ABSTRACT
Various rodent models of arthritis are essential to dissect the full complexity of human rheumatoid arthritis (RA), a common autoimmune disease affecting joints. The SKG model of arthritis originates from a spontaneous mutation in ZAP-70 found in a BALB/c colony. This mutation affects T cell selection due to reduced TCR signalling, which allows leakage of self-reactive T cells from the thymus. To further expand the practical applicability of this unique model in arthritis research, we investigated the arthritogenicity of the SKG mutation in two common black mouse strains C57BL/6.Q and C57BL/10.Q and compared to BALB/c.Q. Mice retained the reduced TCR signalling characteristic of SKG.BALB/c mice, which leads to similar alteration in thymic selection. Importantly, mice also retained susceptibility to chronic arthritis after a single injection of mannan from Saccharomyces cerevisiae, with comparable prevalence and severity regardless of the genetic background. Further characterization of CD4(+) T cells revealed a similar bias towards IL-17 production and activated T cell phenotype in all SKG strains compared to respective wild type controls. Finally, transfer of SKG thymocytes conferred susceptibility to recipients, which confirm the intrinsic defect and pathogenicity of T cells. Overall, these results underline the strong impact that the W163C ZAP-70 mutation has on T cell-driven arthritis, and they support the use of the SKG model in black mice, which is useful for further investigations of this distinctive arthritis model to better understand autoimmunity.
Subject(s)
Arthritis, Experimental/genetics , Arthritis, Rheumatoid/genetics , Mutation/genetics , Th17 Cells/physiology , ZAP-70 Protein-Tyrosine Kinase/genetics , Animals , Autoimmunity/genetics , Clonal Selection, Antigen-Mediated , Disease Models, Animal , Genetic Predisposition to Disease , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Mutant Strains , Receptors, Antigen, T-Cell/metabolism , Signal Transduction/genetics , Species SpecificityABSTRACT
BACKGROUND: Over the last 15 years, many studies demonstrated the myogenic regenerative potential of bone marrow mesenchymal stem cells (BM-MSC), making them an attractive tool for the regeneration of damaged tissues. In this study, we have developed an animal model of esophagogastric myotomy (MY) aimed at determining the role of autologous MSC in the regeneration of the lower esophageal sphincter (LES) after surgery. METHODS: Syngeneic BM-MSC were locally injected at the site of MY. Histological and functional analysis were performed to evaluate muscle regeneration, contractive capacity, and the presence of green fluorescent protein-positive BM-MSC (BM-MSC-GFP(+) ) in the damaged area at different time points from implantation. KEY RESULTS: Treatment with syngeneic BM-MSC improved muscle regeneration and increased contractile function of damaged LES. Transplanted BM-MSC-GFP(+) remained on site up to 30 days post injection. Immunohistochemical analysis demonstrated that MSC maintain their phenotype and no differentiation toward smooth or striated muscle was shown at any time point. CONCLUSIONS & INFERENCES: Our data support the use of autologous BM-MSC to both improve sphincter regeneration of LES and to control the gastro-esophageal reflux after MY.
