B cells in the aged: CD27, CD5, and CD40 expression

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Abstract

Ageing is characterized by numerous changes in lymphocyte subpopulations. In the present paper we have focused on B cells carrying the surface markers CD27, CD5 and CD40. CD27 is considered a marker of primed (memory) cells and its engagement promotes the differentiation of memory B cells into plasma cells. CD5 is expressed on B1 cells, which are considered to be responsible for T cell-independent antibody production other than autoantibodies. The CD40 molecule binds CD40L (CD154) and is necessary for T-dependent antibody responses. Here we show that the absolute number of CD5+ and CD40+ B cells is decreased in the elderly, while CD27+ B lymphocytes only marginally decrease in centenarians. However, there is a decrease of the percentage of CD5+ B cells, an increase of CD27+ B cells, while CD40 does not change significantly. These data, together with the increased number of NK cells during aging, suggest different regulation of antibody production in the elderly which might be another example of immune remodeling with aging, based on interactions between human B and NK cells.

Introduction

Many authors have described a large variety of modifications of immune cells and functions in aged individuals. Most of these studies have focused on the T cell compartment as it is thought to be particularly impaired in old subjects (Colonna Romano et al., 2002a, Cossarizza et al., 1997, Globerson and Effros, 2000, Pawelec et al., 2002). On the other hand, it has been well documented that NK and NKT cells may be considered a marker of successful aging and healthy old people and centenarians show an increased number of these cells ‘ex vivo’ (Franceschi et al., 1995; Solana and Mariani, 2000).

However, changes are not limited to T cells, and B cells have been studied as well (Cossarizza et al., 1997, Olsson et al., 2000, Potestio et al., 1999). Although they are numerically reduced, the consensus is that the modest functional change occurring in the B cell compartment may be dependent on T cells (Le Maoult et al., 1997, Song et al., 1997, Weksler, 2000). Pioneering observations on serological responses to foreign agents in the aged suggested a modification in the ability of old subjects to mount a proper response (Baumgartner, 1934). Subsequently, it was established that vaccination produced lower antibody responses in elderly compared with young humans. This defect in the antibody response has been related to the increased susceptibility and severity of infectious diseases in the elderly (Le Maoult et al., 1997). Analysis of the antibody response and of the number of B cells that bind foreign antigens both in old humans and experimental animals demonstrated that immunosenescence is not a state of immune deficiency but a state of immune dysregulation, also evidenced by alteration in the B cell repertoire (Le Maoult et al., 1997). Indeed, it has been demonstrated that although the antibody response to foreign antigens is lower in old compared with the youngest individuals, the number of B cells secreting autoantibodies is enhanced (Weksler 2000). Moreover, it has been reported that NK cells are involved in B lymphocyte maturation, Ig secretion and isotype switching (Rodriguez et al., 1987). It has also been demonstrated that B cells interact with NK cells, and that this interaction causes the activation of NK cells and the production of IFN-γ (Grewal and Flavell, 1998). Finally, it has also been demonstrated that human NK cells can induce antibody responses by B cells. This function is not dependent on T lymphocytes, although it seems that the interaction between CD40 and CD154 plays a critical role (Blanca et al., 2001). Therefore, it appears that these two cell types are able to cooperate to generate good B cell activity. Moreover, it has been suggested that CD5+ and memory (CD27+) B lymphocytes (Agematsu et al., 2000) may be relevant for the production of antibodies induced by NK cells (Blanca et al., 2001).

On this basis, we evaluated the number of B lymphocytes bearing these markers, and investigated the relationship with NK cells in young, old and centenarian subjects.

In this paper we demonstrate that the percentage of memory (CD27+) B cells parallels the increase of NK cells, whereas the overall number of CD27+ B cells is not altered in old subjects, because of the decrease in total lymphocytes. This simultaneous increase of memory B lymphocytes and NK cells suggests the possibility that this may represent another example of remodeling of the immune system (Franceschi et al., 1995): i.e. NK cells cooperate with B memory cells for the production of immunoglobulins in the secondary response (Blanca et al., 2001). Indeed, although CD4 T lymphocytes are impaired, NK cells might help the antibody response by B cells. Remodeling of the immune system has been suggested to explain the findings in successfully aged individuals (centenarians). According to this hypothesis, in the successfully aged, some immune functions (due to T cell activation) are impaired, but others (such as NK cells and inflammation) are enhanced (Franceschi et al., 1995, Franceschi et al., 2000). This function, that does not involve T lymphocytes, depends on the interaction between CD40 and CD154 and it has been suggested that both CD5+ and CD27+ B cells are directly involved in antibody production mediated by NK cells (Grewal and Flavell, 1998, Blanca et al., 2001). This might explain the ‘normal’ antibody production in elderly.

Section snippets

Subjects studied

Eighty-five healthy subjects (32 age-range 20–48, 41 age-range 66–97 and 12 age-range 99–103) were studied. None of the selected subjects was affected by neoplastic, infectious or autoimmune disease and none was receiving any drug influencing immune function at the time of the study. Informed consent was obtained according to the Italian law.

Flow cytometry

Freshly collected blood (100 μl) was incubated with anti-CD5-FITC/CD19-Phycoerythin (PE), anti-CD40-FITC/CD19-PE, anti-CD27-FITC/CD19-PE (Caltag,

Results

We evaluated B lymphocytes bearing CD5, CD40 and CD27. Our data (Fig. 1) show that the percentage of CD19+CD5+ lymphocytes significantly decrease with age (panel A); CD40+ B lymphocytes do not show any significant change (panel B) whereas the percentage of CD27+ B cells (memory) increases in the elderly (panel C). Due to the well-known reduction of total numbers of B cells in the aged, this increase has no impact on the absolute number of memory B cells present, whereas naive B lymphocytes

Discussion

It is believed that the most dramatic changes in the immune system of the elderly occur within the T cell compartment. These modifications might be at least partly responsible for the increased incidence and severity of infection and cancer in the elderly (Franceschi et al., 2000, Pawelec et al., 2002, Wikby et al., 1998). T lymphocyte impairment also affects γδ T cells that are considered a good linkage between innate and adaptive immunity and represent the first line of defense that precedes

Acknowledgements

These studies have been supported by grants from MIUR, Rome (ex 40% Immunogenetics of Longevity, C.C.), MIUR, Rome (ex 60% GCR); EU program ImAginE.

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