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Jochen Mattner, MDAssistant Professor Department of Pediatrics; Division of Cellular and Molecular Immunology
Undetected bacterial or viral infections elicit strong immune responses that can produce autoimmune diseases. Compelling evidence for a bacterial trigger has been recently reported for primary biliary cirrhosis (PBC), a chronic liver disease where individuals exhibit signs of chronic immune responses against the ubiquitous xenobiotic alphaproteobacterium Sphingomonas. Dr. Mattner’s laboratory has created a mouse model of Sphingomonas infection that results in a liver disease similar to human PBC. Based on the identification of alpha-glycuronosylceramides that replace lipopolysaccharide (LPS) in the cell wall of Sphingomonas as antigens recognized by natural killer T (NKT), he showed that NKT cells provide agonistic signals for autoantibody producing B cells and self-reactive T cells that trigger the disease phenotype upon transplantation. This mechanism is supported by several reports that NKT cells are strikingly absent from the blood and are redistributed to the liver in patients with PBC. Dr. Mattner also uses a line of non-obese diabetic (NOD) congenic mice generated by the introgression of defined genetic parts from B6 mice onto the NOD background. These mice exhibit more severe liver lesions and overzealous T cell responses than other mouse strains upon infection, while they are (partially) protected from other spontaneous autoimmune diseases (example: type 1 diabetes). Of note, he has identified a NOD congenic strain that is particularly susceptible to PBC. This strain has been generated by introgressing the defined diabetes susceptibility locus 10 and 18 (Idd10/18) from chromosome 3 of B6 mice onto the NOD background. He is currently identifying the candidate genes within this introgressed region and exploring how they participate in the regulation of PBC pathogenesis.
Dr. Mattner collaborates with Drs. Bezerra and Ridgway on the study of primary biliary cirrhosis. Projection of Core use: Gene and Protein Expression, Bioinformatics, and Integrative Morphology Cores.
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The altered regulation of candidate genes within the introgressed Idd10/18 region upon infection with Sphingomonas results in dendritic cell activation with subsequent increased IFN-g and IL-17 release and susceptibility to PBC. Figure of a manuscript submitted for publication.
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