Dendritic cells and the pathogenesis of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease in which unknown arthrogenic autoantigen is presented to CD4+ T cells. The strong association of the disease with an epitope within the HLA-DR chain shared between various alleles of HLA-DR4 and DR1 emphasizes the importance of antigen presentation. This immune response predominantly occurs in the synovial tissue and fluid of the joints and autoreactive T cells are readily demonstrable in both the synovial compartment and blood. Circulating dendritic cells (DC) are phenotypically and functionally identical with normal peripheral blood (PB) DC. In the synovial tissue, fully differentiated perivascular DC are found in close association with T cells and with B cell follicles, sometimes containing follicular DC. These perivascular DC migrate across the activated endothelium from blood and receive differentiative signals within the joint from monocyte-derived cytokines and CD40-ligand+ T cells. In the SF, DC manifest an intermediate phenotype, similar to that of monocyte-derived DC in vitro. Like a delayed-type hypersensitivity response, the rheumatoid synovium represents an effector site. DC at many effector sites have a characteristic pattern of infiltration and differentiation. It is important to note that the effector response is not self-limiting in RA autoimmune inflammation. In this article, we argue that the presentation of self-antigen by DC and by autoantibody-producing B cells is critical for the perpetuation of the autoimmune response. Permanently arresting this ongoing immune response with either pharmaceutical agents or immunotherapy is a major challenge for immunology.
Thomas
R
R
Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Australia. rthomas@medicine.pa.uq.edu.au
MacDonald
K P
KP
Pettit
A R
AR
Cavanagh
L L
LL
Padmanabha
J
J
Zehntner
S
S
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D009000:Monocytes / Q000166:cytology; D011518:Proto-Oncogene Proteins / Q000276:immunology; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000276:immunology
D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D014157:Transcription Factors; D051841:Transcription Factor RelB