Perturbations to the well-being of tissues in plants and invertebrates generate fragments of endogenous molecules that are recognized by innate immune receptors. Vertebrates have homologous receptors on specialized cells such as dendritic cells, but whether these receptors respond to fragments of endogenous molecules is not known. We tested the idea that Toll-like receptors on dendritic cells might recognize polysaccharide fragments of heparan sulfate proteoglycan. Dendritic cells were found to mature in response to heparan sulfate as measured by costimulatory protein expression, morphology, and T lymphocyte stimulation, but this maturation was absent when Toll-like receptor 4 was mutated or inhibited. These findings suggest that Toll-like receptors in vertebrates may monitor tissue well-being by recognizing fragments of endogenous macromolecules.

The interleukin 7 receptor (IL-7R) plays a crucial role in early B-and T-cell development. It consists of a unique a chain and a common y chain [IL-2 receptor y chain (IL-2Ry)]. Gene inactivation of IL-7, IL-7R, and IL-2Ry resulted in severe impairment of B and T lymphopoiesis in mice. In addition, IL-2Ry-deficient mice lack yS T cells in the skin and have the impaired development of natural killer (NK) cells and intraepithelial lymphocytes. To explore the role of IL-7/IL-7R system in yS T-and NK-cell development, we have generated and analyzed IL-7R-deficient mice. y6 T cells were absent from skin, gut, liver, and spleen in the deficient mice. In contrast, c43 T and B cells were detected in reduced, but certain, numbers, and NK cells developed normally. The y6 T-cell development in fetal and adult thymus was also completely blocked. These results clearly demonstrate that the signal from IL-7R is indispensable for y6 T-cell development in both thymic and extrathymic pathways. On the contrary, it is suggested that NK-cell development requires cytokine(s) other than IL-7.Interleukin 7 (IL-7) is a growth factor for early B-and T-cell precursors. It was first characterized by its ability to support the growth of B-cell precursors. Subsequently, it has been shown to support survival and growth of early thymocytes and promote rearrangement of T-cell receptor (TCR) ,B and -y chains in fetal thymus and fetal liver cultures (1, 2). In vivo administration of neutralizing antibodies to IL-7 and IL-7 receptor (IL-7R) resulted in the inhibition of both B and T lymphopoiesis (3, 4). IL-7R consists of two polypeptides: a unique a chain (IL-7Ra) and a common -y chain (IL-2R 'y chain, IL-2R-y) (5, 6). IL-7R shares the IL-2R-y with the receptors for IL-2, IL-4, IL-9, and IL-15 (7 and V-y4 but not of V-y3 or V-y5 genes and sustained expression of RAG-1 and RAG-2 genes (1, 2). Collectively, these results strongly suggest that IL-7 may be also involved in the development and the maintenance of 'y6 T cells in the thymus and the periphery. Gene inactivation studies have been carried out to elucidate the in vivo function of various cytokines and their receptors. In IL-2R-y-deficient mice, numbers of T, B, and natural killer (NK) cells are reduced (15,16). In addition, DETCs are absent from the skin and the development of IELs is severely diminished. In contrast, mice deficient for IL-2, IL-4, or both cytokines have normal numbers of mature T and B cells (17, 18). On the other hand, in both IL-7-and IL-7R-deficient mice, the numbers of lymphocytes are reduced (19,20), suggesting that the impairment of T and B lymphopoiesis in IL-2Ry-deficient mice is caused by depletion of the signal by IL-7. However, studies have not been reported on the development of y8 T and NK cells in IL-7R-deficient mice.To elucidate the role of IL-7/IL-7R system in y8 T-cell development, we have generated and analyzed IL-7R-deficient mice. yS T cells were absent from these mice, while decreased, but certain, numbers of mature af3 T cells were detected. ...

Primary immune responses are thought to be induced by dendritic cells. To promote such responses, dendritic cells must be activated by exogenous agonists, such as LPS, or by products of activated leukocytes, such as TNF-α and IL-1. How dendritic cells might be activated in the absence of exogenous stimuli, or without the immediate presence of activated leukocytes, as might occur in immunity to tumor cells or transplants, is unknown. We postulated that heparan sulfate, an acidic, biologically active polysaccharide associated with cell membranes and extracellular matrices, which is rapidly released under conditions of inflammation and tissue damage, might provide such a stimulus. Incubation of immature murine dendritic cells with heparan sulfate induced phenotypic maturation evidenced by up-regulation of I-A, CD40, CD54 (ICAM-1), CD80 (B7-1), and CD86 (B7-2). Dendritic cells exposed to heparan sulfate exhibited a markedly lowered rate of Ag uptake and increased allostimulatory capacity. Stimulation of dendritic cells with heparan sulfate induced release of TNF-α, IL-1β, and IL-6, although the maturation of dendritic cells was independent of these cytokines. These results suggest that soluble heparan sulfate chains, as products of the degradation of heparan sulfate proteoglycan, might induce maturation of dendritic cells without exogenous stimuli, thus contributing to the generation and maintenance of primary immune responses.

A 66-year-old man died of massive gastrointestinal hemorrhage caused by a fistula between the third portion of the duodenum and the abdominal aorta. An autopsy revealed that duodenal tuberculosis had resulted in the development of a fistula into the aorta with no pathological changes, and no active pulmonary tuberculosis was found. Duodenal tuberculosis and primary aortoduodenal fistula (ADF) without an aneurysm are both extremely rare. Thus, we report herein a unique case of primary aortoduodenal fistula without an abdominal aortic aneurysm, but associated with duodenal tuberculosis, and review the current literature.