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1.
Interleukin-7 levels may predict virological response in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy 总被引:1,自引:1,他引:1
Boulassel MR Smith GH Gilmore N Klein M Murphy T MacLeod J LeBlanc R Allan J René P Lalonde RG Routy JP 《HIV medicine》2003,4(4):315-320
Objectives
To examine the relationship between levels of the T‐cell regulatory cytokine interleukin‐7 (IL‐7) and CD4 cell counts during immune reconstitution and to assess its prognostic value in advanced HIV‐1‐infected patients receiving lopinavir/ritonavir‐based therapy.Methods
Thirty‐six HIV‐1‐infected adults who completed 48 weeks of follow‐up visits were included in this prospective study. Patients having failed two or more antiretroviral therapy regimens were treated with lopinavir/ritonavir‐based therapy. An enzyme‐linked immunosorbent assay was used to determine IL‐7 plasma levels, flow cytometry was used to analyse cell surface antigens, and polymerase chain reaction was used to quantify plasma HIV‐1.Results
Pretreatment IL‐7 levels were elevated in all patients (mean 11.0 pg/mL) and were negatively correlated with CD4 cell counts and age (r=?0.59, P<0.001 and r=?0.57, P<0.001, respectively). During the course of treatment, IL‐7 levels decreased by 34% while CD4 cell numbers progressively increased by 88%. Multivariate regression analysis showed that only pretreatment IL‐7 levels predicted viral load at 48 weeks when controlling for baseline CD4 cell counts, viral load and patient demographics.Conclusions
These findings are consistent with regulation of T‐cell recovery by IL‐7, and suggest that IL‐7 measurements might be used to predict virological response.2.
Sarita A. Y. Hartgring Joel A. G. van Roon Marion Wenting‐van Wijk Kim M. G. Jacobs Zalima N. Jahangier Cynthia R. Willis Johannes W. J. Bijlsma Floris P. J. G. Lafeber 《Arthritis \u0026amp; Rheumatology》2009,60(9):2595-2605
Objective
To evaluate the expression and functional ability of the high‐affinity interleukin‐7 receptor (IL‐7Rα) in patients with rheumatoid arthritis (RA).Methods
Expression of IL‐7Rα and IL‐7 was determined in synovial tissue from RA patients and was compared with that in synovial tissue from patients with undifferentiated arthritis (UA) and osteoarthritis (OA). IL‐7Rα expression on CD4 T cells, CD19 B cells, and CD14 monocyte/macrophages from RA synovial tissue, synovial fluid, and peripheral blood was also assessed. The proliferative capacity of IL‐7Rαbright and IL‐7Rαdim/− T cells was measured. In addition, we examined IL‐7R blockade with soluble human IL‐7Rα (hIL‐7Rα) in the prevention of immune activation of peripheral blood mononuclear cells.Results
We found significantly higher IL‐7Rα expression in RA and UA synovial tissue than in OA synovial tissue, and the level of IL‐7Rα expression correlated significantly with the levels of CD3 and IL‐7 expression. CD4 T cells from RA synovial fluid and synovial tissue strongly expressed IL‐7Rα. A substantial percentage of B cells and macrophages from RA synovial fluid and synovial tissue also expressed IL‐7Rα, although less prominently than T cells. We found that peripheral blood IL‐7Rαbright T cells that did not express FoxP3 were highly proliferative as compared with IL‐7Rαdim/− T cells that did express high levels of FoxP3. Soluble hIL‐7Rα inhibited IL‐7–induced proliferation and interferon‐γ production by mononuclear cells from RA patients.Conclusion
Our data suggest that enhanced expression of IL‐7Rα and IL‐7 in RA patients contributes significantly to the joint inflammation by activating T cells, B cells, and macrophages. The inhibition of IL‐7R–mediated immune activation by soluble hIL‐7Rα further indicates an important role of IL‐7Rα in inflammatory responses in RA, suggesting IL‐7Rα as a therapeutic target for immunotherapy in RA.3.
