Members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) superfamily share an intracytoplasmic Toll-IL-1 receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. We describe three unrelated children with inherited IRAK-4 deficiency. Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors. The otherwise healthy children developed infections caused by pyogenic bacteria. These findings suggest that, in humans, the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.

Summary. Diminished bactericidal capacity was found to be characteristic of polymorphonuclear leukocytes (PMN) from five children with the clinical syndrome of granulomatous disease of childhood. The PMN from these children demonstrated nearly normal phagocytic capacity, and the majority of viable bacteria, after 2 hours of incubation in the phagocytosis system, were found associated with leukocytes.The morphology of the unstimulated polymorphonuclear leukocytes from patients with chronic granulomatous disease was similar to those from normal persons of similar ages by light and electron microscopy. In addition, the total lysozyme and phagocytin activity of leukocyte extracts from these patients was similar to those from equal numbers of leukocytes from controls.A striking difference in the cytoplasmic response after phagocytosis characterized the PMN of the patients with granulomatous disease. Whereas degranulation, vacuole formation, and rapid bacterial digestion were the rule in the PMN from controls, little degranulation and persistence of intact bacteria in the cytoplasm characterized disease.The deficiency of bactericidal capacity and the minimal degranulation after active phagocytosis by the PMN of these children with an inherited syndrome suggest that separate metabolic processes are involved in phagocytosis and in intracellular digestion. Continuing study of the metabolic function of leukocytes from these children should provide an opportunity for increased understanding of the metabolic basis for degranulation and intracellular digestion in phagocytic cells.

The bursa of Fabricius and the thymus are "central lymphoid organs" in the chicken, essential to the ontogenetic development of adaptive immunity in that species. Surgical removal of one or both of these organs in the newly hatched chicken, followed by sublethal X-irradiation the next day, has permitted recognition of two morphologically distinct cell systems in the "peripheral lymphoid tissues" of the spleen, gut, and other organs, and clear definition of the separate functions of each cell system. The thymus-dependent development is represented morphologically by the small lymphocytes of the circulation and the white pulp type of development in the tissues. As in mammals, the thymus-dependent tissues of the chicken are basic to the ontogenesis of cellular immunity: graft versus host reactions, responses of delayed hypersensitivity and homograft rejection; and play a less clearly defined role in the antibody response to at least some antigens. Thymectomized-irradiated chickens are deficient in all these responses, and grow more slowly than any of the other experimental groups. In these animals germinal centers, plasma cells, and capacity for immunoglobulin synthesis remain intact. The bursa-dependent development is represented morphologically by the larger lymphocytes of the germinal centers and the plasma cells, and functionally by the immunoglobulins. Bursectomized-irradiated chickens are agammaglobulinemic and unable to produce detectable antibody despite intense, repeated stimulation with bovine serum albumin and Brucella abortus organisms. The thymus-dependent development in these animals seems to be normal; they have adequate numbers of lymphocytes in the circulation and tissues, are able to reject skin homografts, though more slowly than usual, and to exercise graft versus host reactions. The short life span of these chickens has precluded adequate study of responses of delayed hypersensitivity. There was no evidence of significant impairment of reticuloendothelial function in either the bursectomized-irradiated or the thymectomized-irradiated group, as judged by the clearance of colloidal gold and I131-tagged keyhole limpet hemocyanin.

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Summary. Polymorphonuclear leukocytes from patients with chronic granulomatous disease respond to the phagocytosis of latex particles with normal increments in glucose consumption, lactate production, Krebs' cycle activity, and lipid turnover.The leukocytes of these patients fail to show normal increments in respiration, direct oxidation of glucose, and hydrogen peroxide formation during particle uptake.It appears that the stimulation of respiration with the formation of hydrogen peroxide and stimulation of the direct oxidative pathway of glucose metabolism are closely linked to degranulation and intracellular killing of bacteria by polymorphonuclear leukocytes. IntroductionThe study of the metabolic events accompanying phagocytosis of particles by polymorphonuclear leukocytes has been a subject of extensive investigation during the past several years. The most striking changes that occur in metabolism during