The relationship between hepatic immunoglobulin production and CD154 expression in chronic liver diseases

Mayo, Marlyn J.; Mosby, James M.; Jeyarajah, Rohan; Combes, Burton; Khilnani, Smina; Al-halimi, Maha; Handem, Iorna; Grammer, Amrie C.; Lipsky, Peter E.

doi:10.1111/j.1478-3231.2005.01211.x

Cited by 13 publications

(11 citation statements)

References 12 publications

(14 reference statements)

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“…). This finding is consistent with immunologic characteristics of chronic HCV infection in the clinic: ineffective antiviral CD8 + T‐cell responses that coexist with B‐cell abnormalities …”

Section: Discussionsupporting

confidence: 84%

“…Interestingly, a previous report identified CD40L expression in total RNA isolated from livers of HCV patients suffering from aberrant Ig‐related syndromes . Our own findings pinpoint CD40L expression exclusively on CD4 + Foxp3 + T cells during liver disease (Fig.…”

Section: Resultssupporting

confidence: 71%

“…Chronic liver disease presents a unique dichotomy of Ig-mediated extrahepatic symptoms and heightened B-cell activation (13,17,18) that coexist with an intrahepatic immunosuppressive milieu characterized by increased frequencies of CD4 1 Foxp3 1 T cells. (5)(6)(7)9,11) Our own findings are consistent with these B cellmediated sequelae of disease (Fig.…”

Section: Fibrosis-elicited Cd4 1 Foxp3 1 T Cells Suppress Cd8 1 T-celmentioning

confidence: 99%

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CD4+Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T‐cell suppression during chronic liver disease

et al. 2016

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Persistent hepatotropic viral infections are a common etiologic agent of chronic liver disease. Unresolved infection can be attributed to non-functional intrahepatic CD8+ T cell responses. In light of dampened CD8+ T cell responses, liver disease often manifests systemically as Ig-related syndromes due to aberrant B cell functions. These two opposing yet co-existing phenomena implicate the potential of altered CD4+ T cell help. Elevated CD4+ Foxp3+ T cells were evident in both human liver disease and a mouse model of chemically induced liver injury despite marked activation and spontaneous IgG production by intrahepatic B cells. While this population suppressed CD8+ T cell responses, aberrant B cell activities were maintained due to expression of CD40L on a subset of CD4+ Foxp3+ T cells. In vivo blockade of CD40L attenuated B cell abnormalities in a mouse model of liver injury. A phenotypically similar population of CD4+ Foxp3+ CD40L+ T cells was found in diseased livers explanted from patients with chronic hepatitis C infection. This population was absent in non-diseased liver tissues and peripheral blood.Conclusion-Our data indicate that liver disease elicits alterations in the intrahepatic CD4+ T cell compartment that suppress T cell immunity while concomitantly promoting aberrant IgGmediated manifestations. (9) and in human patients (5,6,10). While this is beneficial for the liver, this population has been implicated in aiding establishment of chronic hepatotropic infections, such as HCV, in human patients by suppressing CD8+ T cell responses (6,11,12). Aside from the effects on CD4+ T cell functions, HSC-derived RA can augment B cell survival, plasmablast differentiation and IgG production (4). Aberrant B cell function during liver fibrosis has been linked to systemic manifestations such as hyperglobulinemia, elevated titers of autoimmune anti-nuclear antibody (ANA), and mixed cryoglobulinemia (MC) (reviewed in (13)). The dual effects of fibrotic processes on local suppression of CD8+ T cell responses by accumulation of CD4+Foxp3+T cells with concomitant dysfunctional intrahepatic B cells suggests a potential interplay between fibrosis, CD4+ T cell helper functions and B cells. KeywordsHere, we investigated the effects of hepatic fibrosis on the CD4+ T cell compartment and its consequence on the IgG-mediated sequelae of liver disease. Using chemically induced liver injury in mice we found that fibrotic animals demonstrated a CD4+ T cell-dependent increase in serum IgG levels. Despite constitutive intrahepatic B cell production of IgG, there was a liver-specific accumulation of "regulatory" CD4+Foxp3+ T cells during liver injury. Fibrosis-elicited CD4+Foxp3+ T cells effectively suppressed CD8+ T cell responses to cognate antigen while concomitantly permitting B cell activation in vitro. Phenotypic analysis demonstrated that a subset of the fibrosis-elicited CD4+Foxp3+ T cell population expressed CD40L and failed to suppress B cell functions in vitro. In accordance to our findings in the mouse model,...

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Section: Discussionsupporting

confidence: 84%

Section: Resultssupporting

confidence: 71%

Section: Fibrosis-elicited Cd4 1 Foxp3 1 T Cells Suppress Cd8 1 T-celmentioning

confidence: 99%

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CD4+Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T‐cell suppression during chronic liver disease

et al. 2016

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“…Genetic defects in CD40L led to a disorder characterized by elevated serum IgM, which recaptures one of major serology features of PBC [160]. Early reports indicate that hepatic CD40L mRNA was significantly increased in PBC compared with healthy controls and several other liver diseases [161]. However, no genetic mutation has been detected in CD40L loci in PBC.…”

Section: Dna Methylationmentioning

confidence: 97%

Epigenetics and Primary Biliary Cirrhosis: a Comprehensive Review and Implications for Autoimmunity

Xie

Lian

2015

Clinic Rev Allerg Immunol

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Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that develops based upon the interaction of genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified dozens of predisposing variants including HLA, IL12A, and CTLA4 but have been disappointed in identifying a "smoking gun." These discoveries highlight the importance of the genetic background involved in immunological dysregulation. Although concordance rate of PBC in monozygotic (MZ) twins is among the highest reported in autoimmune disorders, incomplete disease concordance in twins associated with differentially expressed genes has been demonstrated. However, little is understood about how environmental aspects contribute to the disease and why middle-aged women are more susceptible. As a result, epigenetic factors, which convert signals indicating environmental changes into dynamic and heritable alterations of transcriptional potential, are getting increased attention by researchers in both basic and clinical studies. Among epigenetic mechanisms, the instability and skewed gene expression in the X chromosome may account for the female preponderance in PBC. In addition, transcriptional regulation of histone modification and DNA methylation underscores potential involvement in disease pathogenesis. High-throughput techniques are being used to identify epigenetic regulators. In this review, we attempt to outline recent progress regarding epigenetics in PBC and other autoimmune diseases.

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“…The high levels of IgG seen in AIH may be a consequence of sustained B-cell activation in the liver as elevated intrahepatic levels of CD154, a critical activation signal for B cells, are detected in the liver of patients with AIH [103]. Expanded portal tracts take on a tertiary lymphoid structure as portal-associated lymphoid tissue and such structures include B cells [104].…”

Section: Autoantibodies In Aih Pathogenesismentioning

confidence: 99%

Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management

2010

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Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating c-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4? and CD8? T cells are involved together with effector responses mediated by NK cells, cd T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.

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The relationship between hepatic immunoglobulin production and CD154 expression in chronic liver diseases

Abstract: These findings suggest that CD40-CD154 signals may be involved in Ig production within the liver of autoimmune liver diseases.

Cited by 13 publications

References 12 publications

CD4+Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T‐cell suppression during chronic liver disease

CD4+Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T‐cell suppression during chronic liver disease

Epigenetics and Primary Biliary Cirrhosis: a Comprehensive Review and Implications for Autoimmunity

Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management

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