scholarly journals Identification and function of T cells reactive with citrullinated vimentin in HLA-DRB1*0401 humanised mice and rheumatoid arthritis patients

2010 ◽  
Vol 69 (Suppl 2) ◽  
pp. A73-A73
Author(s):  
O Snir ◽  
M Rieck ◽  
K Klich ◽  
L Klareskog ◽  
J H Buckner ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Citrullinated Vimentin ◽  
Humanised Mice ◽  
And Function

CD101 Expression and Function in Normal and Rheumatoid Arthritis-affected Human T Cells and Monocytes/Macrophages

2010 ◽  
Vol 38 (3) ◽  
pp. 419-428 ◽  
Author(s):  
DRAGAN V. JOVANOVIC ◽  
LAURENCE BOUMSELL ◽  
ARMAND BENSUSSAN ◽  
XAVIER CHEVALIER ◽  
ARTURO MANCINI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Map Kinase ◽  
Surface Expression ◽  
P38 Map Kinase ◽  
Autoimmune Response ◽  
Human Immune System ◽  
Kinase Activation ◽  
And Function

Objective.It was recently reported that CD101 surface expression discriminates potency among CD4+CD25+ FoxP3+ regulatory T cells in the mouse. We investigated whether CD101 may also have a role in the suppressor function of regulatory T cells in humans given that the latter population may affect the autoimmune response in patients with rheumatoid arthritis (RA).Methods.Sorted T cells and monocyte/macrophage cell populations were analyzed by flow cyto metry using conjugated antibodies specific for cell-surface markers. T cell proliferation assays were conducted by [3H]thymidine incorporation and CD8highcytotoxicity measurements by Cyto-Scan-LDH cytotoxicity assays. ELISA were used to measure cytokines in cell culture supernatants and Western blotting was performed for profiling mitogen-activated protein (MAP) kinase activation using specific antiphospholipid antibodies.Results.CD101 expression coincided with PMA-induced monocyte/leukocyte lineage differentiation. CD8highCD101− T cells exhibited greater cytotoxic activity than CD8highCD101+ T cells, while no difference was observed between CD4CD25highCD101+ and CD4CD25highCD101− Treg inhibitory activity through responder T cells. LPS-induced proinflammatory cytokine production and p38 MAP kinase activation were made possible by ligation of CD101 with an anti-CD101 antibody F(ab’)2fragment.Conclusion.These results suggested a modulatory/coregulatory function of CD101 in the human immune system, in contrast to murine models, in which CD101 surface expression discriminates potency among FoxP3+ regulatory T cells. Cytotoxic CD8highCD101+ T cells were markedly less cytotoxic than CD8highT cells negative for the CD101 antigen and were conspicuously downregulated in patients with RA, suggesting a possible role for CD101 expression and function in the control of certain manifestations of RA pathology.

scholarly journals A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis

2013 ◽  
Vol 210 (12) ◽  
pp. 2569-2582 ◽  
Author(s):  
Stephen W. Scally ◽  
Jan Petersen ◽  
Soi Cheng Law ◽  
Nadine L. Dudek ◽  
Hendrik J. Nel ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Human Leukocyte ◽  
Healthy Individuals ◽  
Leukocyte Antigen ◽  
Cell Numbers ◽  
Autoreactive T Cell ◽  
Drb1 Locus ◽  
Citrullinated Vimentin

Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)-DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLA-DRB1*04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine–containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01+ individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4+ T cells in the peripheral blood of HLA-DRB1*04:01+ RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA.

A molecular basis for citrullination dependent rheumatoid arthritis

2014 ◽  
Vol 70 (a1) ◽  
pp. C253-C253
Author(s):  
Stephen Scally ◽  
Jan Petersen ◽  
Soi Cheng Law ◽  
Nadine Dudek ◽  
Hendrick Nel ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Molecular Basis ◽  
Bone Erosion ◽  
Strong Association ◽  
Arginine Deiminase ◽  
Healthy Controls ◽  
Citrullinated Vimentin ◽  
Positively Charged ◽  
Self Antigens

Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease, characterized by inflammation of synovial tissue, joint pannus and bone erosion. The human leukocyte antigen (HLA) locus plays a vital role in immunity, encoding highly polymorphic molecules that present peptides to T cell lymphocytes. RA has a strong association with a region of the HLA-DRB1 locus known as the `shared epitope' (SE) and the presence of autoantibodies specific for citrullinated proteins. The SE maps to a highly polymorphic N-terminal region of the HLA-DRβ chain around amino acids 70-74. This region encodes a positively charged residue at position 71 that is thought to dictate the amino acid that is accommodated in the P4 pocket of the antigen-binding groove. Citrullination, the conversion of positively charged arginine to polar citrulline, is a physiological process catalyzed by peptidyl arginine deiminase. Previous studies have shown that citrullination of self-antigens can significantly increase the affinity of epitopes for SE alleles. Here we provide a molecular basis for how citrullinated vimentin and aggrecan epitopes can be presented by the SE alleles, HLA-DRB1*0401 and HLA-DRB1*0404. Citrulline was accommodated in the electropositive P4 pocket of HLA-DRB1*0401/04, whilst arginine was not. In addition, the RA resistant HLA-DRB1*0402 allomorph was capable of binding both arginine and citrulline in its electronegative P4 pocket. Peptide elution studies revealed that arginine was presented by HLA-DRB1*0402 but not by HLA-DRB1*0401/04. Moreover, citrullinated vimentin showed a greater sensitivity to proteolysis by cathepsin L, when compared to unmodified vimentin, indicating that citrullination can impact the repertoire of self-antigens presented. Using HLA Class II tetramers, we identified citrullinated vimentin and aggrecan specific CD4+ T cells from both HLA-DRB1*0401+ RA patients and healthy controls. In RA patients, the number of autoreactive T cells correlated with disease activity and were deficient in regulatory T cells compared to healthy controls. Together these findings provide significant insight into the role citrullination plays in the pathogenesis of RA[1].

scholarly journals CD4+FOXP3+ T Cells in Rheumatoid Arthritis Bone Marrow Are Partially Impaired

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 549
Author(s):  
Magdalena Massalska ◽  
Anna Radzikowska ◽  
Ewa Kuca-Warnawin ◽  
Magdalena Plebanczyk ◽  
Monika Prochorec-Sobieszek ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Marrow ◽  
T Cells ◽  
Ex Vivo ◽  
Enzyme Linked Immunosorbent Assay ◽  
Suppressive Activity ◽  
Replacement Surgery ◽  
Hip Replacement Surgery ◽  
Stromal Cell Derived Factor ◽  
And Function

There is evolving evidence that dysregulation of immune homeostasis in the bone marrow (BM) adjacent to the inflamed joints is involved in the pathogenesis of. In this study, we are addressing the phenotype and function of regulatory T cells (Tregs) residing in the BM of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). BM and peripheral blood samples were obtained from RA and OA patients undergoing hip replacement surgery. The number and phenotype of Tregs were analyzed by flow cytometry and immunohistochemistry. The function of Tregs was investigated ex vivo, addressing their suppressive activity on effector T cells. [3H]-Thymidine incorporation assay and specific enzyme-linked immunosorbent assay were used for quantification of cell proliferation and pro-inflammatory (TNF, IFN-γ) cytokine release, respectively. Significantly lower numbers of CD4+FOXP3+ T cells were found in the BM of patients with RA compared to control patients with OA. High expression of CD127 (IL-7α receptor) and relatively low expression of CXCR4 (receptor for stromal cell-derived factor CXCL12) are characteristics of the CD4+FOXP3+ cells residing in the BM of RA patients. The BM-resident Tregs of RA patients demonstrated a limited suppressive activity on the investigated immune response. Our results indicate that the reduced number and impaired functional properties of CD4+FOXP3+ T cells present in the BM of RA patients may favor the inflammatory process, which is observed in RA BM.

scholarly journals The Role of Different Subsets of Regulatory T Cells in Immunopathogenesis of Rheumatoid Arthritis

Arthritis ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Maryam Gol-Ara ◽  
Farhad Jadidi-Niaragh ◽  
Reza Sadria ◽  
Gholamreza Azizi ◽  
Abbas Mirshafiey
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Joint Inflammation ◽  
Frequency Function ◽  
Systemic Inflammatory Disease ◽  
Progression Of Disease ◽  
Cartilage Erosion ◽  
And Function

Rheumatoid arthritis (RA) is a common autoimmune disease and a systemic inflammatory disease which is characterized by chronic joint inflammation and variable degrees of bone and cartilage erosion and hyperplasia of synovial tissues. Considering the role of autoreactive T cells (particularly Th1 and Th17 cells) in pathophysiology of RA, it might be assumed that the regulatory T cells (Tregs) will be able to control the initiation and progression of disease. The frequency, function, and properties of various subsets of Tregs including natural Tregs (nTregs), IL-10-producing type 1 Tregs (Tr1 cells), TGF-β-producing Th3 cells, CD8+ Tregs, and NKT regulatory cells have been investigated in various studies associated with RA and collagen-induced arthritis (CIA) as experimental model of this disease. In this paper, we intend to submit the comprehensive information about the immunobiology of various subsets of Tregs and their roles and function in immunopathophysiology of RA and its animal model, CIA.

