Yingjun Ding

In this study, we investigated the hypothesis that regulatory T cells (Treg) are involved in the immunomodulatory effects of statins on rheumatoid arthritis (RA) patients. The 12-week study cohort consisted of 55 RA patients and 42 control subjects allocated to either a group treated with atorvastatin (AT) (20 mg/day) or a non-AT group. Treg numbers, suppressive function, serum inflammatory markers, and disease activity were evaluated before and after the therapy. Furthermore, the effects of AT on the frequency and suppressive function of Treg were determined in vitro. Our data revealed that the suppressive function of Treg from RA patients significantly decreased compared with that of control subjects. AT significantly reduced erythrosedimentation, C-reactive protein, and disease activity. Concomitantly, Treg numbers and suppressive functions were significantly improved by AT. Consistent with the in vivo experiments, AT promoted the generation of Treg from primary T cells and enhanced preexisting Treg function in vitro. Moreover, we showed that PI3K-Akt-mTOR and ERK signal pathways were involved in the induction of Treg by AT. In conclusion, AT significantly increased Treg numbers and restored their suppressive function in the RA patients, and this may be relevant in the modulation of uncontrolled inflammation in this disorder. In this study, we investigated the hypothesis that regulatory T cells (Treg) are involved in the immunomodulatory effects of statins on rheumatoid arthritis (RA) patients. The 12-week study cohort consisted of 55 RA patients and 42 control subjects allocated to either a group treated with atorvastatin (AT) (20 mg/day) or a non-AT group. Treg numbers, suppressive function, serum inflammatory markers, and disease activity were evaluated before and after the therapy. Furthermore, the effects of AT on the frequency and suppressive function of Treg were determined in vitro. Our data revealed that the suppressive function of Treg from RA patients significantly decreased compared with that of control subjects. AT significantly reduced erythrosedimentation, C-reactive protein, and disease activity. Concomitantly, Treg numbers and suppressive functions were significantly improved by AT. Consistent with the in vivo experiments, AT promoted the generation of Treg from primary T cells and enhanced preexisting Treg function in vitro. Moreover, we showed that PI3K-Akt-mTOR and ERK signal pathways were involved in the induction of Treg by AT. In conclusion, AT significantly increased Treg numbers and restored their suppressive function in the RA patients, and this may be relevant in the modulation of uncontrolled inflammation in this disorder. Regulatory T cells (Treg), a subset of T cells that constitutively expresses CD4 and CD25, play a crucial role in preventing autoimmune disorders and actively controlling autoimmune responses (1Brusko T.M. Putnam A.L. Bluestone J.A. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities.Immunol. Rev. 2008; 223: 371-390Crossref PubMed Scopus (302) Google Scholar). Foxp3, a member of the fork-head/winged-helix family of the transcriptional factor, has been identified as the best marker of Treg (2Zheng Y. Rudensky A. Foxp3 in the control of the regulatory T cell lineage.Nat. Immunol. 2007; 8: 457-462Crossref PubMed Scopus (566) Google Scholar). Recently, a downregulation of CD127 has been shown to be closely correlated with Foxp3 (3Liu W. Putnam A.L. Xu-Yu Z. Szot G.L. Lee M.R. Zhu S. Gottlieb P.A. Kapranov P. Gingeras T.R. Fazekas de St. Groth B. CD127 expression inversely correlates with FOXP3 and suppressive function of human CD4+ Treg cells.J. Exp. Med. 2006; 203: 1701-1711Crossref PubMed Scopus (2095) Google Scholar). Thus, it can be used as a reliable surface marker for Treg. It has been well documented that Treg are involved in the pathogenesis of autoimmune disorders, such as multiple sclerosis (4Viglietta V. Baecher-Allan C. Weiner H.L. Hafler D.A. