title: Acute Liver Injury Is Independent of B Cells or Immunoglobulin M.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom; Clinical Surgery, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: James A
authors.initials: JA
authors.lastname: Richards
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Martina
authors.initials: M
authors.lastname: Bucsaiova
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Hesketh
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ventre
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom; Hepatology, Division of Health Sciences, School of Clinical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Henderson
authors.affiliation: Hepatology, Division of Health Sciences, School of Clinical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Simpson
authors.affiliation: The University of Edinburgh, Edinburgh, United Kingdom; Department of Pathology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Christopher O C
authors.initials: CO
authors.lastname: Bellamy
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Howie
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom; Clinical Surgery, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Wigmore
mesh_terms: D000082:Acetaminophen / Q000506:poisoning; D055371:Acute Lung Injury / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D006505:Hepatitis / Q000276:immunology / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007075:Immunoglobulin M / Q000172:deficiency* / Q000378:metabolism; D016031:Liver Transplantation; D051379:Mice; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology
chemical_list: D018398:Homeodomain Proteins; D007075:Immunoglobulin M; C064658:RAG-1 protein; D000082:Acetaminophen