Joel A. G. van Roon Marieke C. Verweij Marion Wenting‐van Wijk Kim M. G. Jacobs Johannes W. J. Bijlsma Floris P. J. G. Lafeber 《Arthritis \u0026amp; Rheumatology》2005,52(6):1700-1710
Objective
To determine the level of intraarticular expression of interleukin‐7 (IL‐7) in patients with rheumatoid arthritis (RA) and to investigate the mechanisms by which IL‐7 facilitates activation of CD4+ T cells and monocyte/macrophages in RA.Methods
IL‐7 levels were measured in synovial fluid obtained from patients with RA and patients with osteoarthritis (OA). Immunohistologic analysis was used to assess the expression of IL‐7 in synovial tissue from patients with RA. Proliferation and activation markers were determined in order to measure the effect of IL‐7 on mononuclear cells, isolated CD4+ T cells, and monocyte/macrophages from the peripheral blood and synovial fluid. Cocultures of CD4+ T cells and monocytic cells in the absence or presence of a semipermeable membrane were performed to assess the extent to which IL‐7 induces its effects, either contact dependently or via soluble mediators.Results
IL‐7 levels were increased in synovial fluid from patients with RA compared with the levels in synovial fluid from patients with OA. Macrophages, fibroblasts, and endothelial cells in the joint lining tissue expressed abundant IL‐7. In vitro, synovial fluid CD4+ T cells and macrophages were hyperresponsive to IL‐7 when compared with peripheral blood cells. Furthermore, IL‐7 enhanced cell contact–dependent activation of CD4+ T cells and monocyte/macrophages.Conclusion
The abundant intraarticular expression of IL‐7 and the stimulation by IL‐7 of contact‐dependent activation of CD4+ T cells and monocytic cells indicate that this cytokine plays an important proinflammatory role in RA synovitis. Further identification of IL‐7–induced pathways may improve understanding of the important interactive role of CD4+ T cells and monocytic cells in RA.4.
Objective
To analyze the frequency, surface phenotype, and cytokine secretion of CD4+ T cells in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS) compared with both healthy control subjects and patients with rheumatoid arthritis (RA).Methods
Eight‐color flow cytometry was used to analyze the surface phenotype and cytokine production of PBMCs from 20 patients with AS, 12 patients with RA, and 16 healthy control subjects, following stimulation ex vivo with phorbol myristate acetate and ionomycin for 5 hours. Secretion of interleukin‐17 (IL‐17) by PBMCs was measured by enzyme‐linked immunosorbent assay, following stimulation with anti‐CD3/CD28 for 4 days.Results
The percentages of IL‐17–positive CD4+ T cells and IL‐22–positive CD4+ T cells were increased in the PBMCs of both patients with AS and patients with RA compared with healthy control subjects, whereas there were no differences in the percentages of interferon‐γ (IFNγ)–positive or IL‐10–positive CD4+ T cells. Likewise, concentrations of IL‐17 in supernatants from patients with AS were significantly higher compared with those from healthy control subjects. In patients with RA, the concentrations of IL‐17 were increased but not significantly. There was a correlation between the percentages of IL‐17–positive CD4+ T cells detected in PBMCs and the amounts of IL‐17 in culture supernatants (r = 0.414, P = 0.0034). All IL‐17–producing cells were CD4+CD45RO+; most expressed both CCR6 and CCR4, but only 50% expressed the IL‐23 receptor (IL‐23R). Nevertheless, there was a positive relationship between the percentage of IL‐23R–positive CD4+ T cells and the frequency of IL‐17–positive CD4+ T cells or IL‐22–positive CD4+ T cells (r = 0.57, P < 0.0001 and r = 0.46, P = 0.001, respectively). A significant proportion of cells that produced IL‐17 also produced IL‐22 and IFNγ, but none produced IL‐10.Conclusion
The frequencies of IL‐17–positive and IL‐22–positive CD4+ T cells were increased in PBMCs from patients with AS and patients with RA, resulting in secretion of higher quantities of IL‐17 by PBMCs following stimulation. These data support the hypothesis that Th17 cells, particularly when present in excess of IL‐10–producing cells, are involved in the pathogenesis of inflammatory arthritis.5.