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis.J. Exp. Med. 2004; 199: 971-979Crossref PubMed Scopus (1500) Google Scholar) and type 1 diabetes (5Tang Q. Henriksen K.J. Bi M. Finger E.B. Szot G. Ye J. Masteller E.L. McDevitt H. Bonyhadi M. Bluestone J.A. In vitro-expanded antigen-specific regulatory T cells suppress auto­immune diabetes.J. Exp. Med. 2004; 199: 1455-1465Crossref PubMed Scopus (989) Google Scholar), and they have certain protective effects. Rheumatoid arthritis (RA) is a chronic inflammatory arthropathy associated with systemic inflammation and often leads to clinically significant functional impairment. The etiology of RA is unclear. However, it is accepted that autoimmune responses play distinct roles in the pathogenesis of RA. Studies of experimental models of inflammatory arthritis have revealed that Treg are the protective regulators of the disorder (6Morgan M.E. Flierman R. van Duivenvoorde L.M. Witteveen H.J. van Ewijk W. van Laar J.M. de Vries R.R. Toes R.E. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells.Arthritis Rheum. 2005; 52: 2212-2221Crossref PubMed Scopus (328) Google Scholar, 7Morgan M.E. Sutmuller R.P. Witteveen H.J. van Duivenvoorde L.M. Zanelli E. Melief C.J. Snijders A. Offringa R. de Vries R.R. Toes R.E. CD25+ cell depletion hastens the onset of severe disease in collagen induced arthritis.Arthritis Rheum. 2003; 48: 1452-1460Crossref PubMed Scopus (262) Google Scholar, 8Nguyen L.T. Jacobs J. Mathis D. Benoist C. Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis.Arthritis Rheum. 2007; 56: 509-520Crossref PubMed Scopus (115) Google Scholar). However, to date, there is limited information about the role of Treg in RA (9Han G.M. O'Neil-Andersen N.J. Zurier R.B. Lawrence D.A. CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis.Cell. Immunol. 2008; 253: 92-101Crossref PubMed Scopus (112) Google Scholar, 10van Amelsfort J.M. Jacobs K.M. Bijlsma J.W. Lafeber F.P. Taams L.S. CD4+CD25+ regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid.Arthritis Rheum. 2004; 50: 2775-2785Crossref PubMed Scopus (437) Google Scholar, 11Möttönen M. Heikkinen J. Mustonen L. Isomäki P. Luukkainen R. Lassila O. CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis.Clin. Exp. Immunol. 2005; 140: 360-367Crossref PubMed Scopus (259) Google Scholar, 12de Kleer I.M. Wedderburn L.R. Taams L.S. Patel A. Varsani H. Klein M. de Jager W. Pugayung G. Giannoni F. Rijkers G. CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis.J. Immunol. 2004; 172: 6435-6443Crossref PubMed Scopus (333) Google Scholar, 13Valencia X. Stephens G. Goldbach-Mansky R. Wilson M. Shevach E.M. Lipsky P.E. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells.Blood. 2006; 108: 253-261Crossref PubMed Scopus (662) Google Scholar, 14Ehrenstein M.R. Evans J.G. Singh A. Moore S. Warnes G. Isenberg D.A. Mauri C. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF-α therapy.J. Exp. Med. 2004; 200: 277-285Crossref PubMed Scopus (1056) Google Scholar). Statins, which inhibit 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, have been shown to possess anti-inflammatory and immunomodulatory properties and contribute to cholesterol reduction (15Schönbeck U. Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors statins as antiinflammatory agents?.Circulation. 2004; 109: II18-II26Crossref PubMed Google Scholar). A number of studies have shown that statin treatment benefits RA patients, which may be partly due to its immunomodulatory properties (16Mäki-Petäjä K.M. Booth A.D. Hall F.C. Wallace S.M. Brown J. McEniery C.M. Wilkinson I.B. Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis.J. Am. Coll. Cardiol. 2007; 50: 852-858Crossref PubMed Scopus (229) Google Scholar, 17Kanda H. Yokota K. Kohno C. Sawada T. Sato K. Masao Y. Komagata Y. Shimada K. Yamamoto K. Mimura T. Effects of low-dosage simvastatin on rheumatoid arthritis through reduction of Th1/Th2 and CD4/CD8 ratios.Mod. Rheumatol. 2007; 17: 364-368Crossref PubMed Google Scholar). In this study, we employed both in vivo and in vitro strategies to evaluate the effects of statins on Treg in RA patients and tested the hypothesis that Treg are involved in the immunomodulatory effects of statins on RA patients. In this study, we enrolled 55 patients with active RA who fulfilled the 1987 American College of Rheumatology criteria for RA (18Arnett F.C. Edworthy S.M. Bloch D.A. McShane D.J. Fries J.F. Cooper N.S. Healey L.A. Kaplan S.R. Liang M.H. Luthra H.S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.Arthritis Rheum. 