Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression.

INTRODUCTION: Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to systematically analyse the phenotype, cytokine profile and frequency of interleukin-17 (IL-17) producing CD4-positive T cells in mononuclear cells isolated from peripheral blood, synovial fluid and synovial tissue of RA patients with established disease, and to correlate cell frequencies with disease activity. METHODS: Flow cytometry was used to analyse the phenotype and cytokine production of mononuclear cells isolated from peripheral blood (PBMC) (n = 44), synovial fluid (SFMC) (n = 14) and synovium (SVMC) (n = 10) of RA patients and PBMC of healthy controls (n = 13). RESULTS: The frequency of IL-17-producing CD4 T cells was elevated in RA SFMC compared with RA PBMC (P = 0.04). However, the frequency of this population in RA SVMC was comparable to that in paired RA PBMC. The percentage of IL-17-producing CD4 T cells coexpressing tumor necrosis factor alpha (TNFα) was significantly increased in SFMC (P = 0.0068). The frequency of IFNγ-producing CD4 T cells was also significantly higher in SFMC than paired PBMC (P = 0.042). The majority of IL-17-producing CD4 T cells coexpressed IFNγ. IL-17-producing CD4 T cells in RA PBMC and SFMC exhibited very little IL-22 or IL-23R coexpression. CONCLUSIONS: These findings demonstrate a modest enrichment of IL-17-producing CD4 T cells in RA SFMC compared to PBMC. Th17 cells in SFMC produce more TNFα than their PBMC counterparts, but are not a significant source of IL-22 and do not express IL-23R. However, the percentage of CD4 T cells which produce IL-17 in the rheumatoid joint is low, suggesting that other cells may be alternative sources of IL-17 within the joints of RA patients.

The influence of head size and sex on the outcome of Birmingham hip resurfacing.

BACKGROUND: Hip resurfacing has gained popularity for the treatment of young and active patients who have arthritis. Recent literature has demonstrated an increased rate of revision among female patients as compared with male patients who have undergone hip resurfacing. The aim of the present study was to identify any differences in survival or functional outcome between male and female patients with osteoarthritis who were managed with metal-on-metal hip resurfacing. METHODS: A prospective collection of data on all patients undergoing Birmingham Hip Resurfacing at a single institution was commenced in July 1997. On the basis of the inclusion and exclusion criteria, 1826 patients (2123 hips, including 799 hips in female patients and 1324 hips in male patients) with a diagnosis of osteoarthritis who had undergone the procedure between July 1997 and December 2008 were identified. The variables of age, sex, preoperative Oxford Hip Score, component size used, surgical approach, lead surgeon, and surgeon experience were analyzed. A multivariate Cox proportional hazard survival model was used to identify which variables were most influential for determining revision. RESULTS: The mean duration of follow-up was 3.46 years (range, 0.03 to 10.9 years). The five-year cumulative survival rate for the 655 hips that were followed for a minimum of five years was 97.5% (95% confidence interval, 96.3% to 98.3%). There were forty-eight revisions. Revision was significantly associated with female sex (hazard rate, 2.03 [95% confidence interval, 1.15 to 3.58]; p = 0.014) and decreasing femoral component size (hazard rate per 4-mm decrease in size, 4.68 [95% confidence interval, 4.36 to 5.05]; p < 0.001). Revision was not associated with age (p = 0.88), surgeon (p = 0.41), surgeon experience (p = 0.30), or surgical approach (p = 0.21). A multivariate analysis including the covariates of sex, age, surgeon, surgeon experience, surgical approach, and femoral component size demonstrated that sex was no longer significantly associated with revision when femoral component size was included in the model (p = 0.37). Femoral component size alone was the best predictor of revision when all covariates were analyzed (hazard rate per 4-mm decrease in size, 4.87 [95% confidence interval, 4.37 to 5.42]; p < 0.001). CONCLUSIONS: The present study demonstrates that although female patients initially may appear to have a greater risk of revision, this increased risk is related to differences in the femoral component size and thus is only indirectly related to sex. Patient selection for hip resurfacing is best made on the basis of femoral head size rather than sex.

