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II-08 The role of neutrophils in B cell dysregulation in systemic lupus erythematosus
  1. Anna Bird,
  2. Javier Rangel-Moreno,
  3. Martin Chang,
  4. Jennifer Hossler,
  5. Nida Meednu and
  6. Jennifer Anolik
  1. Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Centre, Rochester, NY 14642


Background SLE is an autoimmune disease involving pathological dysregulation of both innate and adaptive immune compartments and loss of B cell tolerance. Recent evidence showing that neutrophils are dysregulated in SLE has led us to hypothesise that this innate immune cell may contribute to loss of B cell tolerance, both as a producer of cytokines and of self-antigen, in the form of apoptotic debris or neutrophil extracellular traps (NETs). Indeed, in previously published work from our group we demonstrated that neutrophils contribute to a Type I interferon signature in the bone marrow (BM) of SLE patients and represent a significant source of cytokines known to affect B cell function such as BAFF and APRIL. In order to ask whether neutrophils promote loss of B cell self-tolerance and immune activation, we examined neutrophil function over the course of disease and the impact of neutrophil depletion in the NZB/W lupus model.

Materials and methods NZB/NZW F1 female mice were injected intraperitoneally every other day with anti-Ly6G antibody (500 ug), either from 25 to 30 weeks of age (established disease) or 14 to 26 weeks (disease onset). Proteinuria was monitored weekly. At the end of the therapy, mice were euthanized and spleen, BM and kidneys were collected to enumerate neutrophils and lymphocytes by flow cytometry and immunofluorescence and antibody secreting cells (ASC) by ELISpot.

Results BM neutrophils are increased in frequency in lupus, display increased apoptosis, and have elevated production of BAFF, APRIL and IFNα near developing B cells. We also find an enrichment of IFNα-producing neutrophils in the spleen in close proximity to B cells late in disease. Surprisingly, following neutrophil depletion early in disease, there was an acceleration of proteinuria and pronounced increases in germinal centre formation, anti-dsDNA titers, and anti-dsDNA ASCs in the spleen, BM, and kidney. However, neutrophil depletion after onset of overt disease pathology does not impact SLE progression. To elucidate the specific mechanisms underlying neutrophil effects on B cell auto-reactivity, we further examined the cytokine profile and splenic localization of neutrophils over the course of disease. Early in disease splenic neutrophils were in closer proximity to T cells, whereas B cell interactions increased with disease progression.

Conclusions These data delineate a shifting balance of regulatory and activating roles for neutrophils during SLE progression, possibly dominated by suppressive effects on T cell activation and/or differentiation early and production of pro-inflammatory cytokines later in disease.

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