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Altered functionality of anti-bacterial antibodies in patients with chronic hepatitis C virus infection.

Lamontagne A, Long RE, Comunale MA, Hafner J, Rodemich-Betesh L, Wang M, Marrero J, Di Bisceglie AM, Block T, Mehta A - PLoS ONE (2013)

Bottom Line: Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease.In addition, markers of microbial exposure were determined.In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure.

View Article: PubMed Central - PubMed

Affiliation: Drexel University College of Medicine, and Department of Microbiology and Immunology and Drexel Institute for Biotechnology and Virology, Doylestown, Pennsylvania, USA. anne.lamontagne@drexelmed.edu

ABSTRACT

Background: Using comparative glycoproteomics, we have previously identified a glycoprotein that is altered in both amount and glycosylation as a function of liver cirrhosis. The altered glycoprotein is an agalactosylated (G0) immunoglobulin G molecule (IgG) that recognizes the heterophilic alpha-gal epitope. Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease.

Methods: The N-linked glycosylation of anti-gal IgG molecules from patients with fibrosis and cirrhosis was determined and the effector function of anti-bacterial antibodies from over 100 patients examined. In addition, markers of microbial exposure were determined.

Results: Surprisingly, the subset of agalactosylated anti-gal antibodies described here, was impaired in their ability to mediate complement mediated lysis and inhibited the complement-mediated destruction of common gut bacteria. In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure.

Conclusions: Anti-gal antibodies in patients with liver cirrhosis were reduced in their ability to mediate complement mediated lysis of target cells. As bacterial infection is a major complication in patients with cirrhosis and bacterial products such as LPS are thought to play a major role in the development and progression of liver fibrosis, this finding has many clinical implications in the etiology, prognosis and treatment of liver disease.

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Change in LRAGG in response to IFN Treatment in patients with liver fibrosis.(A) The change in the level of LRAGG in patients who responded to IFN and cleared their HCV and had low LRAGG at start of treatment. As this figure shows, there is no significant change in patients who started with low levels of LRAGG in response to IFN therapy. (B) In contrast, those patients who responded to IFN and cleared their HCV and started had greater than 5-fold increase over normal at the start of treatment show a significant decrease following treatment (P<0.05) (C). However, patients who do not respond to IFN treatment show a significant increase (P<0.05) following treatment when they began with low levels (C) and stayed high when they started with greater than 5-fold increase in LRAGG over normal (D).
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pone-0064992-g005: Change in LRAGG in response to IFN Treatment in patients with liver fibrosis.(A) The change in the level of LRAGG in patients who responded to IFN and cleared their HCV and had low LRAGG at start of treatment. As this figure shows, there is no significant change in patients who started with low levels of LRAGG in response to IFN therapy. (B) In contrast, those patients who responded to IFN and cleared their HCV and started had greater than 5-fold increase over normal at the start of treatment show a significant decrease following treatment (P<0.05) (C). However, patients who do not respond to IFN treatment show a significant increase (P<0.05) following treatment when they began with low levels (C) and stayed high when they started with greater than 5-fold increase in LRAGG over normal (D).

Mentions: We then determined the level of LRAGG in these patients. In this case we found it was of great interest to determine the pattern of changes in the fold increase or decrease in LRAGG in those patients who began a treatment course with either low or high levels of LRAGG. Figure 5A shows the fold increase in LRAGG in Responders who started treatment with low levels of LRAGG (defined as less than a 5-fold increase over commercial sera). As Figure 5A shows there is no significant change in LRAGG following the course of treatment; in other words those who started low stayed low. However, Figure 5B shows a significant decrease in LRAGG in Responder patients who started treatment with high LRAGG levels (defined as 5-fold or greater increase over commercial sera) (P<0.05). The pattern was reversed in patients in the Non-responder group; they saw a significant increase in LRAGG (P<0.05) when they started therapy with low levels (Figure 5C) and no significant overall change when they started with high LRAGG (Figure 5D).


