ALTERED CIRCADIAN-RHYTHMS OF NATURAL-KILLER (NK) CELL-ACTIVITY IN PATIENTS WITH AUTOIMMUNE RHEUMATIC DISEASES

Natural Killer (NK) cells are a lymphocyte subset actively involved in cytotoxicity against tumor-transformed and virus-infected cells; they are a reliable model for the study of neuroendocrine-immune interacti ons. In previous works we demonstrated that in healthy subjects NK act ivity of peripheral blood mononuclear cells (PBMC) and susceptibility to endogenous modifiers display statistically validated circadian rhyt hms. In rheumatoid arthritis (RA) and in other autoimmune rheumatic di seases abnormalities of the circadian rhythm of serum cortisol and alt ered levels of NK cell activity have been reported. We evaluated the c ircadian pattern of NK cell activity in 7 hospitalized patients with a utoimmune rheumatic diseases (4 RA. 1 scleroderma, 2 mixed connective tissue disease). Temporal variations of in vitro responses to either p ositive recombinant (immune interferon, r IFN-gamma IFN-gamma: 650 UI/ ml; recombinant interleukin-2, r IL-2 IL-2: 100 UI/ml) or negative (co rtisol: 10(-6) M) modifiers were also studied. Blood was drawn at 4h i ntervals for 24 h, starting at 08(00). PBMC preparations were immediat ely separated and incubated for 20h in the presence or absence of modi fiers. NK activity was assessed with a direct non-radiometric 4h cytol ytic assay, using K 562 cells as targets. Significant circadian variat ions of spontaneous NK activity were documented only in women with RA, with a peak in the evening hours and a minimum in the night or in the early morning (p<0.05, PR 51.5%, PHI 18(29). Population-mean cosinor analysis did not yield detection of significant circadian variations o f in vitro responsiveness to modifiers. By single cosinor analysis, ho wever, we could find individual rhythmicities of susceptibility to rIF N-gamma (I subject with AR: p < 0.05, PR 91.7%, PHI 08(05)), to rIL-2 subject with AR: p < 0.05, PR 87.7%, PHI 05(13)), and to cortisol (I s ubject with AR: p < 0.05, PR 88.1%, PHI 10(24)). These data, albeit pr eliminary, suggest that the circadian rhythms of the spontaneous NK ce ll activity and susceptibility to modifiers are no longer recognizable in many patients with autoimmune rheumatic diseases. When present, th ey are remarkably phase-shifted with respect to healthy subjects. Furt her studies are needed to ascertain the role, if any, of circadian rhy thmic hormones and cytokines in the pathogenesis of this altered tempo ral organization.