Manifestations of inflammatory arthritis are critically dependent on LFA-1.
Leukocyte infiltration of synovial fluid and tissues is the hallmark of inflammatory arthritis. Selectins and beta2 integrins have been implicated in the multistep process of leukocyte adhesion to vascular endothelium. However, previous work has revealed disparate requirements for leukocyte recruitments to specific anatomic locales. Moreover, the mechanisms regulating recruitment of leukocytes to the joint in inflammatory arthritis models are not fully understood. We hypothesized that beta2 integrins, expressed on leukocytes, might play a pathogenic role in synovial inflammation. Using mice deficient in all beta2 integrins (CD18 null mice), we demonstrate that expression of these heterodimeric adhesion molecules is critical for arthritis induction in the K/B x N serum transfer model. Using null-allele mice and blocking mAbs, we demonstrate specifically that CD11a/CD18 (LFA-1) is absolutely required for the development of arthritis in this model. Blocking mAbs further revealed an ongoing requirement for LFA-1 I-domain adhesive function in disease perpetuation. These findings suggest that the LFA-1 I-domain forms an attractive target for treatment of human inflammatory arthritis.
Watts
Gerald M
GM
Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Beurskens
Frank J M
FJ
Martin-Padura
Ines
I
Ballantyne
Christie M
CM
Klickstein
Lloyd B
LB
Brenner
Michael B
MB
Lee
David M
DM
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001169:Arthritis, Experimental / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D040881:CD11a Antigen / Q000235:genetics / Q000378:metabolism; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
D015703:Antigens, CD; D040881:CD11a Antigen; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; C480027:ICAM-2 protein, mouse; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D018799:Intercellular Adhesion Molecule-1