Anti-CD4 monoclonal antibody treatment in acute and early chronic antigen-induced arthritis: influence on T helper cell activation

Because IL-1β plays an important role in inflammation in human and murine arthritis, we investigated the contribution of the inflammasome components ASC, NALP-3, IPAF, and caspase-1 to inflammatory arthritis. We first studied the phenotype of ASC-deficient and wild-type mice during Ag-induced arthritis (AIA). ASC−/− mice showed reduced severity of AIA, decreased levels of synovial IL-1β, and diminished serum amyloid A levels. In contrast, mice deficient in NALP-3, IPAF, or caspase-1 did not show any alteration of joint inflammation, thus indicating that ASC associated effects on AIA are independent of the classical NALP-3 or IPAF inflammasomes. Because ASC is a ubiquitous cytoplasmic protein that has been implicated in multiple cellular processes, we explored other pathways through which ASC may modulate inflammation. Ag-specific proliferation of lymph node and spleen cells from ASC-deficient mice was significantly decreased in vitro, as was the production of IFN-γ, whereas IL-10 production was enhanced. TCR ligation by anti-CD3 Abs in the presence or absence of anti-CD28 Abs induced a reduction in T cell proliferation in ASC−/− T cells compared with wild-type ones. In vivo lymph node cell proliferation was also significantly decreased in ASC−/− mice, but no effects on apoptosis were observed either in vitro or in vivo in these mice. In conclusion, these results strongly suggest that ASC modulates joint inflammation in AIA through its effects on cell-mediated immune responses but not via its implication in inflammasome formation.

Section: Discussionsupporting

confidence: 93%

Inflammatory Role of ASC in Antigen-Induced Arthritis Is Independent of Caspase-1, NALP-3, and IPAF

Kolly¹,

Karababa²,

Joosten

et al. 2009

“…Therefore, enhanced inflammatory response to Ag challenge in the IFN-␥ Ϫ/Ϫ mice is not attributed to augmented Ab production associated with complement activation, but rather to an increase of cellular effector mechanisms. Taken together, these findings clearly demonstrate that in the AIA model, which is mediated by Th cells (19,20), the absence of the characteristic Th1 cytokine IFN-␥ caused an aggravation and not a decline of inflammatory response. This response exemplifies the complexity and importance of IFN-␥ in autoimmune diseases.…”

Section: Discussionsupporting

confidence: 55%

“…The histopathological features of AIA include hyperplasia of the synovial lining; cellular infiltration of joints and periarticular tissue by neutrophils, macrophages, lymphocytes, and dendritic cells; pannus formation and destruction of cartilage and bone, all features resembling those of human RA. The similarities include also the therapeutic response to some drug treatments and the involvement of CD4 ϩ T cells in the perpetuation of arthritis (19,20). In the present study, we investigated the development of arthritis in IFN-␥-deficient (IFN-␥ Ϫ/Ϫ ) mice to determine the role of IFN-␥ in AIA.…”

Section: H Uman Rheumatoid Arthritis (Ra)mentioning

confidence: 99%

Exacerbation of Antigen-Induced Arthritis in IFN-γ-Deficient Mice As a Result of Unrestricted IL-17 Response

Irmler

Gajda

Bräuer

2007

121

103

Proinflammatory Th1 responses are believed to be involved in the induction and perpetuation of rheumatoid arthritis. However, the role of IFN-γ, the major cytokine produced by Th1 cells, is still incompletely defined. In the present study, we investigated the effects of IFN-γ deficiency (IFN-γ−/−) on the course of experimental murine Ag-induced arthritis (AIA). In the acute stage of disease, IFN-γ−/− AIA mice showed significantly increased inflammatory responses compared with wild-type C57BL/6 AIA mice, i.e., exacerbated joint swelling, increased delayed-type hypersensitivity reaction, and increased histopathological scores of arthritis. Intraarticular administration of exogenous IFN-γ at induction of AIA significantly suppressed these acute aggravation effects. Stimulated cells isolated from lymph nodes and spleen of IFN-γ−/− AIA mice showed increased production of IL-2, IL-4, IL-5, IL-6, but most prominently of IL-17. These elevations were paralleled by decreased humoral immune responses, with low serum levels of total and Ag-specific IgG (IgG1, IgG2ab, IgG2b, IgG3). At immunohistology, the knee joints of IFN-γ−/− AIA mice showed massive neutrophil granulocyte infiltration. Treatment with mAbs neutralizing IL-17 diminished the acute inflammation. In vitro, Th cell expansion and production of IL-17 upon restimulation were effectively and dose dependently inhibited by IFN-γ. These results clearly demonstrate that IFN-γ has anti-inflammatory properties during the initial phase of AIA, and indicate that IFN-γ deficiency exerts disease-promoting effects, preferentially via IL-17-modulated pathways.

“…The mBSA-induced arthritis mouse model is a suitable and reproducible experimental system that exhibits several features with histopathological findings similar to those observed in human RA, including cartilage degradation (22). In this model, the adaptive immune response is dependent on CD4 + T cells and, to a lesser extent, is mediated by serum Ab (23). Therefore, we used this model to explore the role of NOD1 and NOD2 in the pathogenesis of experimental arthritis.…”

Section: Discussionmentioning

confidence: 99%

Joint NOD2/RIPK2 Signaling Regulates IL-17 Axis and Contributes to the Development of Experimental Arthritis

Vieira

Cunha

Franca

et al. 2012

Intracellular pattern recognition receptors such as the nucleotide-binding oligomerization domain (NOD)-like receptors family members are key for innate immune recognition of microbial infection and may play important roles in the development of inflammatory diseases, including rheumatic diseases. In this study, we evaluated the role of NOD1 and NOD2 on development of experimental arthritis. Ag-induced arthritis was generated in wild-type, NOD1−/−, NOD2−/−, or receptor-interacting serine-threonine kinase 2−/− (RIPK2−/−) immunized mice challenged intra-articularly with methylated BSA. Nociception was determined by electronic Von Frey test. Neutrophil recruitment and histopathological analysis of proteoglycan lost was evaluated in inflamed joints. Joint levels of inflammatory cytokine/chemokine were measured by ELISA. Cytokine (IL-6 and IL-23) and NOD2 expressions were determined in mice synovial tissue by RT-PCR. The NOD2−/− and RIPK2−/−, but not NOD1−/−, mice are protected from Ag-induced arthritis, which was characterized by a reduction in neutrophil recruitment, nociception, and cartilage degradation. NOD2/RIPK2 signaling impairment was associated with a reduction in proinflammatory cytokines and chemokines (TNF, IL-1β, and CXCL1/KC). IL-17 and IL-17 triggering cytokines (IL-6 and IL-23) were also reduced in the joint, but there is no difference in the percentage of CD4+ IL-17+ cells in the lymph node between arthritic wild-type and NOD2−/− mice. Altogether, these findings point to a pivotal role of the NOD2/RIPK2 signaling in the onset of experimental arthritis by triggering an IL-17–dependent joint immune response. Therefore, we could propose that NOD2 signaling is a target for the development of new therapies for the control of rheumatoid arthritis.