title: Restoration of skeletal muscle ischemia-reperfusion injury in humanized immunodeficient mice.
abstract: BACKGROUND
  Ischemia and reperfusion (I/R) of tissue provokes an inflammatory process that is highly dependent on circulating natural immunoglobulin M (IgM) and the complement cascade. In mice, a single IgM specificity produced by peritoneal B cells can initiate reperfusion injury. It is unknown whether humans express natural IgM with a similar specificity. It is also unknown whether pathogenic IgM is produced solely from peritoneal B cells or can also be made by circulating B cells.
  
  
  METHODS
  Immunodeficient mice lacking endogenous immunoglobulin were used. Mice were reconstituted with 0.9% normal saline, human serum, or xenografted human peripheral blood lymphocytes (PBLs) and then subjected to tourniquet-induced hindlimb I/R. Serum human IgM and immunoglobulin G (IgG) were measured by enzyme-linked immunosorbent (ELISA) assay. Skeletal muscle was harvested for injury assessment by histology and for immunohistochemistry.
  
  
  RESULTS
  Immunodeficient mice were protected from skeletal muscle injury after hindlimb I/R. Transfer of human serum restored skeletal muscle damage. Rag2/gammaR-/- mice that were engrafted with human PBL (huPBL-SCID) had high levels of human IgM. huPBL-SCID mice developed significantly more skeletal muscle injury than control saline-treated mice (P < or = .01) and human serum-reconstituted Rag2/gammaR-/- mice (P < or = 0.01). Sham-treated huPBL-SCID mice had no muscle injury, demonstrating that human lymphocyte engraftment did not cause injury in the absence of ischemia. Deposition of human IgM was observed on injured but not sham-injured muscle.
  
  
  CONCLUSIONS
  Human serum can initiate murine skeletal muscle I/R injury. Circulating human PBL may be a source of pathogenic IgM. The huPBL-SCID mouse may be a useful model to define the specificity of pathogenic human IgM and to test therapeutics for I/R injury.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA02115, USA.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Sheu
authors.forename: Sean M
authors.initials: SM
authors.lastname: Oakes
authors.forename: Cyrus
authors.initials: C
authors.lastname: Ahmadi-Yazdi
authors.forename: Jalil
authors.initials: J
authors.lastname: Afnan
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
authors.forename: Francis D
authors.initials: FD
authors.lastname: Moore
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency; D006614:Hindlimb; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood / Q000235:genetics; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000276:immunology / Q000473:pathology*; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D053631:Interleukin Receptor Common gamma Subunit; C499308:Rag2 protein, mouse