1988; 31: 315-324Crossref PubMed Scopus (18641) Google Scholar). A patient was determined to have active RA if he or she met at least two of the following criteria: (1) the patient had six tender joints, (2) 45 min of morning stiffness, and (3) three swollen joints. The inclusion criteria included a history of RA for at least 1 year of the ongoing active disease and the use of stable doses of disease-modifying antirheumatic drugs (DMARD) for at least 3 months before recruitment. Exclusion criteria included inability to give informed consent, pregnancy or lactation, dyslipidemia, use of any lipid-lowering medication, presence of known hepatic disease or elevated liver transaminase levels within the previous 3 months, and hydroxychloroquine treatment in the previous 3 months. We also included 42 control subjects matched by age and gender. The investigation conformed to the principles outlined in the Declaration of Helsinki. The trial was approved by the country's ethics committee, and the patients and controls provided written informed The patients to stable doses of anti-inflammatory drugs and the The subjects were allocated to either a group AT treatment (20 and control or a group that AT and for RA disease activity was evaluated the at the and after the therapy. was as van van de van disease activity that and in a study of patients with rheumatoid arthritis.Arthritis Rheum. PubMed Scopus Google Scholar). were at the and and at after the and serum was for the of cholesterol C-reactive and blood cells were and were used for The following were and from the surface cells were with for min at the of Foxp3, cells were and to the before was controls were used to for and to The were on a was to the was and The of the were as Foxp3 and and and The were with The expression of Foxp3 was with as a and was by the primary T cells and Treg were a regulatory to the were with a of T cells were and T cells were after with A of was for T cells and Treg by AT was in was tested as a was in 1 and with 1 to T cells from the RA patients were to the and at a of in with and and serum in the presence of and AT and was and the cells were for at in In experiments, and the inhibitors of ERK and were to the by or with AT. the suppressive function, T cells cells and Treg were at of and in of and were at the of the of was before the was The cells were and by Treg were and with after a with AT. Treg were with and tested the suppression were on the and were Treg were with AT. of 1 Treg and 1 T cells were with in well to a of were and and were to the The T cells from the RA patients were with AT for and with cell were a and the in the was determined a was used for and was by and to The were primary and at and by were A was are as or in and with and of or was used to differences two or a or was used for The of AT in vivo was a or within on the or was used for the multiple In a of was 1 the and characteristics of the study The of RA patients and control were with CD25, and The for the Treg is shown in phenotypic revealed that cells showed a expression of CD127 and a expression of and their regulatory Treg significantly between the RA patients and the control subjects of CD4+ T In with this Foxp3 expression in the to be between the RA patients and the control subjects and characteristics of the study group group cholesterol cholesterol cholesterol are as or rheumatoid C-reactive disease activity anti-inflammatory in a are as or rheumatoid C-reactive disease activity anti-inflammatory Treg and were by and tested in the suppression from the RA patients and the control subjects in the presence of of Treg function was by with at of and The data that the RA patients showed significantly reduced Treg suppression function compared with that of the control subjects for tested We also investigated Treg from the RA patients were to suppress and by T T cells from the RA patients and the control subjects may in their to and we the of by T cells from the two The in the of and in T cells from the RA patients compared with of the control subjects. Treg from the two were with T cells from the RA patients to their effects on In with the of the suppression Treg from the RA patients were at the of the two from the control group The of statins to responses has to in their use for the treatment of RA. we to the to statin in in the Treg RA patients and control subjects in study were allocated to either a group that AT (20 group and or that group and for that the RA patients and the control subjects with or AT treatment were at 3 the effects of statins on disease activity, and inflammatory of RA patients after AT a significant reduction in both and activity, as by decreased significantly by AT and were also reduced by AT was significantly