Structural and Functional Changes of the Invariant NKT Clonal Repertoire in Early Rheumatoid Arthritis.

Invariant NKT cells (iNKT) are potent immunoregulatory T cells that recognize CD1d via a semi-invariant TCR (iNKT-TCR). Despite the knowledge of a defective iNKT pool in several autoimmune conditions, including rheumatoid arthritis (RA), a clear understanding of the intrinsic mechanisms, including qualitative and structural changes of the human iNKT repertoire at the earlier stages of autoimmune disease, is lacking. In this study, we compared the structure and function of the iNKT repertoire in early RA patients with age- and gender-matched controls. We analyzed the phenotype and function of the ex vivo iNKT repertoire as well as CD1d Ag presentation, combined with analyses of a large panel of ex vivo sorted iNKT clones. We show that circulating iNKTs were reduced in early RA, and their frequency was inversely correlated to disease activity score 28. Proliferative iNKT responses were defective in early RA, independent of CD1d function. Functional iNKT alterations were associated with a skewed iNKT-TCR repertoire with a selective reduction of high-affinity iNKT clones in early RA. Furthermore, high-affinity iNKTs in early RA exhibited an altered functional Th profile with Th1- or Th2-like phenotype, in treatment-naive and treated patients, respectively, compared with Th0-like Th profiles exhibited by high-affinity iNKTs in controls. To our knowledge, this is the first study to provide a mechanism for the intrinsic qualitative defects of the circulating iNKT clonal repertoire in early RA, demonstrating defects of iNKTs bearing high-affinity TCRs. These defects may contribute to immune dysregulation, and our findings could be exploited for future therapeutic intervention.

Does obesity predict knee pain over fourteen years in women, independently of radiographic changes?

OBJECTIVE: To examine longitudinal patterns in body mass index (BMI) over 14 years and its association with knee pain in the Chingford Study. METHODS: We studied a total of 594 women with BMI data from clinic visits at years (Y) 1, 5, 10, and 15. Knee pain at Y15 was assessed by questionnaire. Associations between BMI over 14 years and knee pain at Y15 were examined using logistic regression. RESULTS: BMI significantly increased from Y1 to Y15 (P < 0.0005) with medians (interquartile ranges) of 24.5 kg/m(2) (22.5-27.2 kg/m(2) ) and 26.5 kg/m(2) (23.9-30.1 kg/m(2) ), respectively. At Y15, 45.1% of subjects had knee pain. A greater BMI at Y1 (odds ratio [OR] 1.34, 95% confidence interval [95% CI] 1.05-1.69), at Y15 (OR 1.34, 95% CI 1.10-1.61), and change in BMI over 15 years (OR 1.40, 95% CI 1.00-1.93) were significant predictors of knee pain at Y15 (P < 0.05). BMI change was associated with bilateral (OR 1.61, 95% CI 1.05-1.76, P = 0.024) but not unilateral knee pain (OR 1.22, 95% CI 0.73-1.76, P = 0.298). The association between BMI change and knee pain was independent of radiographic knee osteoarthritis (OA). The strength of association between BMI and knee pain at Y15 was similar during followup measurements. CONCLUSION: Over 14 years, a higher BMI predicts knee pain at Y15 in women, independently of radiographic knee OA. When adjusted, the association was significant in bilateral, not unilateral, knee pain, suggesting alternative pathologic mechanisms may exist. The longitudinal effect of BMI on knee pain at Y15 is equally important at any time point, which may assist reducing the population burden of knee pain.