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Fig. 1 | Autoimmunity Highlights

Fig. 1

From: The search for the Holy Grail: autoantigenic targets in primary sclerosing cholangitis associated with disease phenotype and neoplasia

Fig. 1

(Adapted according to [62])

Putative pathophysiological role of mucosal autoimmunity to GP2 in PSC. After mucosal loss of tolerance to glycoprotein 2 (GP2), GP2 IgA is actively secreted by biliary epithelial cells into bile as GP2 secretory IgA (SIgA). Simultaneously, GP2 is shed from exocrine biliary cells along with secretions into the bile. GP2 specifically interacts with putative FimH-positive microbes (FimH+) and binds to GP2 SIgA. The latter could link the recognized microbe with GP2, membrane-bound by a glycosylphosphatidylinositol (GPI) anchor to the apical surface of biliary or intestinal microfold cells of the follicle-associated epithelium. M cells transcytose the GP2-microbe complex and present it to antigen-presenting cells such as IgA-positive (IgA+) B cells or dendritic cells (DC) of the underlying mucosa-associated immune system. Subsequently, IgA+ B cells including GP2-reactive cells are triggered which differentiate directly or by CD4-positive T-helper cells (CD4+ Th) assistance into immunosuppressive IgA-secreting plasma cells (IgA+ PC) shedding interleukin 10 (IL10) and programmed cell-death 1 ligand (PD1-L). The latter two are considered suppressors of tumor-surveillance components such as cytotoxic CD8− positive T cells (CD8+ Tc). Taken together, this hypothetical vicious cycle suggests a new pathogenic mechanism for antibodies encompassing features of types 2 and 3 of hypersensitive immune reactions in accordance with the classification of Coombs and Gell by involving microbiota (coloured oval area).

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