S Ghezzi F Pacciarini S Nozza S Racca SA Mariani E Vicenzi A Lazzarin F Veglia G Tambussi G Poli 《HIV medicine》2010,11(5):349-352
Objective
To investigate the impact of intermittent interleukin‐2 (IL‐2) plus combination antiretroviral therapy (cART) on HIV‐1 entry co‐receptor use.Methods
Primary HIV‐1 isolates were obtained from 54 HIV‐1‐positive individuals at baseline and after 12 months using co‐cultivation of peripheral blood mononuclear cells (PBMC) with activated PBMC of HIV‐negative healthy donors. HIV‐1 co‐receptor use was determined on U87‐CD4 cells.Results
Fourteen out of the 21 (67%) IL‐2‐treated individuals harbouring a primary CCR5‐dependent (R5) HIV‐1 isolate at baseline confirmed an R5 virus isolation after 12 months in contrast to 3 out of 7 (43%) of those receiving cART only. After 12 months, only 1 R5X4 HIV‐1 isolate was obtained from 21 cART+IL‐2‐treated individuals infected with an R5 virus at entry (5%) vs. 2/7 (29%) patients receiving cART alone, as confirmed by a 5‐year follow‐up on some individuals.Conclusions
Intermittent IL‐2 administration plus cART may prevent evolution towards CXCR4 usage in individuals infected with R5 HIV‐1.6.
7.
Ester Hidalgo Sarah J. Essex Lorraine Yeo S. John Curnow Andrew Filer Mark S. Cooper Andrew M. Thomas Helen M. McGettrick Michael Salmon Christopher D. Buckley Karim Raza Dagmar Scheel‐Toellner 《Arthritis \u0026amp; Rheumatology》2011,63(11):3284-3293
Objective
Interleukin‐6 (IL‐6) is a proinflammatory cytokine with regulatory effects on the survival and differentiation of T cells. It exerts its biologic function in 2 ways: by directly binding to the IL‐6 receptor (IL‐6R; CD126) or via trans‐signaling, in which soluble IL‐6R/IL‐6 complexes bind to the signaling component CD130. This study was undertaken to assess the expression and regulation of CD126 and CD130 and determine how these affect the response of CD4+ T cells to IL‐6 in the joints of patients with rheumatoid arthritis (RA).Methods
Flow cytometry and immunofluorescence microscopy were used to determine the expression, function, and regulation of CD126 and CD130 in CD4+ T cells from the peripheral blood (PB), synovial fluid (SF), and synovial tissue of RA patients.Results
Compared to the findings in RA PB, CD4+ T cells in the SF and synovial tissue expressed low levels of CD126. In contrast, whereas CD4+ T cell expression of CD130 was minimal in the SF, its level in the synovial tissue was high. Consistent with this phenotype, synovial tissue T cells responded to trans‐signaling by soluble IL‐6R/IL‐6 complexes, whereas no response was evident in CD4+ T cells from the SF. Down‐regulation of both receptor components in SF T cells could be explained by exposure to high levels of IL‐6. Increased levels of CD130 messenger RNA and protein in synovial tissue CD4+ T cells suggested that CD130 is up‐regulated locally. Among a range of cytokines tested, only IL‐10 induced CD130 expression in T cells.Conclusion
The inflamed microenvironment in the synovial tissue maintains responsiveness to IL‐6 trans‐signaling through the up‐regulation of CD130 expression in CD4+ T cells, and this process may be driven by IL‐10.8.
M. Kiene E. Csernok A. Müller C. Metzler A. Trabandt W. L. Gross 《Arthritis \u0026amp; Rheumatology》2001,44(2):469-473
Objective
To investigate cytokine production patterns of T cell lines (TCL) from patients with Churg‐Strauss syndrome (CSS).Methods
Short‐term polyclonal TCL were generated from peripheral blood of patients with CSS or Wegener's granulomatosis (WG) and healthy controls (HC). TCL were established in the presence of interleukin‐2 (IL‐2) and phytohemagglutinin and were phenotypically characterized by flow cytometry. Th1/Th2 cytokine production by stimulated TCL (72 hours) was analyzed by enzyme‐linked immunosorbent assay.Results
TCL that represented the progeny of in vivo–activated T cells from CSS patients displayed a heterogeneous immunophenotype, with a predominance of CD4+ T cells when compared with WG TCL, which were predominantly CD8+. All CSS TCL shared the ability to produce large amounts of interferon‐γ (IFNγ), IL‐4, and IL‐13 compared with HC (P = 0.014 for all 3). Production of IL‐4 and IL‐13 was higher in CSS TCL than in WG TCL (P = 0.014 for both). IL‐5 production was up‐regulated in WG TCL compared with CSS TCL (P = 0.014). Compared with HC, WG TCL showed increased production of IFNγ (P = 0.021), IL‐5 (P = 0.043), and IL‐13 (P = 0.021).Conclusion
Our results indicate that, while there is evidence for both a type 1 and a type 2 response in CSS, type 2 cytokine production pattern appears to predominate in this disease when compared with WG and HC.9.
