A Convenient Model of Severe, High Incidence Autoimmune Gastritis Caused by Polyclonal Effector T Cells and without Perturbation of Regulatory T Cells

Autoimmune gastritis results from the breakdown of T cell tolerance to the gastric H+/K+ ATPase. The gastric H+/K+ ATPase is responsible for the acidification of gastric juice and consists of an α subunit (H/Kα) and a β subunit (H/Kβ). Here we show that CD4+ T cells from H/Kα-deficient mice (H/Kα−/−) are highly pathogenic and autoimmune gastritis can be induced in sublethally irradiated wildtype mice by adoptive transfer of unfractionated CD4+ T cells from H/Kα−/− mice. All recipient mice consistently developed the most severe form of autoimmune gastritis 8 weeks after the transfer, featuring hypertrophy of the gastric mucosa, complete depletion of the parietal and zymogenic cells, and presence of autoantibodies to H+/K+ ATPase in the serum. Furthermore, we demonstrated that the disease significantly affected stomach weight and stomach pH of recipient mice. Depletion of parietal cells in this disease model required the presence of both H/Kα and H/Kβ since transfer of H/Kα−/− CD4+ T cells did not result in depletion of parietal cells in H/Kα−/− or H/Kβ−/− recipient mice. The consistency of disease severity, the use of polyclonal T cells and a specific T cell response to the gastric autoantigen make this an ideal disease model for the study of many aspects of organ-specific autoimmunity including prevention and treatment of the disease

Plasmacytoid Dendritic Cells Provide Protection Against Bacterial-Induced Colitis

We have examined the influence of depleting plasmacytoid dendritic cells (pDC) in mice on the immune response to the gut pathogen Citrobacter rodentium, an organism that is a model for human attaching effacing pathogens such as enterohaemorraghic E. coli. A significantly higher number of C. rodentium were found in mice depleted of pDC from 7 days after infection and pDC depleted mice showed increased gut pathology and higher levels of mRNA encoding inflammatory cytokines in the colon upon infection. pDC-depletion led to a compromising of the gut mucosal barrier that may have contributed to increased numbers of C. rodentium in systemic organs. pDC-depleted mice infected with C. rodentium suffered substantial weight loss necessitating euthanasia. A number of observations suggested that this was not simply the result of dysregulation of immunity in the colon as pDC-depleted mice infected intravenously with C. rodentium also exhibited exacerbated weight loss, arguing that pDC influence systemic immune responses. Overall, these data indicate that pDC contribute at multiple levels to immunity to C. rodentium including control of bacterial numbers in the colon, maintenance of colon barrier function and regulation of immune responses to disseminated bacteria

Immune control of Legionella infection: an in vivo perspective

Legionella pneumophila is an intracellular pathogen that replicates within alveolar macrophages. Through its ability to activate multiple host innate immune components, L. pneumophila has emerged as a useful tool to dissect inflammatory signalling pathways in macrophages. However the resolution of L. pneumophila infection requires multiple cell types and abundant cross talk between immune cells. Few studies have examined the coordination of events that lead to effective immune control of the pathogen. Here we discuss what is known about L. pneumophila interactions with macrophages and dendritic cell subsets and highlight the paucity of knowledge around how these interactions recruit and activate other immune effector cells in the lung

A major linkage region on distal chromosome 4 confers susceptibility to mouse autoimmune gastritis.

Although much is known about the pathology of human chronic atrophic (type A, autoimmune) gastritis, its cause is poorly\ud understood. Mouse experimental autoimmune gastritis (EAG) is a CD41 T cell-mediated organ-specific autoimmune disease of the\ud stomach that is induced by neonatal thymectomy of BALB/c mice. It has many features similar to human autoimmune gastritis.\ud To obtain a greater understanding of the genetic components predisposing to autoimmune gastritis, a linkage analysis study was\ud performed on (BALB/cCrSlc 3 C57BL/6)F2 intercross mice using 126 microsatellite markers covering 95% of the autosomal\ud genome. Two regions with linkage to EAG were identified on distal chromosome 4 and were designated Gasa1 and Gasa2. The\ud Gasa1 gene maps within the same chromosomal segment as the type 1 diabetes and systemic lupus erythematosus susceptibility\ud genes Idd11 and Nba1, respectively. Gasa2 is the more telomeric of the two genes and was mapped within the same chromosomal\ud segment as the type 1 diabetes susceptibility gene Idd9. In addition, there was evidence of quantitative trait locus controlling\ud autoantibody titer within the telomeric segment of chromosome 4. The clustering of genes conferring susceptibility to EAG with\ud those conferring susceptibility to type 1 diabetes is consistent with the coinheritance of gastritis and diabetes within human\ud families. This is the first linkage analysis study of autoimmune gastritis in any organism and as such makes an important and novel\ud contribution to our understanding of the etiology of this disease

A single major gene controls susceptibility to a neonatal thymectomy induced autoimmune disease

Although much is known about the pathology of human chronic atrophic (type A, autoimmune) gastritis, its cause is poorly understood. Mouse experimental autoimmune gastritis (EAG) is a CD4+ T cell-mediated organ-specific autoimmune disease of the stomach that is induced by neonatal thymectomy of BALB/c mice. It has many features similar to human autoimmune gastritis. To obtain a greater understanding of the genetic components predisposing to autoimmune gastritis, a linkage analysis study was performed on (BALB/cCrSlc x C57BL/6)F2 intercross mice using 126 microsatellite markers covering 95% of the autosomal genome. Two regions with linkage to EAG were identified on distal chromosome 4 and were designated Gasa1 and Gasa2. The Gasa1 gene maps within the same chromosomal segment as the type 1 diabetes and systemic lupus erythematosus susceptibility genes Idd11 and Nba1, respectively. Gasa2 is the more telomeric of the two genes and was mapped within the same chromosomal segment as the type 1 diabetes susceptibility gene Idd9. In addition, there was evidence of quantitative trait locus controlling autoantibody titer within the telomeric segment of chromosome 4. The clustering of genes conferring susceptibility to EAG with those conferring susceptibility to type 1 diabetes is consistent with the coinheritance of gastritis and diabetes within human families. This is the first linkage analysis study of autoimmune gastritis in any organism and as such makes an important and novel contribution to our understanding of the etiology of this disease

Molecular Pathogenesis of Infections Caused by Legionella pneumophila

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

Genetic control of susceptibility to autoimmune gastritis

A familial component to the tendency to develop autoimmune gastritis has long been recognized. Although linkage to certain HLA alleles and an association with the endocrine autoimmune diseases thyroiditis and type 1 diabetes have been reported, little further progress has been achieved in clinical studies. In contrast, the mouse model of gastritis induced in the BALB/c strain by thymectomy in the third day of life has identified four linkage regions; two on distal chromosome 4 (Gasa1 and Gasa2), one on chromosome 6 (Gasa3) and one in the H2 (Gasa4). Three of these four genes colocalize with NOD mouse diabetes susceptibility genes—the strongest concordance identified to date between any two autoimmune diseases—reflecting the association between autoimmune diabetes and type 1 gastritis in humans