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.


Fms-Like Tyrosine Kinase 3 Ligand (Flt3L) Levels Are Elevated in Arthritis: Role of Flt3L in Regulating Monocyte Migratory Pattern in RA.

Ramos2,  Inês, Oliveira3,  Ana, Schilders3,  Geurt, Aarrass3,  Saïda, Lebre3,  Cristina, Tak1,  Paul P.

Academic Med Ctr/Univ of Amsterdam, Amsterdam, The Netherlands
Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands

Background:

Fms-like tyrosine kinase 3 ligand (Flt3L) is a potent endogenous growth factor for myeloid (m)DC and plasmacytoid (p)DC. Its administration to mice and humans leads to dramatic increases of various DC subsets while Flt3L-/- mice show reduced DC numbers. Flt3L and its receptor have been poorly studied in the setting of autoimmune diseases in general and in experimental arthritis in particular. Since in rheumatoid arthritis (RA), circulating blood DC subsets numbers are reduced and enriched in synovial fluid (SF) and synovial tissue (ST), we investigated whether Flt3L can contribute to local accumulation of DC in these compartments by inducing migration of cells from the peripheral blood (PB).

Methods:

Patients with active RA, psoriatic arthritis (PsA), other forms of spondyloarthritis (SpA), osteoarthritis (OA), gout and healthy donors (HD) were included in this study. Soluble (s)Flt3L levels in SF and serum were determined using a commercially available ELISA. Expression of membrane-bound (m)Flt3L, Flt3L receptor (CD135) and chemokine receptors in PB mononuclear cells (PBMC) and SFMC were assessed by FACS. Immunohistochemical analysis was performed to detect Flt3L and CD135 RA synovial tissue. Monocytes from HD were isolated and cultured for 24h with recombinant Flt3L and chemokine receptor expression was assessed by FACS.

Results:

The levels of Flt3L in RA, PsA, and SpA, OA and gout SF were significantly higher compared to paired serum. In addition, Flt3L levels were significantly higher in RA, PsA and SpA SFs compared to gout SF. In PB monocytes, B cells and mDC the expression of mFlt3L in RA was higher compared to HD. Flt3L receptor expression was confined to monocytes and mDC and higher in RA SF compared to PB. Immunohistochemistry and immunofluorescence data showed the presence of Flt3L and Flt3L receptor in RA ST. Interestingly, Flt3L increased the expression of the chemokine receptors CCR1, CCR2 and CCR5 by monocytes in vitro.

Conclusion:

The increased levels of Flt3L in RA SF could contribute to the specific accumulation of DC in the synovial compartment compared to PB in inflammatory joint disease. Flt3L-induced expression of CCR1, CCR2 and CCR5 by monocytes might be important for the increased recruitment of DCs as well as monocytes and lymphocytes into the inflamed compartment. Achieving a detailed understanding of Flt3L function(s) in RA may lead to the development of novel immunotherapies for immune-mediated inflammatory diseases.

To cite this abstract, please use the following information:
Ramos, Inês, Oliveira, Ana, Schilders, Geurt, Aarrass, Saïda, Lebre, Cristina, Tak, Paul P.; Fms-Like Tyrosine Kinase 3 Ligand (Flt3L) Levels Are Elevated in Arthritis: Role of Flt3L in Regulating Monocyte Migratory Pattern in RA. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1519
DOI: 10.1002/art.29285

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