Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenisis
Session Type: Abstract Submissions (ACR)
Transforming growth factor-beta inducible gene-h3 (βig-h3) is abundantly expressed in synovial tissues of rheumatoid arthritis (RA) and has a regulatory role in growth, differentiation, adhesion, migration, and survival of cells. Previously, we found that βig-h3 regulates the adhesion and migration of T cells expressing a high level of α5β1 integrin. Therefore, we sought to investigate whether βig-h3 regulates the adhesion of specific T cell subsets selectively and whether it recruits T cells into arthritic tissues differentially according to expression of βig-h3 in a soluble form or in situwithin synovial tissues.
T cells were isolated using negative selection kit with MACS. T cell subsets were isolated with antibodies against CD4, CD45RO, and a5 integrin using FACS AriaTM. Adhesion of T cell subsets was investigated on βig-h3-coated microtitre plates. βig-h3 overexpressing mice were generated by the insertion of hβig-h3 transgene downstream of albumin promotor. βig-h3 deficient mice were also prepared by deleting βig-h3 gene using homologous recombination. Collagen antibody induced arthritis (CAIA) model was prepared. Recruitment of effector T cells was evaluated using in vivo homing assay.
Results: T cells isolated from SF of RA were mostly α5β1Hi, while most of those from PB of controls were α5β1Lo. Adhesion of SF T cells on the coated βig-h3 was enhanced compared with normal or RA PB T cells, which was inhibited by the function blocking antibody against α5β1 integrin. RGD peptide, which also binds to αvβ3 integrin, did not block βig-h3-mediated adhesion of T cells, while dhfas-1, a fragment of the 4th fas-1 domain of βig-h3, blocked the adhesion in a dose-dependent manner. The proportion of CD45RO+ cells among T cells was increased in the PB and SF of RA compared to PB of controls. Most of the CD45RO+ T cells were α5β1Hi population, while almost all the CD45RO– T cells were α5β1Lo population. βig-h3-mediated adhesion were higher in the CD4+CD45RO+α5Hi T cells compared with CD4+CD45RO+α5Lo and CD4+CD45RO–α5Lo T cells (0.40 ± 0.03 vs 0.19 ± 0.03 and 0.22 ± 0.02, respectively, P < 0.01). In βig-h3-trasgenic CAIA mice, arthritis severity was efficiently ameliorated compared with control (P < 0.05) and tissue sections revealed a decreased number of infiltrating T cells. In βig-h3 deficient mice, the severity of CAIA was significantly less severe compared to wild type C57BL6/J mice (P < 0.05), which was consistent with reduced histologic scores. To evaluate the role of βig-h3 in T cell recruitment into synovial tissues, in vivo homing of T cells was assessed after adoptive transfer of CSFE-labeled effector T cells. Homing of effector T cells into joint tissue was significantly reduced in βig-h3 deficient CAIA mice compared with that of wild type CAIA mice (P< 0.05).
Conclusion: The present data indicate that βig-h3 may play a critical role in the regulation of inflammation by the selective recruitment of memory/effector T cells into the synovial tissues of RA through the interaction with α5β1 integrin. These results implicate a soluble βig-h3-based therapeutic strategy for the treatment of inflammatory arthritis.
K. H. Sa,
J. H. Kang,
M. M. Alam,
K. H. Lee,
C. H. Im,
E. J. Nam,
I. S. Kim,
Y. M. Kang,
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