Bacterial motif DNA as an adjuvant for the breakdown of immune self-tolerance to pyruvate dehydrogenase complex

Jones, David

doi:10.1053/jhep.2002.35067

Cited by 45 publications

(23 citation statements)

References 47 publications

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“…149 Lastly, we note that auxiliary mechanisms have been postulated that might enhance the response to infectious agents, thus making mimicking proteins more immunogenic or the host more sensitive towards an aberrant immune response. A similar process can be hypothesized from data obtained using bacterial CpG motifs that can accelerate the breakdown of tolerance in SJL/J mice, 150 as well as induce the characteristic hyperIgM observed in PBC sera. 129 The role of xenobiotics in the scenario of molecular mimicry leading to PBC warrants further discussion.…”

Section: Molecular Mimicrysupporting

confidence: 55%

Genes and (auto)immunity in primary biliary cirrhosis

et al. 2005

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Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strenghtens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed.

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Section: Molecular Mimicrysupporting

confidence: 55%

Genes and (auto)immunity in primary biliary cirrhosis

et al. 2005

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“…Phosphorothioate-stabilised CpG-oligonucleotide sequences activate and preferentially elicit Th1 cytokine production by cultured mouse DCs (Jones et al, 2002). In our studies, we have shown that CpG-ODN stimulation of murine DC cultures results in the production of the Th1-polarising cytokine IL-12 at levels comparable to those produced by BCG.…”

Section: Discussionmentioning

confidence: 57%

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy

et al. 2003

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Intravesical bacillus Calmette -Guerin (BCG) is a treatment for transitional cell carcinoma (TCC) and carcinoma in situ (cis) of the urinary bladder, but some patients remain refractory. The mechanism of cancer clearance is not known, but T cells are thought to play a contributory role. Tissue dendritic cells (DCs) are known to initiate antigen-specific immune responses following activation of receptors, which recognise molecular patterns on the surface of microorganisms. A family of these receptors, the toll-like receptors (TLRs), are also crucial for activating DC to produce cytokines that polarise the T-cell response towards a T helper (Th)1 or Th2 phenotype. This study compared the potential of intact BCG to activate DC with that of the defined TLR4 ligand lipopolysaccharide (LPS) and the TLR9 ligand CpG-oligonucleotide. It was found that all three stimuli efficiently activated normal DC, but cells expressing a mutant TLR4 responded poorly to stimulation with LPS. Importantly, stimulation with BCG induced both IL-12 and IL-10, suggesting subsequent development of a poorly focused T-cell immune response containing both Th1 and Th2 immune function. By contrast, LPS-and CpG-oligonucleotides induced only IL-12, indicating the potential to produce a Th1 response, which is likely to clear cancer most efficiently. Given the toxicity of LPS, our data suggest that CpG-oligonucleotides may be beneficial for intravesical therapy of bladder cancer.

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“…Intercurrent localized infection resulting in cell necrosis and PDC release in the context of toll-like receptor (TLR) ligand expression would be one potential mechanism (of particular possible importance given the potential for stimulation via TLR9 (a key TLR for B-cell activation 29 ) to promote T-cell autoreactivity in both the PDC-tolerance breakdown and other autoimmune disease models. [30][31][32] Another potential mechanism for exposure to self-PDC at least could be through the recently demonstrated expression of PDC on the surface membrane by cells undergoing apoptosis, 33 with localized infection inducing focal apoptosis representing a potential mechanism for the tissue tropism of the process. Further work is required in this area.…”

Section: Discussionmentioning

confidence: 99%

A key role for autoreactive B cells in the breakdown of T‐cell tolerance to pyruvate dehydrogenase complex in the mouse†

et al. 2005

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The key immunological event in the pathogenesis of the autoimmune liver disease primary biliary cirrhosis is breakdown of T-cell self-tolerance to pyruvate dehydrogenase complex (PDC). The mechanism resulting in this breakdown of tolerance remains unclear. Mice exposed to self-PDC mount no immune response; however, animals coexposed to self-PDC and PDC of foreign origin (which in isolation induces a cross-reactive antibody but not an autoreactive T-cell response) show breakdown of T-cell as well as B-cell tolerance. This observation raises the possibility that a cross-reactive antibody response to self-PDC can promote breakdown of T-cell tolerance. The aim of this study was to address the hypothesis that breakdown of T-cell tolerance to PDC can be driven by the presence of B cells and/or antibodies cross-reactive with this self-antigen. Naive female SJL/J mice were exposed to self-PDC alone and in the presence of purified splenic B cells from animals primed with foreign PDC (or controls) or purified immunoglobulin (Ig) G from the same animals. Breakdown of T-cell tolerance was assessed by splenic T-cell

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Bacterial motif DNA as an adjuvant for the breakdown of immune self-tolerance to pyruvate dehydrogenase complex

Cited by 45 publications

References 47 publications

Genes and (auto)immunity in primary biliary cirrhosis

Genes and (auto)immunity in primary biliary cirrhosis

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy

A key role for autoreactive B cells in the breakdown of T‐cell tolerance to pyruvate dehydrogenase complex in the mouse†

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