Galectin 3 induces a distinctive pattern of cytokine and chemokine production in rheumatoid synovial fibroblasts via selective signaling pathways.

OBJECTIVE: High expression of galectin 3 at sites of joint destruction in rheumatoid arthritis (RA) suggests that galectin 3 plays a role in RA pathogenesis. Previous studies have demonstrated the effects of galectins on immune cells, such as lymphocytes and macrophages. This study was undertaken to investigate the hypothesis that galectin 3 induces proinflammatory effects in RA by modulating the pattern of cytokine and chemokine production in synovial fibroblasts. METHODS: Matched samples of RA synovial and skin fibroblasts were pretreated with galectin 3 or tumor necrosis factor alpha (TNFalpha), and the levels of a panel of cytokines, chemokines, and matrix metalloproteinases (MMPs) were determined using enzyme-linked immunosorbent assays and multiplex assays. Specific inhibitors were used to dissect signaling pathways, which were confirmed by Western blotting and NF-kappaB activation assay. RESULTS: Galectin 3 induced secretion of interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor, CXCL8, and MMP-3 in both synovial and skin fibroblasts. By contrast, galectin 3-induced secretion of TNFalpha, CCL2, CCL3, and CCL5 was significantly greater in synovial fibroblasts than in skin fibroblasts. TNFalpha blockade ruled out autocrine TNFalpha-stimulated induction of chemokines. The MAPKs p38, JNK, and ERK were necessary for IL-6 production, but phosphatidylinositol 3-kinase (PI 3-kinase) was required for selective CCL5 induction. NF-kappaB activation was required for production of both IL-6 and CCL5. CONCLUSION: Our findings indicate that galectin 3 promotes proinflammatory cytokine secretion by tissue fibroblasts. However, galectin 3 induces the production of mononuclear cell-recruiting chemokines uniquely from synovial fibroblasts, but not matched skin fibroblasts, via a PI 3-kinase signaling pathway. These data provide further evidence of the role of synovial fibroblasts in regulating the pattern and persistence of the inflammatory infiltrate in RA and suggest a new and important functional consequence of the observed high expression of galectin 3 in the rheumatoid synovium.

Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: site-specific versus activation-dependent survival of T cells and neutrophils.

OBJECTIVE: Synovial fibroblasts share a number of phenotype markers with fibroblasts derived from bone marrow. In this study we investigated the role of matched fibroblasts obtained from 3 different sources (bone marrow, synovium, and skin) to test the hypothesis that synovial fibroblasts share similarities with bone marrow-derived fibroblasts in terms of their ability to support survival of T cells and neutrophils. METHODS: Matched synovial, bone marrow, and skin fibroblasts were established from 8 different patients with rheumatoid arthritis who were undergoing knee or hip surgery. Resting or activated fibroblasts were cocultured with either CD4 T cells or neutrophils, and the degree of leukocyte survival, apoptosis, and proliferation were measured. RESULTS: Fibroblasts derived from all 3 sites supported increased survival of CD4 T cells, mediated principally by interferon-beta. However, synovial and bone marrow fibroblasts shared an enhanced site-specific ability to maintain CD4 T cell survival in the absence of proliferation, an effect that was independent of fibroblast activation or proliferation but required direct T cell-fibroblast cell contact. In contrast, fibroblast-mediated neutrophil survival was less efficient, being independent of the site of origin of the fibroblast but dependent on prior fibroblast activation, and mediated solely by soluble factors, principally granulocyte-macrophage colony-stimulating factor. CONCLUSION: These results suggest an important functional role for fibroblasts in the differential accumulation of leukocyte subsets in a variety of tissue microenvironments. The findings also provide a potential explanation for site-specific differences in the pattern of T cell and neutrophil accumulation observed in chronic inflammatory diseases.

Metatarsal head resection in the rheumatoid foot: 5-year follow-up with and without resection of the first metatarsal head.

