Innate Immunity and Primary Biliary Cirrhosis

Selmi, Carlo; Lleo, Ana; Pasini, Simone; Zuin, Massimo; Gershwin, M. Eric

doi:10.2174/156652409787314525

Cited by 57 publications

(40 citation statements)

References 91 publications

(117 reference statements)

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“…In addition to abnormalities in the adaptive immune system in PBC, the innate immunity may contribute to exacerbating the biliary damage ensued by the adaptive immune response [29]. PBC portal infiltrates may contain abundant macrophages and natural killer cells as well as natural killer T cells.…”

Section: Altered Immunoregulation In Pbcmentioning

confidence: 99%

Role of the Anion Exchanger 2 in the Pathogenesis and Treatment of Primary Biliary Cirrhosis

Medina

2011

Dig Dis

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The essential anion exchanger (AE) involved in biliary bicarbonate secretion is AE2/SLC4A2, a membrane protein which has also been recognized to be relevant for the regulation of the intracellular pH (pH_i) in several cell types. Previously, we reported that the expression of AE2 mRNA is diminished in liver biopsies and peripheral blood mononuclear cells from patients with primary biliary cirrhosis (PBC). Immunohistochemical studies indicated that the expression of the AE2 protein is decreased in the bile ducts and hepatocytes in PBC livers. Moreover, we found that bile duct cells isolated from PBC patients and cultured for a few passages exhibit defective Na⁺-independent Cl^–/HCO₃^– exchange. Interestingly, positron emission tomography studies have shown that PBC patients, even at early stages of the disease, fail to secrete bicarbonate to bile in response to secretin, a defect that can be partially reversed after several months of treatment with ursodeoxycholic acid. Altogether, these findings sustain our hypothesis that dysfunctions related to AE2 might have a role in the pathogenesis of PBC. Inadequate AE2 function in lymphocytes may disturb pH_i regulation in these cells and alter immune homeostasis leading to autoimmunity. On the other hand, reduced AE2 in cholangiocytes could cause cholestasis and oxidative stress of bile duct cells. Cholangiocyte changes, together with altered immune homeostasis, could favor the development of antimitochondrial antibodies and the autoimmune attack on biliary ducts. Our recent findings that Ae2_a,b-deficient mice indeed display most of these features strongly support the notion that AE2 abnormalities may be involved in the pathogenesis of PBC.

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Section: Altered Immunoregulation In Pbcmentioning

confidence: 99%

Role of the Anion Exchanger 2 in the Pathogenesis and Treatment of Primary Biliary Cirrhosis

Medina

2011

Dig Dis

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“…Bacterial and viral epitopes induce innate immune responses through binding to TLRs. TLRs were described in cultured human biliary epithelial cells [109][110][111]177] . These findings make the inclusion of innate immunity mandatory in any pathogenetic model of PBC.…”

Section: Current Views On the Pathogenesis Of Pbcmentioning

confidence: 99%

Primary biliary cirrhosis: From bench to bedside

Notas

2015

WJGPT

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Primary biliary cirrhosis (PBC) is a chronic nonsuppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient's genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated.A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed. Core tip: Primary biliary cirrhosis (PBC) is a chronic nonsuppurative destructive intrahepatic cholangitis leading to cirrhosis of largely unknown pathophysiology. We examined the epidemiological and geoepidemiological data as well as the pathogenetic aspects of PBC. A novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated.

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“…PAMPs engage pattern-recognition receptors, such as Toll-like receptors (TLRs), expressed on cells of the innate immune system, i.e., monocytes, dendritic cells and natural killer cells, all of which are therefore able to modulate the function of adaptive humoral and cellular immunity. 85 Only recently has the study of innate immunity as a potential activator of autoimmune responses received a significant impetus and is no longer overlooked by clinical immunologists. 85 The liver has been recognized both structurally and functionally as a major organ of innate immunity.…”

Section: Innate Immunitymentioning

confidence: 99%

“…85 Only recently has the study of innate immunity as a potential activator of autoimmune responses received a significant impetus and is no longer overlooked by clinical immunologists. 85 The liver has been recognized both structurally and functionally as a major organ of innate immunity. One of the largest resident populations of cellular components of the innate immune system, including natural killer and natural killer T (NKT) cells, resides in the liver.…”

Section: Innate Immunitymentioning

confidence: 99%