Sarita A. Y. Hartgring Cynthia R. Willis Dina Alcorn Laurel J. Nelson Johannes W. J. Bijlsma Floris P. J. G. Lafeber Joel A. G. van Roon 《Arthritis \u0026amp; Rheumatology》2010,62(9):2716-2725
Objective
To study the effects of interleukin‐7 receptor α‐chain (IL‐7Rα) blockade on collagen‐induced arthritis (CIA) and to investigate the effects on T cell numbers, T cell activity, and levels of proinflammatory mediators.Methods
We studied the effect of anti–IL‐7Rα antibody treatment on inflammation and joint destruction in CIA in mice. Numbers of thymocytes, splenocytes, T cell subsets, B cells, macrophages, and dendritic cells were assessed. Cytokines indicative of Th1, Th2, and Th17 activity and several proinflammatory mediators were assessed by multianalyte profiling in paw lysates. In addition, T cell–associated cytokines were measured in supernatants of lymph node cell cultures.Results
Anti–IL‐7Rα treatment significantly reduced clinical arthritis severity in association with reduced radiographic joint damage. Both thymic and splenic cellularity were reduced after treatment with anti–IL‐7Rα. IL‐7Rα blockade specifically reduced the total number of cells as well as numbers of naive, memory, CD4+, and CD8+ T cells from the spleen and significantly reduced T cell–associated cytokines (interferon‐γ, IL‐5, and IL‐17). IL‐7Rα blockade also decreased local levels of proinflammatory cytokines and factors associated with tissue destruction, including tumor necrosis factor α, IL‐1β, IL‐6, matrix metalloproteinase 9, and RANKL. IL‐7Rα blockade did not significantly affect B cells, macrophages, and dendritic cells. B cell activity, indicated by serum anticollagen IgG antibodies, was not significantly altered.Conclusion
Blockade of IL‐7Rα potently inhibited joint inflammation and destruction in association with specific reductions of T cell numbers, T cell–associated cytokines, and numerous mediators that induce inflammation and tissue destruction. This study demonstrates an important role of IL‐7R–driven immunity in experimental arthritis and indicates the therapeutic potential of IL‐7Rα blockade in human arthritic conditions.10.
Kiran Nistala Halima Moncrieffe Katy R. Newton Hemlata Varsani Patricia Hunter Lucy R. Wedderburn 《Arthritis \u0026amp; Rheumatology》2008,58(3):875-887
Objective
To identify interleukin‐17 (IL‐17)–producing T cells from patients with juvenile idiopathic arthritis (JIA), and investigate their cytokine production, migratory capacity, and relationship to Treg cells at sites of inflammation, as well as to test the hypothesis that IL‐17+ T cell numbers correlate with clinical phenotype in childhood arthritis.Methods
Flow cytometry was used to analyze the phenotype, cytokine production, and chemokine receptor expression of IL‐17–producing T cells in peripheral blood and synovial fluid mononuclear cells from 36 children with JIA, in parallel with analysis of forkhead box P3 (FoxP3)–positive Treg cells. Migration of IL‐17+ T cells toward CCL20 was assessed by a Transwell assay. Synovial tissue was analyzed by immunohistochemistry for IL‐17 and IL‐22.Results
IL‐17+ T cells were enriched in the joints of children with JIA as compared with the blood of JIA patients (P = 0.0001) and controls (P = 0.018) and were demonstrated in synovial tissue. IL‐17+ T cell numbers were higher in patients with extended oligoarthritis, the more severe subtype of JIA, as compared with patients with persistent oligoarthritis, the milder subtype (P = 0.046). Within the joint, there was an inverse relationship between IL‐17+ T cells and FoxP3+ Treg cells (r = 0.61, P = 0.016). IL‐17+,CD4+ T cells were uniformly CCR6+ and migrated toward CCL20, but synovial IL‐17+ T cells had variable CCR4 expression. A proportion of IL‐17+ synovial T cells produced IL‐22 and interferon‐γ.Conclusion
This study is the first to define the frequency and characteristics of “Th17” cells in JIA. We suggest that these highly proinflammatory cells contribute to joint pathology, as indicated by relationships with clinical phenotypes, and that the balance between IL‐17+ T cells and Treg cells may be critical to outcome.11.
