Background/Purpose: Lung is involved in up to 50% patients with SLE. Among manifestations of pulmonary lupus, pneumonitis, vasculitis and diffuse pulmonary hemorrhage (DPH) carry a high mortality rate, and are without any effective treatment. Advances in the pathogenesis of pulmonary lupus have been hampered because of the heterogeneity of clinical findings, paucity of access to the affected tissue, and the lack of suitable model systems. 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. Previous studies have used this model to show that animals that lack B cells (Igμ^-/-) have a reduced prevalence of DPH. Here, we examined the role of innate B1 B cells in the pathogenesis of pulmonary lupus using the TMPD-DPH model.

Methods: We injected TMPD to induce pulmonary lupus in C57BL/6 (B6) mice and analyzed B cells and B cell subsets in the lungs and peritoneal cavity. To determine the role of innate B cells, we injected CD19^-/- mice (deficient in B1a B cells) and wild-type B6 mice with 500 μl TMPD intraperitoneally. Furthermore, we adoptively transferred wild-type peritoneal fluid cells which are enriched in B1 B cells into CD19^-/- and in Igμ^-/- mice (have no B cells). We assessed disease using weight-loss, a semi quantitative scoring system for lung inflammation and hemorrhage, and a quantitative measurement for lung hemorrhage.

Results: 73% of 62 TMPD-injected wild-type B6 mice exhibited weight-loss, pneumonitis, vasculitis, and/or DPH compared to none of controls 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 that are abundant in B1 B 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 a set of immune/inflammatory genes including chemokine Cxcl13 that are known to drive B1 B-cells’ migration.

Conclusion: Exposure to TMPD induces B1 B cells to traffic from the peritoneum into the lungs and cause pneumonitis/DPH. Our observations have implications for pulmonary complications of lupus, vasculitis and other rheumatic diseases by identifying a specific B cell subset as a potential target for therapy. Furthermore, humans can be exposed to hydrocarbon oils present in crude oil and in mineral oils used in cosmetics, laxatives, and food-coatings.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/trafficking-of-innate-b-cells-to-the-lungs-as-a-novel-mechanism-in-a-model-of-pulmonary-lupus-and-vasculitis/