Double negative (CD19+IgG+IgD−CD27−) B lymphocytes: A new insight from telomerase in healthy elderly, in centenarian offspring and in Alzheimer's disease patients

Abstract

a b s t r a c tImmunosenescence is characterized by the impairment of humoral immunity with changes in the memory/naive B cell compartment. In particular we have previously reported the percentage increase of a Memory IgD − CD27 − (Double Negative, DN) B cell population in aged people. In this study, we have further characterized DN B cells with the aim to better understand their contribution to immunosenescence. As DN B cells show a poor ability to proliferate in vitro, we have evaluated the expression of the inhibitory receptors CD307d and CD22 on these cells from young and old individuals. In addition we have evaluated the ability to activate DN B cells by the simultaneous use of innate (CpG) and adaptive (␣-Ig/CD40) ligands. Our data demonstrate that the refractoriness to proliferate of DN B cells does not depend on the expression of inhibitory receptors, but it is due to the kind of stimulation. Indeed, when DN B cells are stimulated engaging both BCR and TLR9, they become able to proliferate and reactivate the telomerase enzyme. In the present study, we have also compared the telomerase activity in a group of people genetically advantaged for longevity as centenarian offspring (CO) and in a group of moderate-severe Alzheimer's disease (AD) patients, who represent a model of unsuccessful aging. Our study suggests that telomerase reactivation of DN B cells, as well as their number and ability in activating, depend essentially by the biological age of the subjects studied, so the evaluation of DN B cells might allow to gain insight to healthy and unsuccessful aging.

Immune System Dysfunction in the Elderly

“…Immunosenescence is characterized by the impairment of humoral immunity with changes in the memory/naive B cell compartment (Martorana et al 2014). The increase of memory B cells (IgG(+) IgD(-)CD27(-), double negative, DN) population in the elderly, in which there is also a typical inflammatory micro-environment.…”

“…In the elderly, naïve/memory B cell populations present a different expression of the studied receptors that could be discussed in terms of "inflamm-aging". In particular IgG(+)IgD(-)CD27(-) DN B cells show a tissue trafficking phenotype and they can be stimulated to produce granzyme B (Bulati et al 2014). Double negative (IgG+IgD-CD27-) B cells are increased in a cohort of moderate-severe Alzheimer's disease patients and show a pro-inflammatory trafficking receptor phenotype (Bulati et al 2015).…”

B Cell Immunophenotyping and Transcriptional Profiles of Memory B Cells in Patients with Myasthenia Gravis

“…A double-negative B lymphocyte is a recently recognized B cell entity of which exact role and origin remain to be demonstrated. However, increasing evidences suggest that they belong to memory B cell category, but are incapable of antigen presentation or replication, so-called "exhausted" or "senescent" memory B cells [12,13]. Expansion of DN B lymphocytes has been reported in elderly population or various chronic inflammatory conditions; Alzheimer' s disease (AD) [14], rheumatoid arthritis (RA) [15], systemic lupus arthritis (SLE) [16], and chronic Human Immunodeficiency Virus (HIV) [17].…”

The Role of Inflammatory Mediators in the Pathogenesis of Alzheimer’s Disease

“…115 Moreover, Martorana et al found an augmented subset of B cells with a memory doublenegative phenotype in elderly people. 116 Interestingly, Colonna-Romano et al reported that B cells are late memory or exhausted cells, which may be a manifestation of ageing or a dysregulation of the immune system. 117 …”