ENDOTOXIN AND IL-1 HYPORESPONSIVENESS IN A PATIENT WITH RECURRENT BACTERIAL-INFECTIONS

We describe a 15-yr-old girl with recurrent bacterial infections who i s refractory to the effects of LPS in vivo and in vitro and IL-1 in vi tro. Intravenous challenge of the patient with Escherichia coli endoto xin caused a subnormal febrile response, little alteration in the numb er of circulating neutrophils, and subnormal elevations in the plasma levels of TNF-alpha, IL-6, IL-8, lactoferrin, and granulocyte CSF; how ever, normal levels of the anti-inflammatory mediators IL-1 receptor a ntagonist and soluble TNF receptor (60 kDa) were induced. Studies in v itro indicated the patient's monocytes expressed CD14, the LPS recepto r, and bound LPS in a specific manner, but failed to produce TNF-alpha and granulocyte CSF after stimulation with LPS, and failed to respond to IL-1, heat-killed Staphylococcos aureus, and soluble glucan. Perip heral blood patient neutrophils exhibited normal expression of CD14, b ut failed to respond to treatment with LPS (100-1000 ng/ml for 30 min at 37 degrees C), a treatment that caused increased expression of the surface markers, C10, CD18, CD11b, CD67, and CD45, and decreased expre ssion of L-selectin in normal neutrophils. Treatment of normal and pat ient neutrophils with FMLP (0.1 mu M) resulted in equivalent altered e xpression of these surface markers. Patient neutrophils could not be p rimed by either LPS or IL-1 beta for enhanced FMLP-induced O-2(-) gene ration, but primed normally to TNF-alpha and platelet-activating facto r. This patient's hyporesponsiveness to LPS and IL-1 is most likely du e to a defect very early in the signal-transduction pathway.