Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism.
B-cell accumulation and formation of ectopic germinal centers are characteristic changes in the diseased joints of patients with rheumatoid arthritis (RA). Earlier studies suggested that interactions between B lymphocytes and specialized synovial "nurse-like" cells peculiar to the RA synovium may be responsible for the homing and sustained survival of B cells in the synovium. However, in this study, we found that B cells spontaneously migrate beneath ordinary fibroblast-like synoviocytes (FLSs) and then experience prolonged survival. FLSs isolated from joints of patients with osteoarthritis also supported this activity, termed B-cell pseudoemperipolesis. We found that FLSs constitutively expressed the chemokine stromal cell-derived factor-1 (SDF-1), and that pertussis toxin or antibodies to the SDF-1 receptor (CXCR4) could inhibit B-cell pseudoemperipolesis. However, expression of SDF-1 is not sufficient, as dermal fibroblasts also expressed this chemokine but were unable to support B-cell pseudoemperipolesis unless previously stimulated with IL-4 to express CD106 (VCAM-1), a ligand for the alpha(4)beta(1) integrin, very-late-antigen-4 (VLA-4 or CD49d). Furthermore, mAb's specific for CD49d and CD106, or the synthetic CS1 fibronectin peptide, could inhibit B-cell pseudoemperipolesis. We conclude that ordinary FLSs can support B-cell pseudoemperipolesis via a mechanism dependent upon fibroblast expression of SDF-1 and CD106.
Burger
J A
JA
Department of Medicine, Division of Hematology/Oncology, University of California-San Diego, 9500 Gilman Drive, La Jolla, California 92093-0663, USA.
Zvaifler
N J
NJ
Tsukada
N
N
Firestein
G S
GS
Kipps
T J
TJ
D001172:Arthritis, Rheumatoid / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002463:Cell Membrane Permeability; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D008564:Membrane Potentials; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D013583:Synovial Membrane / Q000166:cytology / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4