Upregulation of lymphocyte β-adrenergic receptor in Down's syndrome: a biological marker of a neuroimmune deficit

Abstract

To test the hypothesis of an altered central nervous system influence upon the immune system of Down's syndrome (DS) patients and in order to establish a peripheral biological marker of neuroimmune deficit, we have studied the characteristics of the β 2-adrenergic receptor (B 2AR) system in peripheral blood monocytes (PBMC) of 12 pre-pubertal (six boys and six girls) individuals and correlated alterations in binding with changes in distribution of lymphocyte subsets. Using the very potent β-adrenergic antagonist, iodocyanopindolol ([ 125I]CYP), as a ligand, the present study shows that a typical BAR population of the β 2-subtype is present in PBMC from DS children, with binding kinetics and structural specificity similar to those measured in PBMC from patients with other (non-genetic) forms of mental retardation, or in PBMC from age-matched healthy subjects. On the other hand, this study revealed a significance increase in B 2AR binding capacity of PBMC from DS subjects ( B max = 5258 ± 470 sites/cell) compared to the values measured in the control population of retarded children ( B max = 1965 ± 280 sites/cell), characterized by an approximately three-fold increase in the B max, without changes in binding affinity ( K D = 40.5 ± 2.0 and 36.6 ± 2.5 pM in DS and retarded patients, respectively). The flowcytometric markers revealed a profound alteration in the distribution of lymphocyte subtypes with an almost 50% decrease in B cell and T-helper populations, a three-fold increase in T-cytotoxic suppressor, a seven-fold increase in lymphocyte-activated killer cells (LAK) and 30% increase in natural killer (NK) subpopulations. When fluorescence-labelled lymphocytes were visualized in the cytofluorograph and sorted for their use in the radioreceptor assay, B cells had approximately twice the number of B 2AR when compared to T cells; and cytotoxic/suppressor showed a higher binding capacity compared to T-helper cells. On the other hand, labelled lymphocytes from DS patients showed a specific increase in receptor number in B cells, T-cytotoxic suppressor and NK subpopulations. It is concluded that a profound catecholaminergic dysfunction not previously appreciated in DS is reflected by a significant alteration in lymphocyte subset distribution and by a specific up-regulation of lymphocyte B 2AR in phenotypically and functionally distinct T and B cells as well NK subpopulations, suggesting a possible denervation supersensitivity phenomenon. From the present data it seems tempting to speculate that the B 2AR might represent a valuable marker of neuroimmune dysfunction in DS and possibly other brain pathologies.