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

Abstract

Background: 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. Objective: We sought to investigate how defective gp91 phox expression in patients with CGD and CGD carriers might affect the B-cell compartment and maintenance of long-term memory. Methods: 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. Results: We show that the memory B-cell compartment is impaired among patients with CGD, as indicated by reduced total (CD19 1 CD27 1 ) and resting (CD19 1 CD27 1 CD21 1 ) memory B cells in parallel to increased naive (CD19 1 CD27 2 IgD 1 ) B-cell frequencies. Data on CGD carriers reveal that such alterations are related to gp91 phox 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

Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age

“…The DN B cells are characteristic of immune senescence in HC [10] and are also associated with autoimmunity [32] and chronic diseases such as systemic lupus erythe-matosus, chronic granulomatous disease and HIV [4, 44, 45]. In agreement with previous reports, higher frequencies of DN B cells were observed before vaccination in old HC compared to young HC [10, 11].…”

Toll‐like receptor signaling in primary immune deficiencies

“…Thus, NADPH oxidase or resultant ROS may be important for proper expression of TLR5 and TLR9 in neutrophils, with the absence of NADPH or ROS resulting in impaired responses to stimulation by these TLR ligands, and thereby less efficient phagocytosis . The NADPH oxidase system was further shown to be important in the context of TLR9 stimulation in B cells, with defects in long‐term antibody memory responses recently reported in CGD patients . The authors linked deficient ROS production in B cells to reduced frequencies of memory B cells in patients, with a milder phenotype seen in carriers of CGD mutations (Fig.…”

Reactive oxygen homeostasis – the balance for preventing autoimmunity

“…9 There is evidence for ROS having an influence on the process of memory B cell formation, as there is a correlation between the amount of neutrophils with normal NOX2 activity and the percentage of memory B cells in CGD patients. 68,84 In contrast, circulating CD19…”

“…61,[63][64][65][66] Moreover, ROS can modulate the interaction of B cells with CD4 þ T cells by promoting MHC II antigen presentation and influence the number of circulating memory B cells. [67][68][69] T cells T cells are often found in the vicinity of potent oxidative burst-mounting phagocytes. ROS influence T cell activation, modulate T cell receptor signaling pathways, suppress T cell proliferation, and downregulate their responsiveness.…”