Acute Liver Injury Is Independent of B Cells or Immunoglobulin M

Acute liver injury is a clinically important pathology and results in the release of Danger Associated Molecular Patterns, which initiate an immune response. Withdrawal of the injurious agent and curtailing any pathogenic secondary immune response may allow spontaneous resolution of injury. The role B cells and Immunoglobulin M (IgM) play in acute liver injury is largely unknown and it was proposed that B cells and/or IgM would play a significant role in its pathogenesis.Tissue from 3 models of experimental liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury) and patients transplanted following paracetamol overdose were stained for evidence of IgM deposition. Mice deficient in B cells (and IgM) were used to dissect out the role B cells and/or IgM played in the development or resolution of injury. Serum transfer into mice lacking IgM was used to establish the role IgM plays in injury.Significant deposition of IgM was seen in the explanted livers of patients transplanted following paracetamol overdose as well as in 3 experimental models of acute liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury). Serum transfer into IgM-deficient mice failed to reconstitute injury (p = 0.66), despite successful engraftment of IgM. Mice deficient in both T and B cells (RAG1-/-) mice (p<0.001), but not B cell deficient (μMT) mice (p = 0.93), were significantly protected from injury. Further interrogation with T cell deficient (CD3εKO) mice confirmed that the T cell component is a key mediator of sterile liver injury. Mice deficient in B cells and IgM mice did not have a significant delay in resolution following acute liver injury.IgM deposition appears to be common feature of both human and murine sterile liver injury. However, neither IgM nor B cells, play a significant role in the development of or resolution from acute liver injury. T cells appear to be key mediators of injury. In conclusion, the therapeutic targeting of IgM or B cells (e.g. with Rituximab) would have limited benefit in protecting patients from acute liver injury

IgM and B cells are not critical to resolution of injury in the liver.

<p>Given the apparent lack of pathogenicity of IgM or B cells in this model of hepatic IRI, it was decided to see if they had a significant role in the resolution from injury. The recovery from injury was compared between WT and μMT mice. Representative H&E sections (x25 magnification), demonstrate similar injury at 24 hours, which resolved almost completely by day 7 post-IRI in both WT and μMT mice (residual necrosis<2% all mice [WT (n = 3), μMT (n = 4)]).</p

The role of B and T cells in hepatic IRI.

<p>To investigate whether the protection seen in RAG1-/- mice resulted from B and/or T cells, WT controls and mice deficient respectively in mature B cells (μMT) and T cells (CD3εKO) underwent 40 minutes left hepatic lobe ischemia (n = 12/group). Following 24 hours, reperfusion a significant reduction (Kruskall-Wallis p = 0.0037) was seen in mice lacking T, but not B cells.</p

IgM deposition in acute sterile liver injury.

<p>Tissue sections of explanted livers from patients transplanted for fulminant liver failure secondary to paracetamol overdose were stained looking for evidence of IgM deposition; extensive deposition of IgM is demonstrated within areas of parenchymal injury (<b>A</b>). Tissue sections from male WT mice, with demonstrable sterile liver injury on sections stained with H&E following injection of 200mg/kg paracetamol or 10mg/kg con A also showed extensive IgM staining upon immunohistochemical staining (<b>B</b>). Male mice underwent 40 minutes left lobe ischemia and were then reperfused for 0 hours to 7 days (n = 2–6 per timepoint). The extent of IgM deposition was compared with the histological injury seen on slides stained with H&E; x25 magnification slides are shown at selected time points (<b>C</b>). IgM deposition was calculated as a percentage of total section area across the time-course (median + Standard Error of Mean (SEM)) (<b>D</b>); this deposition of IgM was rapid (seen within 1 hour) and disappeared with macroscopic resolution of injury.</p