scholarly journals OP0127 TRANSCRIPTIONAL ACTIVITY OF SURVIVIN CONTRIBUTES TO MATURATION AND FUNCTION OF THE INTERFERON-GAMMA PRODUCING T CELLS IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 83.1-84
Author(s):  
M. Erlandsson ◽  
K. M. Andersson ◽  
N. Nair ◽  
A. Damdimopoulos ◽  
S. Töyrä Silfverswärd ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Interferon Gamma ◽  
Th1 Cells ◽  
Memory Cells ◽  
Cd4 Cells ◽  
Cell Markers ◽  
Histone Marks ◽  
Th Cell ◽  
And Function

Background:Interferon gamma (IFNg) signalling and downstream effects make important contribution in pathogenesis of rheumatoid arthritis (RA). Here, we propose a mechanism by which oncoprotein survivin participates in development of IFN-dependent repertoire of T cells in RA patients.Objectives:We study the role of survivin in the phenotype of CD4 T cells of RA patients.Methods:CD4 cells of RA patients and healthy controls were purified from blood, activated and subjected to RNAseq, ChIPseq with antibodies to survivin (BIRC5) was performed on CD4+ cells. Histone H3 ChIPseq was performed using antibodies to H3K27ac, H3K27me3 and H3K4me3. Statistical analysis was performed In R-studio using the Bioconductor package DESeq2, clustering using Spearman and Ward.D2.Results:Unsupervised clustering of CD4 samples by expression of 48 core Th cell markers identified subsets of CD28hiCD27hiIFNnegcentral memory cells (Tcm), CD28loCD27loIFNloeffector memory cells (Tem) and CD28nullCD27nullIFNhiterminal effector cells (Tte). Tte cells showed classical features of Th1 cells including high levels of TBX21, TNFa and IL32 and signs of activation in IFN signalling machinery. Interestingly, they combined the features of peripheral Tregs CD25hiFoxp3hiIKZF2negand IL10 producing cells together with type 1 regulatory cells, which rely on transcription factors BATF and IRF1 for the differentiation and produced high amounts of perforin and granzyme B. Importantly, Tte CD4 cells had also high transcription of BIRC5 (p=1.15e-18).To study if BIRC5 is a part of IFN signalling, CD4 cells were cultured with survivin inhibitor YM155 and activated with IFNg. RNAseq analysis revealed 2033 (FC<2.0, n=336) differentially expressed genes in the IFN stimulated cultures. Interestingly, a substantial number of these IFN-dependent genes was significantly reduced in the survivin-deficient cultures and included among others CD28, FoxP3, IKZF2, ICOS, BATF, PRDM1, CXCR3, IRF4 and IRF8. Analysis of the peak sequences identified enrichment for composite motifs for IRFs (ETS:IRF, p1.0e-124; bZIP:IRF, p=1.0e-640), indicating that survivin is important for IFNg signalling. Numerically, the peaks containing ETS:IRF motifs were most prevalent and identified in total within 49.7% of all survivin-ChIP peaks. Frequent was co-localisation of the IRF:bZIP and IRF:ETS motifs within the survivin peaks. Among the IRF motifs dominated those suitable for IRF1 (p=1,0e-127) and IRF8 (p=1,0e-84). However, the DNA binding motifs of these two are alike.Encouraged by the survivin ChIPseq results, we wanted to know its relation to histone marks. We observed that 50% of survivin peaks containing both IRF:bZIP and IRF:ETS motifs are co-localized with the H3K27ac marks. In total, 16 of 48 core Th cell markers used for patients clustering were identified by survivin ChIPseq, co-localized with IRF composite motifs and histone marks. They were also dependent of survivin for expression.Conclusion:his study showed that survivin binds to DNA and regulates the core gene expression contributing to maturation and function of the IFNg producing Th1 cells.References:-Disclosure of Interests:Malin Erlandsson: None declared, Karin ME Andersson: None declared, Nisha Nair: None declared, Anastasius Damdimopoulos: None declared, Sofia Töyrä Silfverswärd: None declared, Rille Pullerits: None declared, Anne Barton Consultant of: AbbVie, Maria I Bokarewa: None declared

scholarly journals CD4+CD25+ regulatory T cells in rheumatoid arthritis: Differences in the presence, phenotype, and function between peripheral blood and synovial fluid

2004 ◽  
Vol 50 (9) ◽  
pp. 2775-2785 ◽  
Author(s):  
Jocea M. R. van Amelsfort ◽  
Kim M. G. Jacobs ◽  
Johannes W. J. Bijlsma ◽  
Floris P. J. G. Lafeber ◽  
Leonie S. Taams
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Synovial Fluid ◽  
Regulatory T Cells ◽  
Peripheral Blood ◽  
And Function
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