IMPAIRED INTERFERON-PRODUCTION AND NATURAL-KILLER-CELL ACTIVATION IN PATIENTS WITH THE SKIN-CANCER PRONE DISORDER, XERODERMA-PIGMENTOSUM

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder with sun sensitivity, markedly increased skin cancer susceptibility, and d efective DNA repair without consistently identified symptoms of immune deficiency. We examined natural killer (NK) cell activity and interfe ron production in peripheral blood lymphocytes (PBL) of eight XP patie nts who had multiple primary skin cancers. The XP patients had normal numbers of T cells and NK cells, as well as normal lymphokine-activate d killer cell activity and normal tumor necrosis factor-alpha producti on. Unstimulated NK cell function was 40% of normal controls in five X P patients, but was normal in three other XP patients. However, PBL fr om all the XP patients tested showed no enhancement of NK activity by the interferon inducer, polyinosinic acid:polycytidilic acid (polyIC) but enhancement by interferon-alpha was normal, suggesting an impairme nt in interferon production. Parallel studies in non-XP skin cancer pa tients revealed that both unstimulated and polyIC-enhanced NK activity were normal. Further investigation using PBL from XP patients reveale d that the production of interferon-gamma after stimulation with inter feron inducers (polyIC, interleukin 2, or K562 tumor cells) was 13-43% of normals. These data indicate that XP lymphocytes have a defect in production of interferons and suggest that defective interferon produc tion, as well as DNA repair defects, may play an important role in the susceptibility of XP patients to skin cancer.