Th1/Th17 polarization and acquisition of an arthritogenic phenotype in arthritis-susceptible BALB/c, but not in MHC-matched, arthritis-resistant DBA/2 mice

Abstract

Proteoglycan (PG) aggrecan-induced arthritis (PGIA) is a murine model of rheumatoid arthritis (RA). Although BALB/c and DBA/2 mice share the same MHC (H-2d) haplotype, the BALB/c strain is susceptible to PGIA, while DBA/2 mice are resistant. Therefore, these two inbred mouse strains provide an opportunity to study arthritis susceptibility factors excluding the effects of MHC-associated genetic components. The goal of this study was to monitor changes in the cellular composition and activation state following intra-peritoneal (i.p.) immunization to induce PGIA; additionally, we sought to identify new susceptibility factors by comparing PG-induced immune responses in BALB/c and DBA/2 mice. Upon i.p. PG injection, resident naive B1 cells are replaced by both T cells and conventional B cells in the peritoneum of BALB/c mice. These peritoneal T cells produce IFNγ and IL-17, cytokines shown to be important in RA and corresponding arthritis models. Moreover, peritoneal cells can adoptively transfer PGIA to SCID mice, demonstrating their arthritogenic properties. Our results indicate that repeatedly injected antigen leads to the recruitment and activation of immune cells in the peritoneum; these cells then trigger the effector phase of the disease. The migration and activation of Th1/Th17 cells in the peritoneal cavity in response to PG immunization, which did not occur in the arthritis-resistant DBA/2 strain, may be critical factors of arthritis susceptibility in BALB/c mice.

Proteoglycan‐induced arthritis and recombinant human proteoglycan aggrecan G1 domain–induced arthritis in BALB/c mice resembling two subtypes of rheumatoid arthritis

“…PGIA has been postulated to be a Th1-type disease (26–29), with significant IL-17 production (30), where IFN-γ determines the requirement for IL-17 (29). Because the production of both IFN-γ and IL-17 were more robust in GIA than in PGIA, GIA could represent an intermediate form of the disease between the Th1- and Th17-mediated forms.…”

Critical proinflammatory role of thymic stromal lymphopoietin and its receptor in experimental autoimmune arthritis

“…This is also supported by the finding that TSLP administration could increase Th17 numbers (this study) and that TSLP-activated MDCs, from both the peripheral blood and the synovial fluid of RA patients, potently induced IL-17 by autologous CD4 T cells from the same patients (42). A selective reduction in IL-17 production could also explain the robustly reduced immunopathology in TSLPR Ϫ/Ϫ mice, since PGIA has been shown to be strongly Th17-dependent (41,43,44).…”

Peritoneal T lymphocyte regulation by macrophages

“…Among numerous research applications, the murine peritoneal cavity (PerC) has served immunology as a site to study inflammation in vivo and as a source of activated (thioglycollate- or peptone-elicited) myeloid cells for in vitro studies (Fortier 2001; Davies and Gordon 2005; Turchyn et al 2007; Boldizsar et al 2009). The resident myeloid cells of the PerC have been described both as inflammatory monocytes and as immature macrophages (LaGasse and Weissman 1996; Geissman et al 2003; Kamei and Carman 2010).…”