Graphs show data for CD4+ T cells (B), CD8+ T cells (C) and CD19+ B cells (D)

Graphs show data for CD4+ T cells (B), CD8+ T cells (C) and CD19+ B cells (D). 2OA manifest autoimmune cholangitis, typical mitochondrial autoantibodies, increased liver lymphoid cell numbers, an increase in CD8+ liver infiltrating cells, particularly CD8+ T cells that co-express CD44, and finally an elevation of serum TNF- and IFN-. In conclusion, these data provide a persuasive argument in favor of an environmental origin for human PBC. There have been important advances in defining mechanisms required for the effector stage of various human autoimmune diseases including the autoreactive populations involved in damage to the biliary epithelial cell (BEC) in primary biliary cirrhosis (PBC). On the other hand, for most autoimmune diseases, even at Saridegib the induction stage, contributing genetic influences and environmental contributions are less well understood. Our laboratory has been studying the putative etiologies for the initiation of PBC for the last decade with the objective to establish a small animal model which would facilitate studies of the mechanisms that are the basis of this disease. During these studies our lab has identified several potential environmental Saridegib initiators, particularly bacteria 1C3 and chemical xenobiotics 4C11 In a genetically susceptible host these initiators can disrupt immune tolerance to the dominant autoantigen of PBC, Saridegib the mitochondrially localized pyruvate dehydrogenase E-2 subunit (PDC-E2), which sets in train a multi-lineage cellular and humoral immune response against this and related autoantigens. This same multi-lineage immune response then becomes the pathogenic and effector agent by virtue of the unique immunobiology of the BEC, as discussed and presented elsewhere in detail 11. The fine mapping of the epitopes recognized by the humoral and cellular autoimmune response against PDC-E2 has led to the observation that these sites are highly conserved molecular sequences flanking lipoic acid binding sites and the responses to these are among the most directed and specific responses in human autoimmunity, and includes reactivity of not only B cells, but also CD4 and CD8 T cell responses 11. These data encouraged us to screen PBC sera against PDC-E2 molecules that carried chemical modifications of either the lysine Saridegib residue (173K) or the lipoic acid co-factor that attaches to 173K. We first demonstrated that several chemical xenobiotics, when coupled via 173K to the dominant autoantigenic peptide of PDC-E2, led to the formation of a neo-antigen that surprisingly reacted at least as well or even better with PBC sera than did the native autoantigen 4, 7, 8; in other words, anti-PDC-E2 antibodies from patients with PBC could recognize xenobiotic modified PDC-E2 peptides that mimic lipoic acid, and such recognition often includes a higher titer reactivity than to the native autoantigen. Second, we have recently performed more detailed quantitative structure-activity relationship (QSAR) analysis and have identified 2-octynoic acid (2OA) as an even better xenobiotic candidate for antigenic modification of the PDC-E2 peptide 7, 8. Third, we ascertained that immunization of rabbits with a particular xenobiotic chemical, 6-bromohexanoate (6BH), coupled to bovine serum albumin (BSA), could break tolerance to PDC-E2 as judged by production of anti-mitochondrial antibodies (AMA) as seen in patients with PBC5, 6. Fourth, and finally, we recently demonstrated that immunization with the compound 6BH, coupled to BSA, led to the development of histological lesions typical of autoimmune cholangitis with the concurrent appearance of AMA in guinea pigs, albeit with a long latency of some 18 months 10. In the present studies, we immunized mice with 2OA coupled to BSA and we observed the appearance of anti-PDC-E2 together with histological lesions typical of autoimmune cholangitis. However, of interest is our finding that immunization of mice with 2OA-BSA leads to autoimmune PBC-like disease following a latency period within just a month, rather than the latency of nearly 18 months Rabbit Polyclonal to HNRCL for guinea pigs immunized with 6BH. These data illustrate the capacity of chemical xenobiotics when conjugated to a potential autoepitope site to induce a PBC-like disease model in mice. Also the data provide a persuasive argument in favor of an environmental (xenobiotic) origin for human PBC. Materials and Methods Murine immunization Female C57BL/6J (B6) mice (n=13 per each group) Saridegib at 8 to.