Background & Aims: Cl /HCO 3 anion exchanger 2 (AE2) is involved in intracellular pH (pH i) regulation and transepithelial acid-base transport, including se-cretin-stimulated biliary bicarbonate excretion. AE2 gene expression was found to be reduced in liver biopsy specimens and blood mononuclear cells from patients with primary biliary cirrhosis (PBC), a dis-ease characterized by chronic nonsuppurative cholan-gitis associated with antimitochondrial antibodies (AMA) and other autoimmune phenomena. In mice with widespread Ae2 gene disruption, we previously reported altered spermiogenesis and reduced gastric acid secretion. We now describe the hepatobiliary and immunologic changes observed in these Ae2 a.b -defi-cient mice. Methods: In this murine model, spleno-cyte pH i and T-cell populations were studied by flow cytometry. CD3-stimulated cytokine secretion was es-timated using cytokine arrays. AMA were evaluated by immunoblotting and proteomics. Hepatobiliary changes were assessed by immunohistopathology, flow cytometry, and serum biochemistry. Cholangio-cyte gene expression was analyzed by real-time poly-merase chain reaction. Results: Ae2 a,b / mice ex-hibit splenomegaly, elevated pH i in splenocytes, increased production of interleukin-12p70 and inter-feron gamma, expanded CD8 T-cell population, and under represented CD4 FoxP3 /regulatory T cells. Most Ae2 a,b / mice tested positively for AMA, show-ing increased serum levels of immunoglobulin M and G, and liver-specific alkaline phosphatase. About one third of Ae2 a,b / mice had extensive portal inflamma-tion with CD8 and CD4 T lymphocytes surround-ing damaged bile ducts. Cholangiocytes isolated from Ae2 a,b / mice showed gene expression changes com-patible with oxidative stress and increased antigen presentation. Conclusions: Ae2 deficiency alters pH i homeostasis in immunocytes and gene expression profile in cholangiocytes, leading to immunologic and hepatobiliary changes that resemble PBC. C l /HCO 3 anion exchanger 2 (AE2; also known as SLC4A2) mediates electroneutral Na -independent Cl /HCO 3 exchange across the plasma membrane. 1,2 This widely expressed exchanger is a relevant acid loader involved in the regulation of intracellular pH (pH i). 1,2 Moreover, AE2 is involved in transepithelial acid-base transport, including proton gastric secretion 3,4 and secre-tin-stimulated biliary HCO 3 excretion. 5 Alkalinization of pH i in lymphocytes has been reported to affect their proliferation, differentiation, and activa-tion status. 6 Because AE2 activity might influence acid-base equilibrium and cell function, not only in lympho-cytes but also in biliary epithelial cells, alterations of this transporter were postulated to play an etiopathogenic role in primary biliary cirrhosis (PBC). 7–9 PBC is an au-toimmune disease of unknown pathogenesis that results in destruction of small-and medium-sized bile ducts. 10,11 The disease occurs mainly in middle-aged women and is characterized by portal inflammation surrounding inter-lobular bile ducts and the presence of antimitochondrial antibodies (AMA). Indeed, up to 90%–95% of patients develop AMA against some components of the 2-oxo dehydrogenase complexes, mainly the inner lipoyl do-main in the E2 component of the pyruvate dehydroge-nase complex (PDC-E2). 12 Although AMA might not be involved in the pathogenesis of the disease, T-cell im-mune responses against PDC-E2 determinants seem to be implicated in organ damage. 11,13 Despite the strong association with autoimmune phe-nomena, PBC responds poorly to classic immunosup-pressants. The fact that ursodeoxycholic acid, a bile acid that induces bicarbonate-rich choleresis, may improve the clinical course of PBC 14 is compatible with the con-cept that defective Cl /HCO 3 exchange may play a role in the pathogenesis of the disease. 9,15 Consistent with this view, AE2 gene expression has been reported to be Abbreviations used in this paper: AE2, Cl /HCO 3 anion exchanger 2; AMA, antimitochondrial antibodies; FACS, fluorescence-activated cell sorter; hALP, hepatic alkaline phosphatase; IL, interleukin; PBC, primary biliary cirrhosis; PCR, polymerase chain reaction; PDC-E2, E2 component of the pyruvate dehydrogenase complex; pH i , intracellular pH; Q-TOF/MS, quadrupole/time-of-flight mass spectrometry; Treg, regulatory T cells.