by the A significant reduction in and was also in the control subjects AT after data characteristics of and cholesterol cholesterol cholesterol are as in a in serum and inflammatory in RA patients after of cholesterol cholesterol cholesterol are as in a are as are as showed a significant in Treg in RA patients or or of CD4+ T and the control subjects AT or or of CD4+ T compared with the and subjects AT AT showed on the of as a of was in subjects who AT or AT both at and after we compared the suppressive function of Treg after AT by a Treg suppressive function in patients who AT as it was at In there was a significant in the suppressive function of Treg in subjects AT or or that was in patients who AT. In the that statins are drugs for RA and that they the frequency of Treg and the suppressive function of cells in RA patients. we to the of the Treg. The T cells of the RA patients were to by shown in the of AT to RA T cells in a in the of The increased number of cells was by the of HMG-CoA that the effects of AT on Treg on HMG-CoA However, a also be in the of AT. Foxp3 is the best marker of previous studies J. A. van Toes R.E. expression of FOXP3 in human CD4+ T J. Immunol. 2007; PubMed Scopus Google Scholar) have a expression of Foxp3 in T by in vitro. we tested cells in the presence of AT were after the T cells were and with Our data that T cells in the presence of AT were to suppress the of AT the preexisting Treg were from the RA patients and with AT for and tested in the suppression The showed that AT increased the expression of Foxp3 in the Treg of the RA patients Consistent with this enhanced suppressive function was in Treg that were with AT effects of AT on Treg were in the control subjects the we the T cells from the RA patients with induced in cells and the cell for the of that cells significantly reduced levels of and ERK compared with of pathways that have been to be to the of Treg and were also was that the of ERK and the PI3K-Akt-mTOR was of the induction of AT on we tested treatment with ERK or a Treg. shown in primary T cells in the presence of or showed expression of both and Foxp3, as was the for AT. RA is a systemic autoimmune disease by a chronic that Treg are involved in the suppression of in human A. J. of regulatory T cells in patients with systemic 2003; PubMed Scopus Google Scholar, A. G. J. C. Z. K. S. M. M. Wilson B. in diabetes.J. 109: PubMed Scopus Google Scholar). it is that Treg are involved in the of rheumatoid In Treg depletion was shown to the of the adoptive transfer of Treg suppress the development of arthritis in the of collagen-induced that there is therapeutic for Treg activity in arthritis (6Morgan M.E. Flierman R. van Duivenvoorde L.M. Witteveen H.J. van Ewijk W. van Laar J.M. de Vries R.R. Toes R.E. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells.Arthritis Rheum. 2005; 52: 2212-2221Crossref PubMed Scopus (328) Google Scholar, 7Morgan M.E. Sutmuller R.P. Witteveen H.J. van Duivenvoorde L.M. Zanelli E. Melief C.J. Snijders A. Offringa R. de Vries R.R. Toes R.E. CD25+ cell depletion hastens the onset of severe disease in collagen induced arthritis.Arthritis Rheum. 2003; 48: 1452-1460Crossref PubMed Scopus (262) Google Scholar, 8Nguyen L.T. Jacobs J. Mathis D. Benoist C. Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis.Arthritis Rheum. 2007; 56: 509-520Crossref PubMed Scopus (115) Google Scholar). there has been on Treg in RA patients. The frequency of Treg in RA patients was to be either elevated (9Han G.M. O'Neil-Andersen N.J. Zurier R.B. Lawrence D.A. CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis.Cell. Immunol. 2008; 253: 92-101Crossref PubMed Scopus (112) Google Scholar) or Amelsfort J.M. Jacobs K.M. Bijlsma J.W. Lafeber F.P. Taams L.S. CD4+CD25+ regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid.Arthritis Rheum. 2004; 50: 2775-2785Crossref PubMed Scopus (437) Google Scholar, 11Möttönen M. Heikkinen J. Mustonen L. Isomäki P. Luukkainen R. Lassila O. CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis.Clin. Exp. Immunol. 2005; 140: 360-367Crossref PubMed Scopus (259) Google Scholar) by The be due to the use of strategies to Treg. In the study, we T cells with the phenotypic characteristics of to be Treg and that cells a to that in subjects. Our showed that the RA patients had numbers of Treg to that of the control Consistent with a previous X. Stephens G. Goldbach-Mansky R. Wilson M. Shevach E.M. Lipsky P.E. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells.Blood. 2006; 108: 253-261Crossref PubMed Scopus (662) Google Scholar), we a reduced of Treg to inhibit and by However, group of that Treg cells from RA patients showed a to suppress cell were for by cells M.R. Evans J.G. Singh A. Moore S. Warnes G. Isenberg D.A. Mauri C. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF-α therapy.J. Exp. Med. 2004; 200: 277-285Crossref PubMed Scopus (1056) Google Scholar). in between study and may be due to differences in the study the medication, the used to and or the suppression were In a role for Treg in the and we that the function of Treg may have to the of the in patients with RA. as immunomodulatory that the of T cells to expression and and cell function B. F. S. F. as a type of Med. PubMed Scopus Google Scholar). Our previous and experimental studies have that statins regulate responses and can be used to inflammatory X. J. B. H. J. M. B. Y. Y. Effects of on in patients with J. 2005; PubMed Scopus Google Scholar, J. X. B. Y. B. H. M. Y. Z. expression and in after 2005; PubMed Scopus Google Scholar, X. Y. C. T. X. J. M. R. Y. M. Th1/Th2 in patients with chronic PubMed Scopus Google Scholar, Y. T. Y. R. J. M. H. Y. X. M. by is associated with in both and activity in after J. Med. PubMed Scopus Google Scholar). statins are a treatment for RA patients, that statins have effects of the disease disease activity, inflammatory and endothelial function treatment for rheumatoid arthritis: a Rheumatol. 2008; PubMed Scopus Google Scholar). The of the of in Rheumatoid the trial of statin that AT is a for RA patients for both RA disease activity and systemic inflammatory activity, which were by and I.B. R. R. O. of in Rheumatoid 2004; PubMed Scopus Google Scholar). However, a cohort study showed that statins have any effects for disease inflammation, which was evaluated by the use of in RA patients S. Evans P. J. there anti-inflammatory of statins in rheumatoid of a J. PubMed Scopus Google Scholar). The effects of statins in RA patients were in the study, as by reduced and the immunomodulatory effects of statins on the Treg cells in vivo the role of cells in RA and the immunomodulatory effects of AT. In the study, we the effects of AT on the and function of Treg. Our that AT significantly increased the frequency of Treg in RA patients. A of Treg was in the control subjects after AT which is with the of and K. G. A. S. A. G. J. The of HMG-CoA reductase inhibitors on CD4+CD25+ T 2008; PubMed Scopus Google Scholar). We the of Treg they their and suppressive function, after in vitro for Our data also showed a restored suppressive function of Treg in the RA patients AT therapy. the protective role of Treg on experimental inflammatory arthritis H. L. T. D. G. P. CD4+CD25+ regulatory T cells inhibit and collagen-induced Rheum. PubMed Scopus Google Scholar), that the of Treg is associated with the effects of AT in RA. S. Mauri C. M.R. a distinct regulatory T cell in patients with rheumatoid arthritis Exp. Med. 2007; PubMed Scopus Google Scholar) that anti-TNF-α the number of Treg by a of Treg that In study, we the presence of a of Treg in RA patients after AT It that anti-TNF-α and AT through In the in vitro study, T primary cells showed a of as by the expression of and Foxp3 in the presence of AT following However, of the Treg the of Treg from human T cells we also a of T cells with the of Treg in the of and previous has a expression of Foxp3 in T cells by J. A. van Toes R.E. expression of FOXP3 in human CD4+ T J. Immunol. 2007; PubMed Scopus Google Scholar). Furthermore, the function was in the presence of the of a of AT to Treg. It has been that AT its anti-inflammatory effects both on J. L. and autoimmune from to Rev. Immunol. 2006; PubMed Scopus Google Scholar) and of S. T. L. Th1/Th2 in T a of modulation of by Exp. Med. 2006; 203: PubMed Scopus Google Scholar) the of HMG-CoA the of Treg is by the HMG-CoA reductase we with AT and that this the induction of Treg by AT. data that the anti-inflammatory effects of AT are by the HMG-CoA reductase the of cholesterol also reduce the of such as or the of the and Y. and 2005; PubMed Scopus Google Scholar). of PI3K-Akt-mTOR and ERK which regulate expression in T cells S. L. A. D. M. M. D. E. T cell controls Foxp3 expression and A. 2008; PubMed Scopus Google Scholar, X. Q. V. Z. Lee C. expression of Foxp3 in T cells is through of Immunol. 