Rulin Jia

Low-dose interleukin-2 treatment selectively modulates CD4 + T cell subsets in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease characterized by altered balance of activity between effector and regulatory CD4+ T cells. The homeostasis of CD4+ T cell subsets is regulated by interleukin (IL)-2, and reduced production of IL-2 by T cells is observed in individuals with SLE. Here we report that treatment with low-dose recombinant human IL-2 selectively modulated the abundance of regulatory T (Treg) cells, follicular helper T (TFH) cells and IL-17-producing helper T (TH17) cells, but not TH1 or TH2 cells, accompanied by marked reductions of disease activity in patients with SLE.

The role of anti-mutated citrullinated vimentin antibodies in the diagnosis of early rheumatoid arthritis.

Objective. Anti-mutated citrullinated vimentin (MCV) antibodies have been reported as a fairly sensitive serological marker of rheumatoid arthritis (RA). We evaluated the diagnostic value of anti-MCV in a large cohort of Chinese patients with early RA. Methods. One hundred seventy patients with early RA (< 1 yr duration), 66 with other rheumatic diseases, 10 with infectious diseases, and 60 healthy individuals were included in our study. Serum anti-MCV and second-generation anti-cyclic citrullinated peptide antibodies (anti-CCP2) were measured by ELISA, and rheumatoid factor (RF) was measured by rate nephelometry. The associated clinical data of patients with early RA were also evaluated. Then disease activity was scored by the formula for Disease Activity Score (DAS)28, and the degree of radiological changes was assessed by Sharp score. Results. The prevalence of serum anti-MCV in patients with early RA (78.2%, 133/170) was significantly higher than that of other rheumatologic patients and patients with infectious diseases. It was 12% (3/25) in systemic lupus erythematosus, 9.5% (2/21) in primary Sjögren’s syndrome, 10% (1/10) in systemic sclerosis, 20% (2/10) in ankylosing spondylitis, 12.5% (1/8) in viral hepatitis type B, and 0% (0/2) in tuberculosis. Anti-MCV was not found in the serum of healthy subjects. The sensitivities of anti-MCV, anti-CCP2, and RF tests for early RA were 78.2%, 61.8%, and 72.4%, respectively, and the specificities were 93.4%, 96.3%, and 80.1%. The combination of anti-MCV and anti-CCP2 positivity showed a very high specificity (97.8%) and positive predictive value (97.1%), but a low sensitivity (58.8%). The sensitivity reached 81.2% when the union of anti-MCV and anti-CCP2 positivities was used as one combined criterion. Statistically, anti-MCV had significant correlation with anti-CCP2 (r = 0.587, p = 0.01, 2-tailed) and RF (r = 0.389, p = 0.01, 2-tailed). In addition, it had an interesting correlation with radiological assessment (r = 0.349, p = 0.05, 2-tailed). The anti-MCV had no significant correlation with other factors, such as erythrocyte sedimentation rate, C-reactive protein, antikeratin antibody, antiperinuclear factor, global visual analog scale score for joint pain, IgA, IgG, IgM, C3, C4, hidden rheumatoid factor for IgA (HRFIgA), HRFIgG, and DAS28. Conclusion. Anti-MCV is a novel diagnostic marker for early RA. It may be more useful if the anti-CCP2 assay is performed concomitantly to diagnose patients with early RA.

Hypoxia-Inducible Factor-1α and Interleukin 33 Form a Regulatory Circuit to Perpetuate the Inflammation in Rheumatoid Arthritis

