RESUMO
In order to characterize the autoimmune response participating in the pathogenesis of rheumatoid arthritis (RA) a cDNA expression library constructed from mRNAs which had been isolated from the inflamed synovium of an RA patients was screened with autologous IgG autoantibodies. This led to the identification of gene rasi-1 which encodes a protein showing sequence identity with the zinc-binding matrix metalloproteinase MMP-19. MMP-19 is detected on the surface of activated PBMCs, TH1 lymphocytes, and Jurkat T lymphoma cells. It exhibits gelatinolytic activity and is recognized by autoantibodies in 26% and, respectively, 33% of sera collected from RA patients and systemic lupus erythematosus (SLE) patients. The novel autoantigen MMP-19 thus could play a role in the pathological processes participating in RA-associated joint tissue destruction.
Assuntos
Artrite Reumatoide/imunologia , Autoantígenos/metabolismo , Leucócitos Mononucleares/enzimologia , Metaloendopeptidases/metabolismo , Sequência de Aminoácidos , Animais , Artrite Reumatoide/sangue , Autoantígenos/genética , Autoantígenos/imunologia , Autoantígenos/isolamento & purificação , Células CHO , Cricetinae , DNA Complementar/biossíntese , DNA Complementar/química , DNA Recombinante/genética , DNA Recombinante/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Metaloproteinases da Matriz Secretadas , Metaloendopeptidases/genética , Metaloendopeptidases/imunologia , Metaloendopeptidases/isolamento & purificação , Análise de Sequência de DNA , Linfócitos T/enzimologia , Linfócitos T/imunologiaRESUMO
In rheumatoid arthritis (RA) the proliferation of synovial lining cells appears to be one of the initial pathologic changes that contributes to the destruction of articular joints. To understand the pathomechanisms involved in these functional changes, we analyzed the transcriptional regulation of the zinc-finger gene 225 (Z-225/Egr-1), a transcription factor expressed in the immediate early events of cellular activation. We found that Z-225 transcripts were significantly up-regulated in RA synoviocytes. In primary and long term culture Z-225 was spontaneously transcribed at elevated levels. In situ hybridization of zinc-finger probe showed characteristic Z-225 transcripts in RA synovial tissues. Identity of these signals to the Z-225 gene product were confirmed in freshly isolated synovial tissue by enzymatic amplification of cDNA by the PCR technique. Z-225 transcripts were also detected and characterized in a cDNA library established from a RA synovial explant. We therefore conclude that RA synoviocytes spontaneously produce Z-225 gene products at elevated levels. Because early growth response gene Z-225 is involved in the regulation of expression of other genes such as proto-oncogenes c-ras and c-sis, which are also up-regulated in the RA synovium, activation of Z-225 transcription in RA may represent a key event in articular joint destruction.