Altered functionality of anti-bacterial antibodies in patients with chronic hepatitis C virus infection.

Lamontagne A, Long RE, Comunale MA, Hafner J, Rodemich-Betesh L, Wang M, Marrero J, Di Bisceglie AM, Block T, Mehta A - PLoS ONE (2013)

Change in LRAGG in response to IFN Treatment in patients with liver fibrosis.(A) The change in the level of LRAGG in patients who responded to IFN and cleared their HCV and had low LRAGG at start of treatment. As this figure shows, there is no significant change in patients who started with low levels of LRAGG in response to IFN therapy. (B) In contrast, those patients who responded to IFN and cleared their HCV and started had greater than 5-fold increase over normal at the start of treatment show a significant decrease following treatment (P<0.05) (C). However, patients who do not respond to IFN treatment show a significant increase (P<0.05) following treatment when they began with low levels (C) and stayed high when they started with greater than 5-fold increase in LRAGG over normal (D).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672197&req=5

pone-0064992-g005: Change in LRAGG in response to IFN Treatment in patients with liver fibrosis.(A) The change in the level of LRAGG in patients who responded to IFN and cleared their HCV and had low LRAGG at start of treatment. As this figure shows, there is no significant change in patients who started with low levels of LRAGG in response to IFN therapy. (B) In contrast, those patients who responded to IFN and cleared their HCV and started had greater than 5-fold increase over normal at the start of treatment show a significant decrease following treatment (P<0.05) (C). However, patients who do not respond to IFN treatment show a significant increase (P<0.05) following treatment when they began with low levels (C) and stayed high when they started with greater than 5-fold increase in LRAGG over normal (D).
Mentions: We then determined the level of LRAGG in these patients. In this case we found it was of great interest to determine the pattern of changes in the fold increase or decrease in LRAGG in those patients who began a treatment course with either low or high levels of LRAGG. Figure 5A shows the fold increase in LRAGG in Responders who started treatment with low levels of LRAGG (defined as less than a 5-fold increase over commercial sera). As Figure 5A shows there is no significant change in LRAGG following the course of treatment; in other words those who started low stayed low. However, Figure 5B shows a significant decrease in LRAGG in Responder patients who started treatment with high LRAGG levels (defined as 5-fold or greater increase over commercial sera) (P<0.05). The pattern was reversed in patients in the Non-responder group; they saw a significant increase in LRAGG (P<0.05) when they started therapy with low levels (Figure 5C) and no significant overall change when they started with high LRAGG (Figure 5D).

Bottom Line: Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease.In addition, markers of microbial exposure were determined.In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure.

View Article: PubMed Central - PubMed

Affiliation: Drexel University College of Medicine, and Department of Microbiology and Immunology and Drexel Institute for Biotechnology and Virology, Doylestown, Pennsylvania, USA. anne.lamontagne@drexelmed.edu

ABSTRACT

Background: Using comparative glycoproteomics, we have previously identified a glycoprotein that is altered in both amount and glycosylation as a function of liver cirrhosis. The altered glycoprotein is an agalactosylated (G0) immunoglobulin G molecule (IgG) that recognizes the heterophilic alpha-gal epitope. Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease.

Methods: The N-linked glycosylation of anti-gal IgG molecules from patients with fibrosis and cirrhosis was determined and the effector function of anti-bacterial antibodies from over 100 patients examined. In addition, markers of microbial exposure were determined.

Results: Surprisingly, the subset of agalactosylated anti-gal antibodies described here, was impaired in their ability to mediate complement mediated lysis and inhibited the complement-mediated destruction of common gut bacteria. In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure.

Conclusions: Anti-gal antibodies in patients with liver cirrhosis were reduced in their ability to mediate complement mediated lysis of target cells. As bacterial infection is a major complication in patients with cirrhosis and bacterial products such as LPS are thought to play a major role in the development and progression of liver fibrosis, this finding has many clinical implications in the etiology, prognosis and treatment of liver disease.

Show MeSH
Related in: MedlinePlus