title: Pathogenic role of B cells in the development of diffuse alveolar hemorrhage induced by pristane.
abstract: Diffuse alveolar hemorrhage is an uncommon, yet often fatal, complication of systemic lupus erythematosus (SLE). Advances in the treatment of alveolar hemorrhage have been hampered because of the heterogeneity of clinical findings and the lack of suitable animal models. A single intraperitoneal injection of pristane induces a lupus-like syndrome characterized by lupus-related autoantibodies and glomerulonephritis in non-autoimmune-prone strains of mice. In addition, C57BL/6 (B6) mice frequently develop alveolar hemorrhage within a few weeks of pristane injection. Immunopathogenesis of pristane-induced alveolar hemorrhage was investigated in the present study. Early (2-4 weeks after injection) mortality due to hemorrhage was unique to C57BL/6 and C57BL/10 strains of mice. Recruitment of the macrophages and neutrophils preceded the hemorrhage by several days, and hemorrhage started 3-7 days after pristane injection in some mice, peaked at 2 weeks (84% in B6) and then resolved by 4 weeks in a majority of mice. Alveolar hemorrhage was independent of MyD88 (myeloid differentiation factor 88), or TLR7 pathways, in contrast to autoantibody production and glomerulonephritis, and was also independent of FcγR or Fas. Rag1(-/-) mice had a reduced prevalence of alveolar hemorrhage compared with B6 (P=0.01) congenics. However, T-cell receptor-deficient mice developed alveolar hemorrhage at a rate comparable to wild-type controls, whereas B6 Igμ(-/-) mice surprisingly had a strikingly reduced prevalence (7% vs 84% in B6, P<0.0001). Reconstitution of B6 Igμ(-/-) mice with wild-type B cells increased the prevalence to 50% (P=0.028). Pristane-induced alveolar hemorrhage is a useful model to study the pathogenesis and develop new therapy for this underappreciated and often life-threatening complication of SLE.
authors.affiliation: Division of Rheumatology and Clinical Immunology and Center for Autoimmune Disease, Department of Medicine, University of Florida, Gainesville, FL 32610-0221, USA.
authors.forename: Tolga T
authors.initials: TT
authors.lastname: Barker
authors.forename: Pui Y
authors.initials: PY
authors.lastname: Lee
authors.forename: Kindra M
authors.initials: KM
authors.lastname: Kelly-Scumpia
authors.forename: Jason S
authors.initials: JS
authors.lastname: Weinstein
authors.forename: Dina C
authors.initials: DC
authors.lastname: Nacionales
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Byron P
authors.initials: BP
authors.lastname: Croker
authors.forename: Eric S
authors.initials: ES
authors.lastname: Sobel
authors.forename: Westley H
authors.initials: WH
authors.lastname: Reeves
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D002460:Cell Line; D006470:Hemorrhage / Q000139:chemically induced* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D013045:Species Specificity; D013379:Substrate Specificity; D013729:Terpenes
chemical_list: D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D013729:Terpenes; C102370:monocytic differentiation factor P48; C064658:RAG-1 protein; C009042:pristane