CD4+CD25+ regulatory T cells in rheumatoid arthritis: Differences in the presence, phenotype, and function between peripheral blood and synovial fluid

Objective. The cartilage proteins melanoma inhibitory activity (MIA) and human cartilage gp-39 (HC gp-39) are candidate autoantigens in rheumatoid arthritis (RA). The present study was undertaken to investigate the endogenous HLA-DR4-restricted presentation of these self proteins, in order to seek in vivo evidence in support of their potential immunologic role. The mechanisms that cause and sustain rheumatoid arthritis (RA) remain poorly elucidated. The association of the disease with certain class II major histocompatibility complex (MHC) haplotypes, however, strongly suggests that specific antigens are presented by antigen-presenting cells (APCs) to CD4ϩ T lymphocytes (1,2). Previous studies indicate that cartilage could be the source of some of these antigens in RA (3-7). In the present study we investigated the local presence and presentation of 2 cartilage-derived proteins that have distinct properties: human cartilage gp-39 (HC gp-39) and a protein called melanoma inhibitory activity (MIA).

Section: Discussionmentioning

confidence: 99%

“…In healthy individuals these cells may have a role in preserving natural immune homeostasis, a function that is suppressed in RA (42). However, so far, the presence of functional HC gp-39-specific T cells in SF has been difficult to detect, possibly due to local T cell exhaustion or suppression (37)(38)(39)(40)42,43).…”

Section: Discussionmentioning

confidence: 99%

Endogenous HLA–DR–restricted presentation of the cartilage antigens human cartilage gp‐39 and melanoma inhibitory activity in the inflamed rheumatoid joint

Lierop¹,

Hoed²,

Houbiers³

et al. 2007

“…CD25 is generally known as a marker of the IL-2 receptor on T lymphocytes and functions as a marker of regulatory or suppressor T cells (17,18). However, CD25 is not only a marker for regulatory T cells, but is also transiently upregulated on activated nonregulatory T cells independently stimulated by CD69 (19). Regardless, when CD4ϩ cell suspensions from BALB/c nu/ϩ mice were depleted of CD25ϩ cells and then injected into athymic BALB/c mice, all recipients developed autoimmune disease (20).…”

Section: Discussionmentioning

confidence: 99%

Cell markers, cytokines, and immune parameters in cement mason apprentices

Carlsten¹,

Roos²,

Kaufman³

et al. 2007

Objective. Cement masons are known to have significant silica exposure, and silica exposure and silicosis are thought to increase risk of autoimmune disease. Because the mechanisms remain obscure, with inconclusive reports of systemic immune effects following silica exposure, our goal was to identify potential early markers of silica-related immunologic and respiratory effects. Methods. We conducted a cross-sectional study of cement mason apprentices and electrician (control) apprentices. Demographics, dust exposure history, symptoms, spirometry, exhaled nitric oxide, and blood (for immunoglobulins, cytokines, cell counts, and surface markers) were obtained from 11 cement mason apprentices and a comparison group of 21 electrician apprentices. Results. Masons had significantly higher (P < 0.05) masonry dust exposure (42 versus 9 dust-hour-years), serum interleukin-1␤ (IL-1␤; 12 versus 9 pg/ml), IL-2 (20 versus 8 pg/ml), IL-4 (193 versus 67 pg/ml), IL-10 (44 versus 21 pg/ml), and interferon-␥ (139 versus 65 pg/ml) compared with electricians. In contrast, masons had significantly lower percentages of CD25؉ (12% versus 20%) and CD69؉ (4% versus 9%) lymphocytes. Conclusion. Mason apprentices had higher levels of serum proinflammatory cytokines and lower percentages of CD25؉ and CD69؉ lymphocytes than did electrician apprentices. These preliminary findings suggest that mason apprentices may be at greater risk of a systemic proinflammatory state that is potentially linked to immune dysregulation. Although distinct limitations of this preliminary data are recognized, this is consistent with early biologic effects leading to increased incidence of autoimmune disease among silica-exposed workers. Prospective studies are needed to validate these initial findings and clarify the temporal sequence of observed relationships.

“…Several studies have indicated that Treg cells confer significant protection against CIA by decreasing the activation and joint homing of autoreactive Th1 cells (3)(4)(5)(6). The observed down-regulation of the self-reactive Th1 response, together with the elevated levels of regulatory cytokines, prompted us to investigate the involvement of CII-specific Treg cells in the in vivo immunosuppressive activity of human AD-MSCs.…”

Section: Immune Tolerance Induction With Human Ad-mscs In Experimentamentioning

confidence: 99%

“…On the other hand, failures in the function of the Treg cell compartment can contribute to the development of RA, and enhancing the function of this compartment may also represent a therapeutic strategy (2)(3)(4)(5)(6).…”

mentioning

confidence: 99%

Treatment of experimental arthritis by inducing immune tolerance with human adipose‐derived mesenchymal stem cells

González¹,

González‐Rey²,

Rico³

et al. 2009

447

363

Objective. Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Adult mesenchymal stem cells (MSCs) were recently found to suppress effector T cell responses and to have beneficial effects in various immune disorders. The purpose of this study was to examine a new therapeutic strategy for RA based on the administration of human adipose-derived MSCs (AD-MSCs).Methods. DBA/1 mice with collagen-induced arthritis were treated with human AD-MSCs after disease onset, and clinical scores were determined. Inflammatory response was determined by measuring the levels of different mediators of inflammation in the joints and serum. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen. The number of Treg cells and the suppressive capacity on self-reactive Th1 cells were also determined.Results. Systemic infusion of human AD-MSCs significantly reduced the incidence and severity of experimental arthritis. This therapeutic effect was mediated by down-regulating the 2 deleterious disease components: the Th1-driven autoimmune and inflammatory responses. Human AD-MSCs decreased the production of various inflammatory cytokines and chemokines, decreased antigen-specific Th1/Th17 cell expansion, and induced the production of antiinflammatory interleukin-10 in lymph nodes and joints. Human ADMSCs also induced de novo generation of antigenspecific CD4؉CD25؉FoxP3؉ Treg cells with the capacity to suppress self-reactive T effector responses.Conclusion. Human AD-MSCs emerge as key regulators of immune tolerance by inducing the generation/activation of Treg cells and are thus attractive candidates for a cell-based therapy for RA.