Altered lymphocyte distribution in Alzheimer’s disease

Abstract

The contribution of immunological factors in the etiopathogenesis of Alzheimer’s disease (AD) is increasingly noted. Apart from cerebral immunological findings, peripheral changes of the immune systems have been reported including lymphocyte function and subset distribution. As data still remain inconsistent, we investigated a sample of 43 patients with AD and of 34 healthy age-matched controls. Distribution of the T-, B- and NK cell subsets was determined by flow cytometry (FACS). We found a significant decrease of CD3⁺ lymphocytes as well as of CD19⁺ lymphocytes. A slight increase of the CD4⁺ and a decrease of the CD8⁺ subpopulation could be observed, without significant change of the CD4⁺/CD8⁺ ratio. CD16⁺56⁺ cells were not altered. Our findings of decreased T- and B-Cell numbers in AD sustain the hypothesis of a general decline of immune activity in AD. A putative association with premature immunosenescence in AD and possible pathogenetic implications are discussed.

Introduction

The etiopathogenesis of Alzheimer’s disease (AD) is still unresolved. Several studies indicate an involvement of the immune system. An increase of inflammatory parameters, such as complement factors, proinflammatory cytokines and activation of microglia have been found co-localized with neuritic plaques in the AD brain. Further, changes of peripheral immune parameters have been shown. The research of the past decades has demonstrated abnormalities of both the humoral and cellular immune responses, suggesting an association of faulty immune regulation and AD. The recognition of reciprocal interactions between brain and immune system (neuroimmune axis, Solomon, 1987) and the finding of CD4⁺ and CD8⁺ T lymphocytes in the brain parenchyma of AD patients (Rogers et al., 1988) led to the hypothesis that immunological aberrations in AD may manifest themselves in peripheral immune reactions (Antonaci et al., 1990).

In this context, several studies have investigated T lymphocyte subpopulations and activation markers in AD in order to find immune-related abnormalities in the peripheral blood. Whereas the total percentage of lymphocytes was not found to be altered (Ikeda et al., 1991, Singh, 1994), alterations of T cell function, differentiation and subset distribution have been observed. Abnormal functioning of suppressor as well as helper T-cells in patients with AD was described (Skias et al., 1985, Singh et al., 1986–87). Nijhuis et al. (1991) observed a significantly decreased activation response in AD compared to age-matched controls. The function of natural killer (NK) cells has also been found to be reduced (Araga et al., 1991). Studies on lymphocyte subpopulations provided conflicting results. While several investigators could not find alterations in subset distribution (Leffell et al., 1985, Singh, 1990, Ikeda et al., 1991, Dysken et al., 1992), other studies found decreased circulating concentrations of CD8⁺ lymphocytes and natural killer (NK) cell activity in AD patients (Skias et al., 1985, Pirttilä et al., 1992, Shalit et al., 1995). Hu et al. (1995) found that a decrease of CD8⁺ lymphocyte subpopulation also appeared in other forms of dementia and therefore might not be specific. Furthermore, the proliferative response of T lymphocytes has been investigated, but, again, data are inconsistent. Whereas former studies did not reveal any alterations in the proliferative response of AD patients (Leffell et al., 1985, Leonardi et al., 1989), meanwhile several authors report a decrease in the proliferative ability of lymphocytes of AD patients (Singh, 1994, Shalit et al., 1995, Trieb et al., 1996).

Our study starts from the hypothesis that systemic immunological changes may be involved in the pathogenesis of AD. We assume a dysregulation of the immune system in terms of a defective immune response which also affects lymphocyte differentiation and subset distribution. In the present study, we investigated T lymphocyte subsets, B lymphocytes and NK cells in peripheral blood of Alzheimer patients and age matched controls by means of immune-associated antigens.