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II-07 Pathogenesis of pulmonary lupus and vasculitis: trafficking of innate B1 B cells to the lungs as a novel mechanism
  1. Ram R Singh1,2,3,4,
  2. Priti Prasad1,2,
  3. Michael Fishbein3 and
  4. Isela Valera1
  1. 1Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine
  2. 2Molecular Toxicology Interdepartmental Program
  3. 3Department of Pathology and Laboratory Medicine
  4. 4Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, USA


Background Up to 50% patients with SLE may develop pneumonitis, vasculitis and diffuse pulmonary hemorrhage (DPH). Advances in the pathogenesis of pulmonary lupus have been hampered because of the heterogeneity of clinical findings and paucity of access to the affected tissue. Hydrocarbon oils, such as 2,6,10,14-tetramethylpentadecane (TMPD), induce lupus-like autoantibodies, nephritis, arthritis, pneumonitis, and DPH depending on the animals’ genetic background. Humans can be exposed to hydrocarbon oils in crude oil and in mineral oils used in cosmetics, laxatives, and food-coatings. Here, we used this model to investigate the pathogenesis of pulmonary lupus, focusing on the role of innate B1 B-cells.

Methods We injected TMPD intraperitoneally in C57BL/6 (B6) mice to induce pulmonary lupus. We adoptively transferred wild-type peritoneal fluid cells which are enriched in B1 B-cells into CD19-/- (that have less B1a B-cells) and in Igμ-/- mice (have no B-cells), and tracked the transferred cells using CD45.1/CD45.2 system. Effect on disease was assessed using weight-loss, a semiquantitative scoring, and a quantitative measurement for lung hemorrhage. We analyzed global gene expression in the lungs using Affymatrix microarray.

Results In wild-type B6 mice, TMPD injection caused weight-loss, pneumonitis, vasculitis, and/or DPH in 73% of 62 animals compared to none of control animals injected with control hydrocarbon oil hexadecane or with PBS or sham. Immunophenotyping revealed abnormalities of all immune cells tested in the diseased lungs. At earlier timepoints prior to histopathological changes, while both hexadecane and TMPD caused myeloid cell abnormalities, only TMPD caused lung-infiltration with B-cells that expressed B1 B-cell subset markers: CD19+CD11b+/CD19+CD5+. Such B1 B-cells were simultaneously reduced in their usual location (peritoneal cavity). CD19-/- mice that have less B1a B-cells developed less DPH, and less B-cell infiltration in the lungs than wildtype mice. The adoptive transfer of wildtype peritoneal fluid cells into the peritoneum of CD19-/- or Igμ-/- mice induced more DPH/pneumonitis than the respective knockout recipients reconstituted with CD19-/- B-cells. The adoptive transfer of CD45.1+ wildtype peritoneal fluid cells into the peritoneum of CD45.2+CD19-/- recipients led to lung-infiltration with CD45.1+ B-cells. Furthermore, TMPD induced in the lungs a differential expression of Cxcl13 that is known to drive B1 B-cells’ migration.

Conclusions Exposure to TMPD induces B1 B-cells to traffic from the peritoneum into the lungs and cause pneumonitis/DPH. Identification of this mechanism in human lupus will have important implications for targeting a specific B-cell subset as a potential therapy.

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