Endogenous HLA-DR-restricted presentation of the cartilage antigens human cartilage gp-39 and melanoma inhibitory activity in the inflamed rheumatoid joint.
OBJECTIVE
The cartilage proteins melanoma inhibitory activity (MIA) and human cartilage gp-39 (HC gp-39) are candidate autoantigens in rheumatoid arthritis (RA). The present study was undertaken to investigate the endogenous HLA-DR4-restricted presentation of these self proteins, in order to seek in vivo evidence in support of their potential immunologic role.


METHODS
MIA and HC gp-39 were assessed in synovial fluid (SF) by enzyme-linked immunosorbent assay and in synovial tissue (ST) by immunohistochemistry. Presentation by SF cells was investigated using specific, HLA-DR-restricted T cell hybridomas.


RESULTS
MIA and HC gp-39 were detected in RA SF and ST, as well as in specimens from patients with other forms of arthritis. When HC gp-39-specific and MIA-specific HLA-DR4-restricted T cell hybridomas raised in HLA-DR4-transgenic mice were incubated with RA SF cells as antigen-presenting cells in the presence of HC gp-39 or MIA peptides, the corresponding T cell hybridomas showed strong responses, which were blocked by anti-HLA-DR antibodies. Weaker but qualitatively similar responses were observed with exogenous protein, indicating uptake and processing of these antigens by SF cells. More importantly, without addition of peptide or protein, endogenous presentation of MIA and HC gp-39 was detected in SF cells from 53% and 80% of HLA-DRB1*0401-positive RA patients, respectively. In addition, SF cells from 3 of 10 patients with spondylarthritis exhibited endogenous HC gp-39 presentation.


CONCLUSIONS
These data indicate that immunodominant epitopes of MIA and HC gp-39 are actively presented in an HLA-DR-restricted manner in the inflamed RA joint. The question remains as to whether this leads to activation of autoreactive T cells, which could play a role in either the immunopathology or the immunomodulation of arthritis.
van Lierop
M J C
MJ
Organon NV, Oss, The Netherlands. mariejose.vanlierop@organon.com
den Hoed
L
L
Houbiers
J
J
Vencovsky
J
J
Ruzickova
S
S
Krystufkova
O
O
van Schaardenburg
M
M
van den Hoogen
F
F
Vandooren
B
B
Baeten
D
D
De Keyser
F
F
Sønderstrup
G
G
Bos
E
E
Boots
A M
AM
D054392:Adipokines; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D000071451:Chitinase-3-Like Protein 1; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000032:analysis*; D006023:Glycoproteins / Q000032:analysis*; D006684:HLA-DR Antigens / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000276:immunology; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D007596:Joints / Q000276:immunology* / Q000503:physiopathology; D037102:Lectins; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000032:analysis*; D013582:Synovial Fluid / Q000737:chemistry; D013601:T-Lymphocytes / Q000276:immunology
D054392:Adipokines; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D037102:Lectins; C090059:MIA protein, human; D009363:Neoplasm Proteins