gp49B1 deficiency is associated with increases in cytokine and chemokine production and severity of proliferative synovitis induced by anti‐type II collagen mAb

• Published in: European journal of immunology 2005-05, Vol.35 (5), p.1530-1538
• Main Authors: Zhou, Joseph S., Friend, Daniel S., Lee, David M., Li, Lin, Austen, K. Frank, Katz, Howard R.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Arthritis; Collagen Type II - immunology; Cytokines - biosynthesis; Cytokines - immunology; gp49B1; Immunoreceptor tyrosine‐based inhibitory motif; Inflammation; Mast Cells - immunology; Membrane Glycoproteins - deficiency; Mice; Neutrophil Infiltration - immunology; Neutrophils; Receptors, Immunologic - deficiency; Synovitis - chemically induced; Synovitis - immunology; Synovitis - pathology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200425895

Mice with a disrupted gp49B gene, which encodes gp49B1 that is expressed on certain hematopoietic cells and has two immunoreceptor tyrosine‐based inhibitory motifs (ITIM), exhibit augmented FcϵRI‐initiated mast cell degranulation and resultant tissue edema. gp49B1‐deficient (gp49B–/–) mice also exhibit exaggerated lipopolysaccharide (LPS)‐induced intravascular neutrophil aggregation leading to cutaneous microangiopathy. To determine whether gp49B–/– mice exhibit elevated cytokine and chemokine levels leading to pathologic inflammation, we quantified clinical and morphologic parameters of arthritis and tissue levels of contributory mediators in gp49B–/– and gp49B1‐sufficient (gp49B+/+) mice injected with anti‐type II collagen monoclonal antibody (mAb) and LPS. Clinical scores for joint swelling and histological assessments of synovial thickness and cartilage matrix depletion at day 7 were significantly 2.3‐ to 2.5‐fold greater and were more prolonged in gp49B–/– mice. At day 5, the amounts of IL‐1β, macrophage inflammatory protein (MIP)‐1α, and MIP‐2 were 2.1‐, 2.5‐, and 12‐fold greater in joint extracts from gp49B–/– mice. A significant 2.7‐fold more neutrophils infiltrated the synovium of gp49B–/– mice at day 7, and neutrophilia persisted with the delayed resolution of the synovitis. mAb‐mediated depletion of neutrophils prevented the synovitis in both strains. Thus, gp49B1 counter‐regulates the cytokine and chemokine induction and attendant neutrophilia that are all essential for synovitis and cartilage matrix depletion.