Twenty-nine patients (45 feet) who underwent metatarsal head resections for rheumatoid forefoot deformities were reviewed retrospectively at a mean follow-up of 6.57 years (range, 5-9.3 years). Resections were confined to the lesser metatarsal heads in 16 feet because of a lack of involvement in the first metatarsal head. In the remaining 29 feet, all metatarsal heads were resected. A questionnaire was provided to assess subjective outcomes. Thirty-three feet (73.3%) had no pain or only mild pain, 5 feet (11%) had moderate pain, and 7 (15.5%) had severe pain. Among the 29 feet with panmetatarsal head resections, 5 (17%) required revision of metatarsal stumps at an average follow-up of 55.2 months (range, 17-84 months; standard deviation, 26.88). Among the 16 feet with only lesser metatarsal head resections, 7 (43.75%) required subsequent first metatarsal head resections at an average follow-up period of 33.14 months (range, 13-56 months; standard deviation, 16.54). In conclusion, metatarsal head resection is a simple procedure that gives long-term pain relief in over two thirds of the patients who have rheumatoid forefoot deformities. A high rate of recurrence of pain and subsequent resection of first metatarsal head is noted if it is not resected primarily. We recommend a low threshold for the inclusion of some form of primary reconstruction of the first metatarsophalangeal joint when resection arthroplasty is performed on the lesser toes.

The role of leukocyte-stromal interactions in chronic inflammatory joint disease.

Rheumatoid arthritis (RA) is a debilitating, chronic, persistent inflammatory disease that is characterised by painful and swollen joints. The aetiology of RA is unknown, however whereas past research has concentrated on the role of immune or inflammatory infiltrating cells in inflammation, it is becoming clear that stromal cells play a critical part in regulating the quality and duration of an inflammatory response. In this review we assess the role of fibroblasts within the inflamed synovium in modulating immune responses; in particular we examine the role of stromal cells in the switch from resolving to persistent inflammation as is found in the rheumatoid synovium.

Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue.

OBJECTIVE: A characteristic feature of the inflammatory infiltrate in rheumatoid arthritis is the segregation of CD4 and CD8 T lymphocyte subsets into distinct microdomains within the inflamed synovium. The aim of this study was to test the hypothesis that chemokines in general and stromal cell-derived factor 1 (SDF-1; CXCL12) in particular are responsible for generating this distinctive microcompartmentalization. METHODS: We examined how synovial CD4/CD8 T cell subsets interacted in coculture assays with fibroblasts derived from chronic inflammatory synovial lesions and normal synovial tissue as well as from fetal lung and adult skin. We used the ability of T cells to migrate beneath fibroblasts (a process called pseudoemperipolesis) as an in vitro marker of T cell accumulation within synovial tissue. RESULTS: Rheumatoid fibroblast-like synoviocytes (FLS) displayed a unique ability to support high levels of CD4 and CD8 T cell pseudoemperipolesis. Nonrheumatoid FLS as well as fetal lung fibroblasts supported low levels of pseudoemperipolesis, while skin-derived fibroblasts were unable to do so. CD8 T cells migrated under fibroblasts more efficiently and at a higher velocity than CD4 T cells, a feature that was intrinsic to CD8 T cells. Rheumatoid fibroblasts constitutively produced high levels of SDF-1 (CXCL12), which was functionally important, since blocking studies showed reductions in T cell pseudoemperipolesis to levels seen in nonrheumatoid FLS. Rheumatoid fibroblasts also constitutively produced high levels of vascular cell adhesion molecule 1 (VCAM-1; CD106), but this did not contribute to T cell pseudoemperipolesis, unlike the case for B cells, which require SDF-1 (CXCL12)-CXCR4 and CD49d-VCAM-1 (CD106) interactions. Importantly, only combinations of rheumatoid FLS and rheumatoid-derived synovial fluid T cells supported pseudoemperipolesis when examined ex vivo, confirming the in vivo relevance of these findings. CONCLUSION: These studies demonstrate that features intrinsic to both fibroblasts (the production of SDF-1) and CD8/CD4 T cells (the expression of CXCR4) are responsible for the characteristic pattern of T lymphocyte accumulation seen in the rheumatoid synovium. These findings suggest that the SDF-1/CXCR4 ligand/receptor pair is likely to play an important functional role in T lymphocyte accumulation and positioning within the rheumatoid synovium.