Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Fas Expression in Myeloid Cells Is Required To Prevent Systemic Autoimmunity.

Cuda1,  Carla M., Agrawal1,  Hemant, Weber2,  Evan, Haines3,  G. Kenneth, Perlman1,  Harris R.

Northwestern University, Chicago, IL
Northwestern University
Yale University


Rheumatoid arthritis (RA) manifests in persistent synovial inflammation, cellular infiltration, and pro-inflammatory cytokine production, and results in progressive cartilage and bone destruction. While the mechanisms underlying these phenotypes are not fully elucidated, insufficient apoptosis is a key player in RA pathogenesis. A critical mediator of the extrinsic apoptotic pathway includes the death receptor (DR) Fas. Lymphocyte-specific deletion of Fas reveals non-apoptotic roles for this DR in proliferation, and although lymphocytes are necessary for the initiation of RA, macrophages are crucial for its persistence. These highly activated and non-proliferating cells contribute to synovial inflammation and cartilage and bone destruction through the production of degradative enzymes, cytokines, and chemokines. However, the impact of myeloid cell-specific loss of Fas and its relationship to RA development and/or progression has yet to be examined.


Mice with Fas flanked by loxP sites (Fasflox/flox) were crossed with mice expressing Cre under control of the murine lysozyme M gene promoter (CreLysM), which functions in mature lysozyme-expressing cells of the myelomonocytic lineage. CreLysMFasflox/flox mice were verified by Real-time PCR and examined to determine non-apoptotic roles of Fas in myeloid cells. Flow cytometric analysis was employed to characterize both myeloid and lymphoid cell distribution and activation in bone marrow, blood and spleen. Luminex-based assays and ELISAs were used to detect serum cytokine and Ig levels as well as in vitro cytokine production by macrophages in response to LPS. Immunofluorescent and immunohistochemical staining revealed kidney pathology.


Myeloid cell-specific loss of Fas significantly increased both total numbers of peripheral circulating blood cells and splenocytes. Increased percentages of bone marrow resident macrophages were seen. Selective deletion also disrupted myeloid cell homeostasis in the periphery by increasing levels of peripheral blood resident and inflammatory monocytes, as well as increasing both the number and activation level of total and inflammatory splenic macrophages. Additionally, in vitro LPS stimulation of both peritoneal macrophages and bone marrow-derived macrophages lacking Fas resulted in increased production of IL-6, TNFa and IL-1b. Loss of Fas in myeloid cells also affected dendritic cells and T cells, with these populations presenting a more activated phenotype. CreLysMFasflox/flox mice displayed significantly increased serum IL-1a, IgG, total IgM and anti-dsDNA IgM levels and presented with more severe kidney pathology based on positive IgG staining, increased cellular infiltration and higher disease scores.


These results demonstrate that loss of Fas in myeloid cells is sufficient to induce inflammatory phenotypes in mice. Thus, we are the first group to show via myeloid cell-specific deletion of Fas that this DR typically associated with apoptosis also acts to prevent systemic autoimmunity. These data will have implications for RA by elucidating previously unknown functions of a potentially useful target for therapy.

To cite this abstract, please use the following information:
Cuda, Carla M., Agrawal, Hemant, Weber, Evan, Haines, G. Kenneth, Perlman, Harris R.; Fas Expression in Myeloid Cells Is Required To Prevent Systemic Autoimmunity. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :853
DOI: 10.1002/art.28621

Abstract Supplement

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