The Injured Liver Induces Hyperimmunoglobulinemia by Failing to Dispose of Antigens and Endotoxins in the Portal System

Abstract

Hyperimmunoglobulinemia is frequently observed in patients with chronic liver diseases. However, the exact mechanism underlying the high level of antibody formation is not fully understood. In our study, we provide evidence for the functional role of the liver and the stimulation of plasma cell proliferation in hyperimmunoglobulinemia. We collected sera from patients with chronic liver diseases, and the level of serum immunoglobulins in patients was examined; this was also investigated in animal models of liver cirrhosis and hepatocellular carcinoma. An end-to-side microsurgical portacaval shunt was used to mimic liver dysfunction in rats. We used portal vein serum and inferior vena cava serum to immunize healthy rats and mice in order to confirm the function of the healthy liver in disposing of antigens and endotoxins from the gut. For the analysis of the state of plasma cell activation, plasma cells from mice were stained with PE-conjugated anti-CD138 and FITC-conjugated anti-BrdU for flow cytometry analysis. Hyperimmunoglobulinemia was observed both in patients with chronic liver diseases and in related animal models, and high plasma LPS levels were also observed. There was a significant increase in the activation and proliferation of plasma cell in mice immunized with antigens or LPS-positive serum compared with controls that were immunized with antigens and LPS-negative serum. We confirmed that the healthy liver plays an important role in disposing of antigens and endotoxins derived from the gut. Hyperimmunoglobulinemia in chronic liver diseases mainly arises due to the collateral circulation secondary to portal hypertension, gut antigens and endotoxins that bypass the liver and reach the antibody-producing cells.

Splicing Factor SLU7 Prevents Oxidative Stress‐Mediated Hepatocyte Nuclear Factor 4α Degradation, Preserving Hepatic Differentiation and Protecting From Liver Damage

“…Albeit less well-known, catabolism of immunoglobulins is one relevant hepatic function in systemic homeostasis. Accordingly, hyperglobulinemia is found in patients and models of severe and chronic liver dysfunction (17,22). Importantly we observed that the hepatic accumulation of IgGs was higher in CCl 4 -treated Slu7 +/mice (Fig.…”

Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis

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Does Hepatic Impairment Affect the Exposure of Monoclonal Antibodies?

“…The mechanism for increased endogenous IgG level has been reported to be associated with increased B‐cell synthesis. The injured liver fails to dispose of gut antigens and endotoxins, and the bypassed antigens and endotoxins lead to B‐cell activation and proliferation, which increases endogenous IgG production . Normal endogenous IgG level is about 1,000 to 1,400 mg/dL, while the level is increased up to 1,700, 2,000, and 6,000 mg/dL in mild, moderate, and severe HI, respectively …”