A possible role of histone-like DNA-binding protein of Streptococcus intermedius in the pathogenesis of bile duct damage in primary biliary cirrhosis.
ABSTRACT Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). It was reported that anti-histone autoantibody was detected in PBC, suggesting that bacterial histone-like DNA-binding protein (HLP) may be involved in the pathogenesis of PBC. To identify bacterial species in PBC to confirm this possibility, serum reactivity to bacterial cells was studied by ELISA. The IgM class Streptococcus intermedius titers were significantly higher in PBC than chronic hepatitis due to hepatitis C virus (CH-C) and healthy subjects. Among the streptococci, S. intermedius was selected for further study. The antigenic peptide of S. intermedius of HLP was synthesized to examine the serum reactivity to Si-HLP. IgM class anti-Si-HLP peptide titers were significantly higher in PBC. Immunoreactivity to anti-Si-HLP was detected in the cytoplasm of biliary epithelial cells and inflammatory cells in the portal area in PBC patients' livers. Streptococci, especially S. intermedius, might play a key role in the pathogenesis of PBC, possibly involving HLP.
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ABSTRACT: We previously reported a mouse model of primary biliary cirrhosis (PBC)-like chronic nonsuppurative destructive cholangitis (CNSDC), in which frequent injections of Streptococcus intermedius induced CNSDC and autoantibody production. The present study was performed to verify the model by examining 1) the reappearance of the PBC-like CNSDC after lymphocyte transfer from model to naïve mice, 2) the involvement of autophagy, and 3) the influence of the strain difference. Mice were inoculated with S. intermedius weekly for 8 weeks, then sacrificed to obtain samples. Spleen cells obtained from S. intermedius-inoculated mice were transferred to RAG2(-/-) mice. CNSDC and elevated serum level of anti-gp210 titers were observed in S. intermedius-inoculated C57BL/6 mice, similar to the results of our previous report using BALB/c mice. Portal inflammation was induced in the livers of RAG2(-/-) mice by the transfer of spleen cells from S. intermedius-inoculated C57BL/6 mice. Among the inflammatory cells in the RAG2(-/-) mice, CD3-positive cells were predominant. Autophagosome-like structures were detected histologically, in the cytoplasm of infiltrated cells around the bile ducts in the livers of S. intermedius-inoculated both C57BL/6 and BALB/c mice. In S. intermedius-inoculated C3H/HeJ mice, inflammation in the portal area was less extensive than that in the hepatic parenchyma. Bacterial component(s) and sequentially upregulated innate and acquired immune responses, accompanied by autophagy, might trigger CNSDC, via autoimmune mechanisms. Throughout the generation of bacteria-triggered PBC-like CNSDC, strain difference may influence the response to S. intermedius-inoculation in the liver.Journal of Clinical Immunology 06/2012; 32(5):1026-37. · 3.38 Impact Factor
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ABSTRACT: The "exposome" is a term recently used to describe all environmental factors, both exogenous and endogenous, which we are exposed to in a lifetime. It represents an important tool in the study of autoimmunity, complementing classical immunological research tools and cutting-edge genome wide association studies (GWAS). Recently, environmental wide association studies (EWAS) investigated the effect of environment in the development of diseases. Environmental triggers are largely subdivided into infectious and non-infectious agents. In this review, we introduce the concept of the "infectome", which is the part of the exposome referring to the collection of an individual's exposures to infectious agents. The infectome directly relates to geoepidemiological, serological and molecular evidence of the co-occurrence of several infectious agents associated with autoimmune diseases that may provide hints for the triggering factors responsible for the pathogenesis of autoimmunity. We discuss the implications that the investigation of the infectome may have for the understanding of microbial/host interactions in autoimmune diseases with long, pre-clinical phases. It may also contribute to the concept of the human body as a superorganism where the microbiome is part of the whole organism, as can be seen with mitochondria which existed as microbes prior to becoming organelles in eukaryotic cells of multicellular organisms over time. A similar argument can now be made in regards to normal intestinal flora, living in symbiosis within the host. We also provide practical examples as to how we can characterise and measure the totality of a disease-specific infectome, based on the experimental approaches employed from the "immunome" and "microbiome" projects.Autoimmunity reviews 12/2012; · 6.37 Impact Factor
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ABSTRACT: Primary biliary cirrhosis (PBC) would develop when the immune system comes across a microorganism with proteins similar to those in the piruvate dehydrogenase complex E2 (PDC-E2), or a neoantigen resulting from a xenobiotic-modified autoantigen. This would lead to an innate immune response where TLRs would play a pivotal mediating role, which would give rise to a local microenvironment favoring an adaptive immune response. Such response would be particularly strong in individuals with selected genetic characteristics. The genetic characteristics underlying this predisposition remain unknown, but they likely entail small numbers of scarcely-active regulatory T cells. The AE2 anion exchanger, which is deficient in patients with PBC, may reduce the number and activity of regulatory T cells. NK cells are also pivotal in the preparation of an adaptive response, as they release a number of cytokines and chemokines that favor and recruit antigen-presenting cells to activate B and T cells - CD4+ Th1 and CD8+. An activation of the former would increase the production of IgM and anti-mitochondrial IgG and IgA antibodies against PDC-E2. An activation of CD8+ cells, also sensitive to PDC-2 as aberrantly expressed on the surface of BECs and SECs, would result in apoptosis for these epithelial cells, and in small bile-duct destruction. Immune response is likely inadequately suppressed because of the small numbers of scarcely-active regulatory T cells, the latter resulting from low genetic expression and activity of the AE2 transporter.Revista espanola de enfermedades digestivas: organo oficial de la Sociedad Espanola de Patologia Digestiva 06/2009; 101(6):413-423. · 1.65 Impact Factor