Recent work has emphasized that the unique destruction of

biliary cells requires the triad of macrophages from patients with PBC, biliary epithelial cell apotopes and AMAs; this leads to a burst of proinflammatory cytokines [23]. In addition, there is evidence that NK cells are involved in biliary cell cytotoxicity, and in this respect it is noteworthy that there is considerable heterogeneity among the NK and perhaps also the NK T cell lineages [24,25]. Thus, previous dogmas with regard to NK cells require HER2 inhibitor re-examination, particularly with regard to function, as there is now evidence for NK cell memory and a regulatory function has also been ascribed to NK cells [25]. One of the strongest cases for NK cell heterogeneity comes from studies of the phenotypical and functional differences of the NK cell lineages that reside within the gut compared with the blood and lymph nodes [26,27]. Thus, while organ-resident NK cells control the magnitude of organ inflammation, they also

have a role concurrently in influencing the generation of autoimmunity and pathology [28,29]. Peripherally derived NK cells have an impact upon autoimmune responses which are manifested by their ability to synthesize cytokines rapidly that, in turn, influence the quality and quantity of acquired immune responses [30–34]. While the CD1d-deficient mouse [35–38] and the use of α-GalCer to activate NK T cells [39–41] are both available to perform standard addition/subtraction NSC 683864 experiments in efforts to define a role for the NK T cell lineage, reagents are not readily available for a similar study of the role of NK cells. This is due to the fact that the use of the Afatinib manufacturer classical NK1·1 monoclonal antibody (mAb) to deplete NK cells also deletes NK T cells, because the latter lineage also expresses NK1·1. As NK T cells have been shown to contribute to the exacerbation of disease in PBC

[5,6], results of the findings reported herein indicate that the depletion of both NK cells and NK T cells prior to immunization has a minimal role in the overall breakdown of tolerance. Thus, and as shown herein, while depletion of NK1·1 cells appeared to delay significantly the generation of autoimmune-specific acquired humoral and cellular responses, the data indicate clearly that depletion of the NK1·1 lineage did not lead to any detectable differences in the pathology seen in the NK1·1-depleted versus control mice. It is well known that liver contains NK cell subsets which have reduced effector function [42,43], but under appropriate inflammatory conditions become potent killers [44]. NK cells sense normal or abnormal cells with their inhibitory or activating receptors [32]. Thus, under normal circumstances, NK cells will not damage autologous cells due to the engagement of inhibitory receptors.