Sustained T cell Rap1 signaling is protective in the collagen-induced arthritis model of rheumatoid arthritis.
Arthritis Rheum
; 62(11): 3289-99, 2010 Nov.
Article
en En
| MEDLINE
| ID: mdl-20662068
ABSTRACT
OBJECTIVE:
Defective activation of T cell receptor-proximal signaling proteins, such as the small GTPase Rap1, is thought to contribute to the pathologic behavior of rheumatoid arthritis (RA) synovial T cells. This study was undertaken to determine whether maintaining Rap1 signaling in murine T cells modifies disease onset or severity in collagen-induced arthritis (CIA).METHODS:
CIA experiments were conducted using wild-type and RapV12-transgenic mice, which express an active mutant of Rap1 in the T cell compartment. Mice were assessed using macroscopic, microscopic, and radiologic measures, and serum levels of anticollagen antibodies were measured by enzyme-linked immunosorbent assay. Phenotypic and functional characterization of wild-type and RapV12-transgenic T cells under homeostatic conditions and during disease onset was performed by flow cytometry.RESULTS:
Disease incidence and severity, synovial infiltration, joint destruction, and anticollagen antibody production were significantly reduced in RapV12-transgenic mice. Although the numbers and percentages of CD3+, CD4+, and CD8+ (naive, effector, and memory) T cells, Treg cells, and Th17 cells were equivalent in wild-type and RapV12-transgenic mice, a significant decrease in the percentage of tumor necrosis factor α-secreting CD8+ T cells was observed in RapV12-transgenic mice during CIA. RapV12-transgenic T cells also inefficiently expressed inducible costimulator and CD40L costimulatory proteins involved in B cell immunoglobulin class switching.CONCLUSION:
Our findings indicate that maintenance of T cell Rap1 signaling in murine T cells reduces disease incidence and severity in CIA, which are associated with specific defects in T cell effector function. Therefore, the restoration of Rap1 function in RA synovial T cells may have therapeutic benefit in RA.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Artritis Experimental
/
Artritis Reumatoide
/
Membrana Sinovial
/
Linfocitos T
/
Proteínas de Unión al GTP rap1
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Arthritis Rheum
Año:
2010
Tipo del documento:
Article
País de afiliación:
Países Bajos