The role of the adaptive immune response, with regard to the development of autoantibodies, has been extensively studied in primary biliary cirrhosis (PBC). However, the importance of innate immunity has been noted only recently. Based on the proposed role of microorganisms in the pathogenesis of the disease, we hypothesize that patients with PBC possess a hyper-responsive innate immune system to pathogen-associated stimuli that may facilitate the loss of tolerance. To address this issue, we isolated peripheral blood monocytes from 33 patients with PBC and 26 age-matched healthy controls and stimulated such cells in vitro with defined ligands for toll-like receptor (TLR) 2 (lipoteichoic acid; LTA), TLR3 (polyIC), TLR4 (lipopolysaccharide; LPS), TLR5 (flagellin), and TLR9 (CpG-B). Supernatant fluids from the cultures were analyzed for levels of 5 different pro-inflammatory cytokines, interleukin (IL)-1β€, IL-6, IL-8, IL-12p70, and TNF-β£. After in vitro challenge with TLR ligands, PBC monocytes produced higher relative levels of pro-inflammatory cytokines, particularly IL-1β€, IL-6, IL-8, and TNF-β£, compared with controls. In conclusion, monocytes from patients with PBC appear more sensitive to signaling via select TLRs, resulting in secretion of selective pro-inflammatory cytokines integral to the inflammatory response that may be critical in the breakdown of self-tolerance. (HEPATOLOGY 2005;42: 802-808.) P rimary biliary cirrhosis (PBC) is a chronic inflammatory cholestatic disease of unknown origin that affects small and medium intrahepatic bile ducts. 1 A wide range of data suggest an autoimmune pathogenesis for the disease, mostly based on the presence of serum anti-mitochondrial autoantibodies (AMAs) 2 and autore-active T cells directed against the same autoantigens. 3 Infectious agents have been proposed as triggers in susceptible individuals through a mechanism known as molecular mimicry. 4 However, few if any examples are found in humans in which molecular mimicry gives rise to autoimmunity in general. 5 Thus, it is most likely not the type of infectious agent that determines the onset of autoimmunity, but rather the qualitative nature of innate immune responses by an individual that could potentially trigger an autoimmune response. An infection would then provide the necessary inflammatory milieu to activate pre-existing autoreactive cellular repertoire. 6 This is most aptly illustrated in experimental autoimmune models that require the use of bacterial adjuvant to break tolerance. 6 Hence, an aberrant innate immune response to infections has the potential to initiate the development of autoimmunity.
Until recently, the adaptive and the innate arms of the immune system were considered as being independent. However, that the innate immune response plays a prominent role in regulating the quality of the adaptive immune response that ensues is becoming increasingly clear. 7 The adaptive immune system, mainly represented by T-and B-lymphocytes, is characterized by slower response kinetics and by the unique capacity to develop antigen-specific memory. Such memory responses thus result in a faster reaction when re-encountering such an-