Aging Down-Regulates the Transcription Factor E2A, Activation-Induced Cytidine Deaminase, and Ig Class Switch in Human B Cells

Abstract

Elderly humans have compromised humoral and cellular immune responses, which lead to reduced protection to infectious agents and to vaccines. Currently, available vaccines suboptimally protect the elderly population. The capacity to class switch the Ig H chain is critical to the effectiveness of humoral immune responses in mice and humans. We have previously shown in mice that the E2A-encoded transcription factor E47, which regulates many B cell functions, is down-regulated in old splenic B cells. This leads to a reduction in the activation-induced cytidine deaminase (AID), which is known to induce class switch recombination and Ig somatic hypermutation. The old activated murine B cells also have less AID and less switched Abs. We have extended our study here to investigate whether aging also affects Ab production and E47 and AID expression in B cells isolated from the peripheral blood of human subjects (18–86 years). Our results obtained with activated CD19+ B cells show that the expression of E47, AID, and Igγ1 circle transcripts progressively decrease with age. We also show an age-related decline in the percentage of switch memory B cells (IgG+/IgA+), an increase in that of naive B cells (IgG−/IgA−/CD27−) for most individuals, and no decrease in that of IgM memory cells in peripheral blood, consistent with our data on the decrease seen in class switch recombination in vitro. Our results provide a possible molecular mechanism for a B cell intrinsic defect in the humoral immune response with aging and suggest avenues for improvement of vaccine response in elderly humans.

Effects of aging on human leukocytes (part II): immunophenotyping of adaptive immune B and T cell subsets

“…Although the total numbers of mature B cells decrease with age (reviewed in Frasca et al 2011), conflicting reports on the ratio of naïve and memory cells exists (Kolar et al 2006;Caraux et al 2010;Bulati et al 2011;Frasca et al 2011). Furthermore, a decrease in classswitched B cells and decrease in affinity antibodies has been observed in the elderly (Frasca et al 2008). The decrease in humoral protection links B cells, similar to T cells, with immunosenescence (Bulati et al 2011;Frasca et al 2011).…”

Mouse CMV infection delays antibody class switch upon an unrelated virus challenge

“…It remains unclear if the effect of CMV infection on Ig class-switch is truly CD4 independent, or if CMV induces a subtle change in the function of CD4 T-cells, which could not be measured by our assay. Alternatively, CMV may impair B-cell responses by disrupting the lymph-node architecture and thus the signaling network that is necessary for the germinal center reaction, or by direct effects on the B-cell compartment, for instance by dysregulating TNFα signaling (Frasca et al, 2012) or by affecting E47 or activation-induced cytidine deaminase, similarly to effects observed in aging mice (Frasca et al, 2008;Frasca et al, 2004). These important questions may be addressed in future experiments.…”

A novel B cell population revealed by a CD38/CD24 gating strategy: CD38−CD24− B cells in centenarian offspring and elderly people

“…However, innate immunity seems to be better preserved, while more severe agedependent changes occur in the adaptive immune system (Franceschi et al 2000b). There are clear changes in B cell generation and repertoire, and as a consequence of this and changes in the T cells, elderly people show defective humoral immunity (Cancro et al 2009;Bulati Fig. (Pawelec et al 2005;Shi et al 2005;Frasca et al 2008;Veneri et al 2009;, and in previous papers, we (Colonna-Romano et al 2009) and others (Gupta et al 2005) have demonstrated that the percentage of naïve B cells are significantly reduced in aged individuals. However, this is still a somewhat controversial finding as some authors reported an increase, a decrease, or no changes in the naïve/memory B cell compartments, as we have reviewed .…”

“…The early progenitors of B lymphocytes develop into pro-, pre-, and immature B cells (LeBien and Tedder 2008) that, after they are controlled for autoreactivity (Carsetti et al 1995;Palanichamy et al 2009), leave the bone marrow and enter the blood as transitional B cells (Allman et al 1993;Chung et al 2003;Mauri and Ehrestein 2008). In humans, peripheral blood naïve and memory B cells have been described on the basis of the differential expression of IgD and CD27 (Anolik et al 2004;Shi et al 2005;Wei et al 2007;Frasca et al 2008) (Fecteau et al 2006;Colonna-Romano et al 2009). …”