Absence of Fms-like tyrosine kinase 3 ligand (Flt3L) signalling protects against collagen-induced arthritis.
OBJECTIVE
Comprehending the mechanisms that regulate activation of autoreactive T cells and B cell antibody production is fundamental for understanding the breakdown in self-tolerance and development of autoimmunity. Here we studied the role of Fms-like tyrosine kinase 3 ligand (Flt3L) signalling in the pathogenesis of collagen-induced arthritis (CIA).


METHODS
CIA was induced in mice lacking Flt3L (Flt3L(-/-)) and wild-type (WT) littermates (C57/BL6, 8-10 weeks old). Mice were killed in the initial phase (acute phase: experiment 1) and late phase (chronic phase: experiment 2) of the disease. Arthritis severity was assessed using a semiquantitative scoring system (0-4), and histological analysis of cellular infiltration, cartilage destruction and peptidoglycan loss was performed. Phenotypic and functional analysis of T and B cells, FoxP3 expression, activation and lymphocyte costimulatory markers, and cytokine production were performed ex vivo by flow cytometry in lymph nodes. Serum collagen type II (CII)-specific antibodies were measured by ELISA.


RESULTS
Flt3L(-/-) mice showed a marked decrease in clinical arthritis scores and incidence of arthritis in both acute and chronic phases of CIA compared with WT mice. Moreover, decreased synovial inflammation and joint destruction was observed. Both the magnitude and quality of T cell responses were altered in Flt3L(-/-). In the acute phase, the amount of CII-specific IgG2a antibodies was lower in Flt3L(-/-) than WT mice.


CONCLUSIONS
These results strongly suggest a role for Flt3L signalling in the development of arthritis.
Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
M I P
MI
Ramos
Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
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ON
Karpus
Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
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P
Broekstra
Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
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S
Aarrass
Haematopoietic Stem Cell Laboratory and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
S E
SE
Jacobsen
Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands University of Cambridge, UK and GlaxoSmithKline, Stevenage, UK.
P P
PP
Tak
Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
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MC
Lebre
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D024043:Collagen Type II / Q000276:immunology; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D001323:Autoantibodies; D024043:Collagen Type II; D007074:Immunoglobulin G; D008565:Membrane Proteins; C084881:flt3 ligand protein
Arthritis; Cytokines; Inflammation; T Cells