| セッション情報 | 特別講演8 |
|---|---|
| タイトル | SL-8：IBD Pathogenesis: An Unfolding Mystery |
| 演者 | Podolsky Daniel K.（University of Texas Southwestern Medical Center, USA） |
| 共同演者 | |
| 抄録 | Genetic approaches have made clear that a large number of loci confer susceptibility to the major forms of IBD. However the magnitude of even the most strongly associated genes confer a relatively modest absolute risk individually, leading to the plausible conclusion that an individual’s risk represents the aggregate of the variant forms of many genes. It is from these approaches as well as studies arising from mechanistic hypotheses that we can now put together a generally coherent view of the pathogenesis of inflammatory bowel disease. That construct places the luminal microflora as the key driver of inflammatory responses in susceptible individuals. In recent years, methodologic approaches allow a more meaningful delineation of the complexity of normal microflora and aggregate changes in that complexity associated with IBD. These changes include an overall reduction in complexity, with selective reduction or increased representation of some specific clades. Very recent studies have defined changes in the overall metabolic profile of the microflora. The interaction between microflora and host mucosa (especially the epithelium) results in mutual changes in metabolic properties in an environment that places an oxidative stress on both. The susceptibility of the host in the presence of the complex ecology of the luminal microflora derives from the impact of various loci on the interrelated functions of mucosal barrier integrity, sensitivity to trigger of innate immune pathways, and the functional characteristics of adaptive immune mechanisms, particularly in sustaining and perpetuating inflammation once initiated. While the differential importance of TH1 and TH2 subsets in CD and UC respectively has been long recognized, more recently it has become clear that TH17 and T suppressor cells also play an important role. Initially, TH17 were thought to play a key role exclusively as effector of tissue injury; it has become clear more recently that they also play a protective role in response to infection. Concurrent with mediating response to the pathogen, TH17 cells appear to modify and shape the response of the host to the normal flora that is always co-present at the time of a superimposed infection. Intestinal mucosa also contain a number of distinct lineages of innate lymphoid cells (ILCs). These ILCs substantially determine the character of the mucosal response to/interaction with flora ? allowing co-existence with normal commensals and promoting active immune and inflammatory responses to pathogens. Of great interest, the stimulus of a pathogen can result in ILCs phenotypically capable of reacting “inappropriately” to normal flora. The genetic susceptibility factors have filled in important details in the components of host interaction with the microflora and response to very low-level invasion. These include the process of autophagy, which is responsible for the host cell’s disposition of microbial populations. With progress in understanding mechanistic pathways, it is increasingly possible to rationally identify potential points of therapeutic leverage in the complex set of processes that contribute to both initiation and continuation of inflammation. |
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