Francesco Ciccia Antonina Accardo‐Palumbo AnnaRita Giardina Piera Di Maggio Alfonso Principato Michele Bombardieri Aroldo Rizzo Riccardo Alessandro Angelo Ferrante Simona Principe Sergio Peralta Francesco Conte Sandro Drago Antonio Craxì Giacomo De Leo Giovanni Triolo 《Arthritis \u0026amp; Rheumatology》2010,62(12):3625-3634
12.
Stphane Genevay Francesco S. Di Giovine Thomas V. Perneger Tania Silvestri Sibylle Stingelin Gordon Duff Pierre‐Andr Guerne 《Arthritis care & research》2002,47(3):303-309
Objective
To perform a genetic association study using markers in the interleukin‐1 (IL‐1) gene cluster and the IL‐4/IL‐4 receptor system genes, seeking evidence for involvement in the onset or the erosive outcome of rheumatoid arthritis (RA).Methods
We tested the allelic distribution of IL‐1A (+4845), IL‐1B (−511), IL‐1B (+3954), IL‐1RN (+2018), IL‐4 variable number of tandem repeat (VNTR), and IL‐4R (+1902) in 233 patients with RA, 99 with polymyalgia rheumatica, and 148 ethnically matched controls. We analyzed the frequency of these gene variants in respect to presence of disease, but also to the degree of radiologic erosions (Larsen score) as a function of disease duration in 157 patients who had available radiographs of both hands.Results
None of the 6 genetic polymorphisms was significantly different in frequency between RA patients and healthy controls or patients with polymyalgia rheumatica. Among RA patients, the rarer (#2) alleles of IL‐4 VNTR and IL‐1B (−511) were both associated with a milder Larsen score progression: The slope of Larsen progression in the rare allele groups diverged significantly from those of the frequent allele groups after approximately 20 years of disease duration (P < 0.001).Conclusion
None of the markers tested were shown to be associated with increased or decreased risk of RA. The rarer alleles of IL‐4 VNTR and IL‐1B (−511) appear to be associated with a less severe course in RA of long duration.13.
Mathilde de Menthon Marion Lambert Elsa Guiard Sara Tognarelli Boris Bienvenu Alexandre Karras Loïc Guillevin Sophie Caillat‐Zucman 《Arthritis \u0026amp; Rheumatology》2011,63(7):2116-2126
Objective
Granulomatosis with polyangiitis (Wegener's) (GPA) is a rare systemic vasculitis of unknown etiology. Contribution of T cell–mediated immunity is suggested by the presence of granulomatous inflammation and T cell infiltrates in different tissues. We undertook this study to determine whether CD4+ T cells aberrantly expressing the NKG2D activating receptor might participate in the pathophysiology of the disease.Methods
We performed a detailed phenotype and functional analysis of CD4+ T cells in a cohort of 90 GPA patients (37 with localized GPA and 53 with generalized GPA) in comparison with 39 age‐matched controls.Results
We observed circulating innate‐like CD4+ T cells expressing an assortment of activating natural killer (NK) cell receptors (NKG2D, 2B4, DNAX‐associated molecule 1, and some killer cell Ig‐like receptors) and their signaling partners. Expansions of NKG2D+CD4+ T cells greater than a critical threshold of 3% yielded 100% specificity for generalized vasculitis versus localized granulomatosis, suggesting their participation in endothelium damage. Excessive interleukin‐15 (IL‐15) transpresentation through increased expression of IL‐15 receptor α (IL‐15Rα), together with abnormal expression of major histocompatibility complex (MHC) class I chain–related A protein on monocyte/macrophages, induced abnormal expansion of NKG2D+CD4+ T cells. These cells were primed in vivo to exert direct, MHC‐independent cytotoxicity toward microvascular endothelial cells expressing the cognate ligands of NK cell receptors.Conclusion
Our results suggest that NK cell–like CD4+ T cells might be the driving force of the vasculitis in GPA, and point to IL‐15 as an important mediator in the progression of GPA toward generalized vasculitis. IL‐15/IL‐15Rα antagonists may thus become novel therapeutic tools to decrease the pool of NK cell receptor–positive CD4+ T cells in selected GPA patients.14.