Hyperplasia of synovial fibroblasts, infiltration with inflammatory cytokines, and tissue hypoxia are the major characteristics of rheumatoid arthritis (RA). Interleukin 33 (IL-33) is a newly identified inflammatory cytokine exacerbating the disease severity of RA. Hypoxia-inducible factor-1α (HIF-1α) showed increased expression in RA synovium and could regulate a number of inflammatory cytokine productions. Nevertheless, its correlation with IL-33 remains largely unknown. Here, we showed that elevated levels of IL-33 were demonstrated in RA patient synovial fluids, with upregulated expression of HIF-1α and IL-33 in the synovial fibroblasts. Knocking down HIF-1α compromised IL-33 expression in rheumatoid arthritis synovial fibroblasts (RASF), while enforcing HIF-1α expression in RASF substantially upregulated IL-33 levels. HIF-1α promoted the activation of the signalling pathways controlling IL-33 production, particularly the p38 and ERK pathways. Moreover, we showed for the first time that IL-33 in turn could induce more HIF-1α expression in RASF, thus forming a HIF-1α/IL-33 regulatory circuit that would perpetuate the inflammatory process in RA. Targeting this pathological pathway and HIF-1α may provide new therapeutic strategies for overcoming the persistent and chronic inflammatory disease.

Elevated serum and synovial fluid TNF-like ligand 1A (TL1A) is associated with autoantibody production in patients with rheumatoid arthritis.

Objectives: Tumour necrosis factor (TNF)-like ligand 1A (TL1A) is involved in rheumatoid arthritis (RA) but its clinical relevance in RA has not been fully elucidated. We analysed TL1A levels in the serum and synovial fluid (SF) of RA patients and investigated its clinical significance. Methods: TL1A levels were measured by enzyme-linked immunosorbent assay (ELISA) in 109 RA patients, 29 patients with osteoarthritis (OA), and 126 healthy controls. Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor immunoglobulin G (RF-IgG) were tested by ELISA. RF-IgM, anti-keratin antibody (AKA), and anti-perinuclear factor (APF) antibodies, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and immunoglobulins were measured by standard laboratory techniques. The associations between TL1A and the clinical and serological features of RA were analysed. Results: TL1A concentrations were significantly elevated in both serum and SF of RA patients compared with OA patients and healthy controls. TL1A levels in RA SF were significantly higher than those in matched serum. A positive correlation was found between SF and serum TL1A levels. Serum TL1A concentrations were associated with RA-specific autoantibodies including RFs (RF-IgG, RF-IgM) and anti-citrullinated protein antibodies. Antibody production by peripheral blood mononuclear cells (PBMCs) from RA patients was elevated upon TL1A stimulation. However, there was no correlation between serum or SF TL1A levels and RA disease activity. Conclusions: TL1A levels are significantly elevated in RA serum and SF and positively correlated with autoantibody production in RA, but failed as a disease activity marker. TL1A promotes antibody production by PBMCs from RA patients. The role of TL1A in the humoral autoimmune response may be important in the development of RA.

Association of STAT4 gene polymorphism with increased susceptibility of rheumatoid arthritis in a northern Chinese Han subpopulation

Several studies have reported STAT4 polymorphism is strongly associated with increased susceptibility to rheumatoid arthritis (RA). However, a study from China showed no association between STAT4 and RA susceptibility in a Chinese Han subpopulation. Since the northern Hans are known to be genetically different from the southern Hans, the aim of this study was to investigate the association of STAT4 polymorphism with RA in a large cohort of a northern Chinese Han subpopulation.

Significance of Antibodies Against the Native Ribosomal P Protein Complex and Recombinant P0, P1, and P2 Proteins in the Diagnosis of Chinese Patients with Systemic Lupus Erythematosus

This study aimed to evaluate autoantibodies against the native ribosomal P complex (anti‐Rib‐PC) and recombinant ribosomal P proteins (anti‐Rib‐P0, anti‐Rib‐P1, anti‐Rib‐P2) for their prevalence, diagnostic relevance and clinical associations in a Chinese cohort with systemic lupus erythematosus (SLE).

