Effects of age on antibody affinity maturation

Abstract

The elderly are more susceptible to infectious diseases. Mortality and morbidity from infections increase sharply over the age of 65 years. At the same time, the efficacy of vaccinations in the elderly is decreased. The elderly also have an increased incidence of cancer and inflammatory diseases. All the above indicate an age-related dysregulation of the immune system. Evidence suggests that the change in the humoral immune response with age is a qualitative rather than a quantitative one, i.e. it is the affinity and specificity of the antibody that changes, rather than the quantity of antibody produced. There are a number of possible causes of this failure, one of which is a defect in the mechanism of hypermutation of immunoglobulin genes. We have studied individual clonal responses within germinal centres of spleen and Peyer's patches in young and old patient groups. Our results indicate that there is no difference in the actual mechanism of hypermutation with age. There are, however, differences that are due either to a change in selection processes or to a change in the founder cells available for activation.

Lineage tree analysis of immunoglobulin variable-region gene mutations in autoimmune diseases: Chronic activation, normal selection

“…Mutational lineage trees of B cell clones from patients with MG, RA, SS, and MS [6,[16][17][18][19][20][21], and from normal human GCs [25][26], were created from published and unpublished IgV sequence data; we also used published lineage trees [12,10,14]. Each dataset contained IGV sequences from different IGV groups and patients (Table 1).…”

“…Sample trees are shown in Tree measurements of AI data sets were compared to those of trees from normal human samples of both Peripheral blood lymphocytes (PBL [8]) and germinal centers (GC [6,26]), revealing large variability between the data of the different groups, including between data sets of the same disease ( Figure 2). Despite this variability, in all but two sets [10,14] the trees were larger than in the normal control data sets, whether we look at the number of leaves L, i.e.…”

“…This method enables a more extensive investigation of the dynamics of the GC response. Previous studies have demonstrated the usefulness of this method, and resulted in new insights of various aspects of the GC reaction in normal situations [3][4], ageing [5][6], B cell malignancies [7,8], and chronic viral diseases (Margolin et al, submitted). In the present study, the GCs of individuals with autoimmune (AI) diseases are studied using lineage tree analysis.…”

Altered Innate Immune Functioning of Dendritic Cells in Elderly Humans: A Role of Phosphoinositide 3-Kinase-Signaling Pathway

“…There is decreased response of T cells to specific Ags or mitogens, altered cytokine secretion patterns, involution of thymus causing changes in the ratio of naive to memory lymphocyte populations, decreased CTL responses, and defects in signal transduction (9 -16). The situation is aggravated further by the failure of B cells to produce high-affinity Abs and to generate long-lasting memory responses (17,18). In contrast to lymphocytes, very little is understood about the functioning of the APCs in aging.…”

Immunoglobulin variable-region gene mutational lineage tree analysis: Application to autoimmune diseases

“…We have applied this method to study age-related differences in the humoral immune response in humans, with the surprising result that the GC reaction dynamics -and the effects of aging on these dynamics -differ between GCs taken from different tissues [13,14]. Applying this method to lineage tree data from Ig primary and secondary diversification processes in rabbits and chickens, which use gene conversion as well as SHM during both primary and secondary diversification [7], has highlighted the unique characteristics of the genetic and selective processes driving the formation of the Ig repertoire in these two species.…”