Ryan Webb Joan T. Merrill Jennifer A. Kelly Andrea Sestak Kenneth M. Kaufman Carl D. Langefeld Julie Ziegler Robert P. Kimberly Jeffrey C. Edberg Rosalind Ramsey‐Goldman Michelle Petri John D. Reveille Graciela S. Alarcn Luis M. Vil Marta E. Alarcn‐Riquelme Judith A. James Gary S. Gilkeson Chaim O. Jacob Kathy L. Moser Patrick M. Gaffney Timothy J. Vyse Swapan K. Nath Peter Lipsky John B. Harley Amr H. Sawalha 《Arthritis \u0026amp; Rheumatology》2009,60(8):2402-2407
Objective
Interleukin‐21 (IL‐21) is a member of the type I cytokine superfamily that has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. The expression of IL‐21 receptor (IL‐21R) is reduced in the B cells of patients with systemic lupus erythematosus (SLE), while serum IL‐21 levels are increased both in lupus patients and in some murine lupus models. We recently reported that polymorphisms within the IL21 gene are associated with increased susceptibility to SLE. The aim of this study was to examine the genetic association between single‐nucleotide polymorphisms (SNPs) within IL21R and SLE.Methods
We genotyped 17 SNPs in the IL21R gene in 2 large cohorts of lupus patients (a European‐derived cohort and a Hispanic cohort) and in ethnically matched healthy controls.Results
We identified and confirmed the association between rs3093301 within the IL21R gene and SLE in the 2 cohorts (meta‐analysis odds ratio 1.16 [95% confidence interval 1.08–1.25], P = 1.0 × 10−4).Conclusion
Our findings indicate that IL21R is a novel susceptibility gene for SLE.15.
16.
Joost Frenkel Ger T. Rijkers Saskia H. L. Mandey Sandra W. M. Buurman Sander M. Houten Ronald J. A. Wanders Hans R. Waterham Wietse Kuis 《Arthritis \u0026amp; Rheumatology》2002,46(10):2794-2803
Objective
To investigate whether the increased interleukin‐1β (IL‐1β) secretion in hyperimmunoglobulinemia D and periodic fever syndrome is due to the accumulation of mevalonate kinase (MK), the substrate of the deficient enzyme, or the lack of its products, the isoprenoid compounds.Methods
The effects of lovastatin and farnesol (FOH), geranylgeraniol (GGOH), and mevalonate on peripheral blood mononuclear cells (PBMCs) from 8 patients with MK deficiency and from 13 controls were studied. Lovastatin inhibits isoprenoid biosynthesis by reducing the production of mevalonate. FOH and GGOH restore isoprenoid biosynthesis downstream from MK. Culture supernatants were collected for cytokine analysis 48 hours after stimulation with monoclonal antibodies against CD2 + CD28.Results
Lovastatin induced a 15‐fold rise in IL‐1β secretion by normal anti–CD2 + CD28–stimulated cells (P < 0.001). This effect could be countered by mevalonate and, to a lesser extent, by FOH and GGOH. In the absence of lovastatin, mevalonate did not change IL‐1β secretion. Stimulated MK‐deficient cells secreted 9‐fold more IL‐1β than control PBMCs (P < 0.005), rising 2.4‐fold in the presence of lovastatin. The effect of lovastatin on IL‐1β secretion was reduced by mevalonate, FOH, and GGOH. Isoprenoid biosynthesis in PBMCs from patients was impaired due to the endogenous MK deficiency. Bypassing this defect with FOH, in the absence of lovastatin, led to a 62% reduction (P < 0.02) in IL‐1β secretion by these cells.Conclusion
In this model, shortage of isoprenoid end products contributes to increased IL‐1β secretion by MK‐deficient PBMCs, whereas excess mevalonate does not.17.
