SUMMARY The genus Legionella contains more than 50 species, of which at least 24 have been associated with human infection. The best-characterized member of the genus, Legionella pneumophila, is the major causative agent of Legionnaires' disease, a severe form of acute pneumonia. L. pneumophila is an intracellular pathogen, and as part of its pathogenesis, the bacteria avoid phagolysosome fusion and replicate within alveolar macrophages and epithelial cells in a vacuole that exhibits many characteristics of the endoplasmic reticulum (ER). The formation of the unusual L. pneumophila vacuole is a feature of its interaction with the host, yet the mechanisms by which the bacteria avoid classical endosome fusion and recruit markers of the ER are incompletely understood. Here we review the factors that contribute to the ability of L. pneumophila to infect and replicate in human cells and amoebae with an emphasis on proteins that are secreted by the bacteria into the Legionella vacuole and/or the host cell. Many of these factors undermine eukaryotic trafficking and signaling pathways by acting as functional and, in some cases, structural mimics of eukaryotic proteins. We discuss the consequences of this mimicry for the biology of the infected cell and also for immune responses to L. pneumophila infection.

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IL-17, produced by a distinct lineage of CD4+ helper T (Th) cells termed Th17 cells, induces the production of pro-inflammatory cytokines from resident cells and it has been demonstrated that over-expression of IL-17 plays a crucial role in the onset of several autoimmune diseases. Here we examined the role of IL-17 in the pathogenesis of autoimmune gastritis, a disease that was previously believed to be mediated by IFN-γ. Significantly higher levels of IL-17 and IFN-γ were found in the stomachs and stomach-draining lymph nodes of mice with severe autoimmune gastritis. Unlike IL-17, which was produced solely by CD4 + T cells in gastritic mice, the majority of IFN-γ-producing cells were CD8 + T cells. However, CD8+ T cells alone were not able to induce autoimmune gastritis. T cells that were deficient in IL-17 or IFN-γ production were able to induce autoimmune gastritis but to a much lower extent compared with the disease induced by wild-type T cells. These data demonstrate that production of neither IL-17 nor IFN-γ by effector T cells is essential for the initiation of autoimmune gastritis, but suggest that both are required for the disease to progress to the late pathogenic stage that includes significant tissue disruption. based on their unique transcription factors and cytokine profiles, which confer separate effector functions [1][2][3][4]. The association of Th1 response with autoimmunity came into question after the discovery of IL-23, which shares the p40 subunit with IL-12, but is engaged with a different second chain, IL-23p19 instead of . It is now clear that the prevention of autoimmune diseases, including experimental autoimmune encephalomyelitis and collagen-induced arthritis, by treatment with neutralising antibodies to IL-12p40 or in IL-12p40-deficient mice is conferred by inhibition of IL-23, but not 7]. Therefore, the IL-23-IL-17 axis rather than the IL-12-IFN-γ axis is critically involved in the development of autoimmunity in these models, which were previously thought to be caused by pathogenic Th1 responses. In light of these discoveries, we examined the role of IL-17 in the onset and progression of autoimmune gastritis. Autoimmune gastritis is a CD4 + T cell-mediated organ-specific autoimmune disease in which the gastric H + /K + ATPase has been identified as the target antigen in both the mouse model and human equivalent [8,9]. The disease is associated with an inflammatory infiltrate in the gastric mucosa, the loss of gastric parietal and zymogenic cells, and hypertrophy of gastric mucosa [10]. Several studies have also indicated that a dysregulated Th1 response is linked to the pathogenesis of autoimmune gastritis; CD4 + T cells isolated from the gastric mucosa of gastritic humans and mice showed a Th1 phenotype [11,12], and neutralising-IFN-γ antibody was able to prevent the onset of murine autoimmune gastritis [13]. Additionally, T cells from mice deficient in IFN-γ (IFN-γ −/− ) or IL-12 have a reduced pathogenicity in causing autoimmune gastritis. On the other hand, IL-4, a signature c...

Autoimmune gastritis is a CD4+ T cell-mediated disease induced in genetically susceptible mice by thymectomy on the third day after birth. Previous linkage analysis indicated that Gasa1 and Gasa2, the major susceptibility loci for gastritis, are located on mouse chromosome 4. Here we verified these linkage data by showing that BALB.B6 congenic mice, in which the distal approximately 40 Mb of chromosome 4 was replaced by C57BL/6 DNA, were resistant to autoimmune gastritis. Analysis of further BALB.B6 congenic strains demonstrated that Gasa1 and Gasa2 can act independently to cause full expression of susceptibility to autoimmune disease. Gasa1 and Gasa2 are located between D4Mit352-D4Mit204 and D4Mit343-telomere, respectively. Numerical differences in Foxp3+ regulatory T cells were apparent between the BALB/c and congenic strains, but it is unlikely that this phenotype accounted for differences in autoimmune susceptibility. The positions of Gasa1 and Gasa2 correspond closely to the positions of Idd11 and Idd9, two autoimmune diabetes susceptibility loci in nonobese diabetic (NOD), mice and this prompted us to examine autoimmune gastritis in NOD mice. After neonatal thymectomy, NOD mice developed autoimmune gastritis, albeit at a slightly lower incidence and severity of disease than in BALB/c mice. Diabetes-resistant congenic NOD.B6 mice, harbouring a B6-derived interval encompassing the Gasa1/2-Idd9/11 loci, demonstrated a slight reduction in the incidence of autoimmune gastritis. This reduction was not significant compared with the reduction observed in BALB.B6 congenic mice, suggesting a difference in the genetic aetiology of autoimmune gastritis in NOD and BALB mice.

Regulatory T cells curb unwanted immune responses and regulate responses to microflora and it is now clear that regulatory T cells play an important role in a number of chronic inflammatory diseases of the gut. First, regulatory T cells are crucial in controlling immune responses to gastric autoantigens and thus preventing autoimmune gastritis and pernicious anemia. Second, regulatory T cells may modulate the response to Helicobacter pylori, thus affecting the ability of the immune system to clear the pathogen and mediate damage to the gastric mucosa. Finally, regulatory T cells play an important role in preventing damaging inflammatory responses to commensal organisms in the lower gut, thus guarding against inflammatory bowel diseases. In the present review, we examine the actions of regulatory T cells in the gut and conclude that further understanding of regulatory T cell biology may lead to new therapeutic approaches to chronic gastrointestinal disease.