Article thumbnail

Myeloid cells, BAFF, and IFN-γ establish an inflammatory loop that exacerbates autoimmunity in Lyn-deficient mice

By Patrizia Scapini, Yongmei Hu, Ching-Liang Chu, Thi-Sau Migone, Anthony L. DeFranco, Marco A. Cassatella and Clifford A. Lowell

Abstract

Autoimmunity is traditionally attributed to altered lymphoid cell selection and/or tolerance, whereas the contribution of innate immune cells is less well understood. Autoimmunity is also associated with increased levels of B cell–activating factor of the TNF family (BAFF; also known as B lymphocyte stimulator), a cytokine that promotes survival of self-reactive B cell clones. We describe an important role for myeloid cells in autoimmune disease progression. Using Lyn-deficient mice, we show that overproduction of BAFF by hyperactive myeloid cells contributes to inflammation and autoimmunity in part by acting directly on T cells to induce the release of IFN-γ. Genetic deletion of IFN-γ or reduction of BAFF activity, achieved by either reducing myeloid cell hyperproduction or by treating with an anti-BAFF monoclonal antibody, reduced disease development in lyn−/− mice. The increased production of IFN-γ in lyn−/− mice feeds back on the myeloid cells to further stimulate BAFF release. Expression of BAFF receptor on T cells was required for their full activation and IFN-γ release. Overall, our data suggest that the reciprocal production of BAFF and IFN-γ establishes an inflammatory loop between myeloid cells and T cells that exacerbates autoimmunity in this model. Our findings uncover an important pathological role of BAFF in autoimmune disorders

Topics: Article
Publisher: The Rockefeller University Press
OAI identifier: oai:pubmedcentral.nih.gov:2916124
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (1999). A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus.
  2. (2009). B-cell-directed therapies for autoimmune
  3. (1998). Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation.
  4. (2002). Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase.
  5. (1998). Interferongamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice.
  6. (2005). New insights from murine lupus: disassociation of autoimmunity and end organ damage and the role of T cells.
  7. (2005). The Lyn tyrosine kinase differentially regulates dendritic cell generation and maturation.