbers were also observed, indicating a poor ability to maintain long-term memory in these patients. Altogether, our data suggest that patients with CGD present a defective B-cell compartment in terms of frequencies of memory B cells, response to in vitro stimulation, and maintenance of long-term antigen-specific memory.