Upregulation of lymphocyte beta-adrenergic receptor in Down's syndrome: a biological marker of a neuroimmune deficit.
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 beta 2-adrenergic receptor (B2AR) 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 beta-adrenergic antagonist, iodocyanopindolol ([125I]CYP), as a ligand, the present study shows that a typical BAR population of the beta 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 significant increase in B2AR binding capacity of PBMC from DS subjects (Bmax = 5258 +/- 470 sites/cell) compared to the values measured in the control population of retarded children (Bmax = 1965 +/- 280 sites/cell), characterized by an approximately three-fold increase in the Bmax, without changes in binding affinity (KD = 40.5 +/- 2.0 and 36.6 +/- 2.5 pM in DS and retarded patients, respectively). The flowcytometric analysis of lymphocyte subsets using a panel of monoclonal antibodies against a series of lymphocyte 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 B2AR 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 B2AR in phenotypically and functionally distinct T and B cells as well NK subpopulations, suggesting a possible denervation supersensitivity phenomenon.(ABSTRACT TRUNCATED AT 400 WORDS)
Morale
M C
MC
OASI Institute for Research on Mental Retardation and Brain Aging (IRCCS), Laboratory of Neuroendocrine Immunology, Troina, Italy.
Batticane
N
N
Cioni
M
M
Marchetti
B
B
D000293:Adolescent; D001402:B-Lymphocytes / Q000378:metabolism; D002648:Child; D004314:Down Syndrome / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D007107:Immune System / Q000503:physiopathology*; D020120:Iodocyanopindolol; D016131:Lymphocyte Subsets / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000378:metabolism; D009420:Nervous System / Q000503:physiopathology*; D010641:Phenotype; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000378:metabolism; D015854:Up-Regulation
D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D010869:Pindolol