2008; PubMed Scopus Google Scholar), have been to be by AT in M. R. L.M. E. J. V. G. J. M. HMG-CoA reductase inhibitors role of and 2007; 50: PubMed Scopus Google Scholar, L. A. M. The the of atorvastatin in after in the 2007; PubMed Scopus Google Scholar). In study, we that AT the of ERK and PI3K-Akt-mTOR and or treatment of primary T cells the effects of AT on Treg. we that the of ERK and PI3K-Akt-mTOR be in the induction of Treg by AT. signal such as and have been also to be involved in the of Treg J. in regulatory T cell development and 2007; PubMed Scopus Google Scholar, L. Y. The of Foxp3 expression in regulatory cells: multiple pathways on the 2007; PubMed Scopus Google Scholar). However, we any effects of AT on for the preexisting Treg AT enhanced their suppressive function in vitro. In conclusion, we have the systemic inflammatory in RA patients by decreased Treg suppressive AT significantly the frequency and function of Treg and disease activity in patients with RA. is the study to the effects of statin on Treg in RA patients. of the of statins on Treg is to its role in the pathogenesis of the disorder also to its of the immunomodulatory its and its statin treatment is a for RA and chronic inflammatory control disease-modifying antirheumatic drugs C-reactive anti-inflammatory peripheral blood cell rheumatoid arthritis cholesterol regulatory T cell T cell

AIMS: Increasing evidences confirm the role of immune activation in the pathogenesis of chronic heart failure (CHF). Regulatory T cells appear central to the control of immune homeostasis. We assessed the hypothesis that the circulating frequency and function of CD4+CD25+ Foxp3+CD127(low) T regulatory cells (Tregs) would be deranged in patients with CHF. METHODS: Ninety-nine CHF patients due to non-ischemic (NIHF) or ischemic etiology (IHF) and 24 control donors were enrolled in the study. Frequency of circulating Tregs was evaluated by flow cytometry. Foxp3 in peripheral blood mononuclear cells (PBMCs) was assayed at the mRNA level by real-time PCR. Functional properties of Tregs to suppress proliferation and pro-inflammatory cytokines secretion of activated CD4+CD25(-) T cells were measured by proliferation assay and ELISA. RESULTS: The results demonstrated that CHF patients had significantly lower frequency of circulating Tregs and reduced Foxp3 expression in PBMCs compared with control donors. Moreover, Tregs from CHF patients showed compromised function to suppress CD4+CD25(-) T cells proliferation and pro-inflammatory cytokines secretion. A similar pattern with reduced Tregs frequency and compromised function was found in both NIHF and IHF patients. Correlation analysis suggested that Tregs frequency and function positively correlated with LVEF, whereas negatively correlated with LVEDD and NT-proBNP in patients with CHF. CONCLUSIONS: Our data are the first to demonstrate that frequencies of circulating Tregs in patients with CHF are reduced and their suppressive function compromised independently of the etiology. Defective Tregs may be an underlying mechanism of immune activation in CHF patients.

OBJECTIVE: To compare features of SS in RA with primary SS and RA without SS. METHODS: Patients hospitalized between January 2007 and December 2010 were retrospectively studied. Seventy-four cases of overlap RA and SS (RA/SS) among 509 cases of RA were identified. Cases of SS (n = 187) detected during the same period acted as controls. RESULTS: Among those with RA/SS, there were 46 cases of RA-onset SS and 12 cases of SS-onset RA. Sixteen patients had simultaneous-onset RA and SS. Compared with RA without SS, RA/SS patients had more severe arthritis; a higher incidence of haematological abnormality, fever and rash; and a higher frequency of RF, ANAs and anti-SSA and anti-SSB antibodies (P < 0.05). Compared with primary SS, RA/SS patients were older, had more severe arthritis, anaemia and lung involvement; a lower incidence of fever, rash, leucopenia, thrombocytopenia and hyperthyroidism; and a higher frequency of RF, anti-keratin antibody, anti-perinuclear factor and anti-cyclic citrullinated antibodies (P < 0.05). Compared with RA and primary SS, RA/SS patients had higher disease activity scores of both RA and SS. CONCLUSION: RA/SS patients have distinctive features, with more complications and systemic involvement. In addition, disease activity is higher in RA/SS.