CIRCADIAN ABNORMALITIES OF NATURAL-KILLER (NK) CELL-ACTIVITY AND IMMUNOREACTIVE ACTH IN THE PERIPHERAL-BLOOD OF PATIENTS WITH AUTOIMMUNE RHEUMATIC DISEASES

The hypothalamic-pituitary-adrenal (HPA) activity is admittedly important for synchronizing several variables of the circadian system. Natural Killer (NK) cells are large granular lymphocytes spontaneously cytotoxic. They are involved in the immunosurveillance against viruses and cancer, whereas their role in autoimmunity is unclear. Both lymphokines and hormones modulate NK cytotoxicity. In previous works we demonstrated that in healthy subjects NK activity of peripheral blood mononuclear cells (PBMC) and in vitro susceptibility to physiological modifiers have a temporal organization with a statistically validated circadian rhythm. In rheumatoid arthritis (RA) and in other autoimmune diseases abnormalities of both HPA function and NK cell activity have been reported. We investigated the circadian profiles of serum ACTH, beta-endorphin and cortisol on the one hand, and of NK cell cytotoxicity on the other, in 7 hospitalized subjects affected by autoimmune diseases. Changes of NK cell activity after exposure in vitro to positive and negative modifiers were also evaluated. Blood was drawn at 4 hour intervals for 24 hours, starting at 08:00. NK activity was assessed with a direct nonradiometric 4-hour cytolytic assay, using K562 cells as a target. Radioimmunoassayable ACTH, beta-endorphin and cortisol were measured using commercially available kits. Circadian variations were statistically validated with the Cosinor method. Normally synchronized, circadian rhythms were detected for serum beta-endorphin and cortisol, whereas significance was not attained for serum ACTH. Circadian variations of spontaneous NK cell activity were apparent only in RA patients; mean acrophase was remarkably phase-shifted with respect to healthy controls. We noticed individual rhythmicities also of percent changes after exposure to modifiers, yet no consistent pattern could be validated. Our data suggest that in autoimmune rheumatic diseases the circadian patterns of natural cytotoxicity and susceptibility to modifiers are lost in the majority, but not in all patients. Among HPA hormones, circadian abnormalities are apparently much more frequent for immunoreactive ACTH, than for beta-endorphin and cortisol.