Trieneke C. G. Timmer Belinda Baltus Mark Vondenhoff Tom W. J. Huizinga Paul P. Tak Cornelis L. Verweij Reina E. Mebius Tineke C. T. M. van der Pouw Kraan 《Arthritis \u0026amp; Rheumatology》2007,56(8):2492-2502
Objective
In ∼25% of synovial tissues from rheumatoid arthritis (RA) patients, infiltrates of T cells, B cells, and follicular dendritic cells (FDCs) are spatially organized into structures resembling lymph nodes with germinal centers. The remainder of the tissues lack FDCs and show either a diffuse or an aggregated T cell and B cell infiltrate. To gain more insight into this specific disease process, we sought to identify the genes expressed in RA tissues with ectopic lymphoid structures.Methods
Gene expression profiling of RA synovial tissues was determined by complementary DNA microarray analysis and quantitative real‐time polymerase chain reaction. The presence of lymphoid follicles and localization of interleukin‐7 (IL‐7) in synovial tissue sections was determined by immunofluorescence staining using specific antibodies.Results
Findings of gene expression analysis confirmed previous reports that tissues with lymphoid structures showed elevated expression of CXCL13, CCL21, CCR7, and lymphotoxin α and β messenger RNA. In addition, the tissues also showed enhanced expression of the chemokines CXCL12 and CCL19 and the associated receptors CXCR4 and CXCR5, which are important for the attraction of T cells, B cells, and dendritic cells. Pathway analysis revealed increased expression of genes involved in JAK/STAT signaling, T cell– and B cell–specific pathways, Fcε receptor type I signaling in mast cells, and IL‐7 signal transduction in the tissues with ectopic lymphoid follicles, accompanied by increased expression of IL‐7 receptor α (IL‐7Rα)/IL‐2Rγ chains and IL‐7. Protein expression of IL‐7 in RA tissues was localized within fibroblast‐like synoviocytes, macrophages, and blood vessels and was colocalized with extracellular matrix structures around the B cell follicles.Conclusion
Activation of the IL‐7 pathway may play an important role in lymphoid neogenesis, analogous to its role in the development of normal lymphoid tissue.18.
Maxime Samson Sylvain Audia Nona Janikashvili Marion Ciudad Malika Trad Jennifer Fraszczak Paul Ornetti Jean‐Francis Maillefert Pierre Miossec Bernard Bonnotte 《Arthritis \u0026amp; Rheumatology》2012,64(8):2499-2503
Objective
From an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti–interleukin‐6 (anti–IL‐6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL‐6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL‐6 blockade on the balance between Th17 cells and Treg cells in patients with active RA.Methods
Patients with active RA for whom TCZ had been prescribed by a rheumatologist were enrolled in this study. Phenotypic analyses of T cell populations were performed, and the Disease Activity Score in 28 joints (DAS28) was assessed. Serum cytokine levels and other parameters of inflammation were measured before the first infusion and after the third infusion of TCZ (8 mg/kg).Results
Compared to controls, levels of Th17 cells (CD4+IL‐17+) were increased and Treg cells (CD4+CD25highFoxP3+) were decreased in the peripheral blood of patients with active RA. The suppressive function of circulating Treg cells was not impaired in patients with active RA. TCZ treatment induced a significant decrease in the DAS28 associated with a significant decrease in the percentage of Th17 cells (from a median of 0.9% to 0.45%; P = 0.009) and an increase in the percentage of Treg cells (from a median of 3.05% to 3.94%; P = 0.0039) in all patients.Conclusion
This study demonstrates for the first time that inhibition of IL‐6 function by TCZ corrects the imbalance between Th17 cells and Treg cells in patients with RA.19.
20.
Iryna Prots Alla Skapenko Jrg Wendler Stefan Mattyasovszky Clarisse L. Yon Bernd Spriewald Harald Burkhardt Rolf Rau Joachim R. Kalden Peter E. Lipsky Hendrik Schulze‐Koops 《Arthritis \u0026amp; Rheumatology》2006,54(5):1491-1500