The Clinical Relevance of IL-17-Producing CD4+CD161+ Cell and Its Subpopulations in Primary Sjögren's Syndrome

Objective. Th17 cells have been demonstrated to play an important role in the onset and development of primary Sjögrens syndrome (pSS). In this study, we evaluated the expansion and clinical significance of circulating CD4+CD161+ T cell and its “effector” (CD4+CD25−CD161+ T cell) and “regulatory” (CD4+CD25+CD161+ T cell) subpopulations. Methods. Fifty-eight pSS patients and 16 healthy controls (HCs) were recruited in our study. The cell populations and intracellular IL-17 expression were analyzed by flow cytometry. The disease activity was evaluated by the EULAR-SS Disease Activity Index (ESSDAI). Autoantibodies were measured by ELISA or indirect immunofluorescence assay. Results. The CD161+ T cell fractions showed higher proportions of IL-17-producing cells. The frequencies of the overall CD4+CD161+ T cell population and its effector subset were positively correlated with disease activity parameters and more severe disease manifestations. A significant elevation of the CD4+CD25+CD161+ T cell subpopulation was observed in the peripheral blood of pSS patients compared to HCs and this subset showed decreased regulatory functions compared with the CD4+CD25+CD161− population. Conclusion. Circulating CD4+CD161+ T cell populations associated with pSS disease activity and severity. These cells might be involved in the development of pSS and could be potential therapeutic targets in the treatment of pSS.

Antilymphocyte antibodies in systemic lupus erythematosus: Association with disease activity and lymphopenia

Purpose. We analyzed the prevalence, clinical correlation, and the functional significance of ALA in patients with systemic lupus erythematosus (SLE). Methods. ALA IgG was detected by indirect immunofluorescence in the serum of 130 SLE patients, 75 patients with various rheumatic diseases, and 45 healthy controls (HC). Results. The sensitivity and specificity of ALA IgG in SLE were 42.3% and 96.7%, respectively. ALA was observed in 55.6% (50/90) of patients with lymphopenia, which was significantly higher than in patients with normal lymphocytes (5/40, 12.5%; P < 0.001). Patients with active SLE showed higher ALA positivity (60.9%) than those with inactive disease (24.2%; χ 2 = 17.925; P < 0.001). ALA correlated significantly with hypocomplementemia, anti-dsDNA antibodies, and higher SLEDAI scores. The incidences of ALA in SLE patients who were seronegative for anti-dsDNA, anti-Sm, or both antibodies were 32.9% (26/79), 41.0% (43/105), and 32.4% (22/68), respectively. The ALA-positive group also had higher incidences of neuropsychiatric SLE (NPSLE) and lupus nephritis (LN). In multivariate analyses, ALA was independently associated with lymphopenia, higher SLEDAI scores, and increased risk for LN. ALA titers significantly decreased as clinical disease was ameliorated following treatment. Conclusions. ALA occurred more frequently in patients with active SLE and was independently associated with lymphopenia, disease activity, and LN.

GITRL is associated with increased autoantibody production in patients with rheumatoid arthritis.

The study aimed to determine the serum level of glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) in patients with rheumatoid arthritis (RA) and investigate its clinical significance. GITRL levels were measured by enzyme-linked immunosorbent assay (ELISA) in 88 RA patients, 20 osteoarthritis (OA) patients, and 20 healthy controls (HCs). Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor immunoglobulin G (RF-IgG) were also tested by ELISA. RF-IgM, anti-keratin antibody (AKA), and anti-perinuclear factor (APF) antibodies and the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and immunoglobulins were measured by standard laboratory techniques. The disease activity was evaluated by the 28-joint count Disease Activity Score (DAS28). GITRL concentrations were significantly elevated in both serum and synovial fluid (SF) of RA patients. GITRL levels in RA sera were significantly higher than those in matched SFs. Positive correlations were found between serum GITRL levels and inflammation parameters or autoantibody production. GITRL levels are significantly elevated in RA serum and SF and are positively correlated with autoantibody production in RA, suggesting a role of GITRL in the development of RA.

Establishment of a decision tree model for diagnosis of early rheumatoid arthritis by proteomic fingerprinting.

The objective of this study was to identify proteomic biomarkers specific for rheumatoid arthritis (RA) by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF‐MS) in combination with weak cationic exchange (WCX) magnetic beads.