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Article ; Online: Characterizing memory T helper cells in patients with psoriasis, subclinical, or early psoriatic arthritis using a machine learning algorithm.

den Braanker, Hannah / Razawy, Wida / Wervers, Kim / Mus, Anne-Marie C / Davelaar, Nadine / Kok, Marc R / Lubberts, Erik

Arthritis research & therapy

2022 Volume 24, Issue 1, Page(s) 28

Abstract: Background: Psoriasis patients developing psoriatic arthritis (PsA) are thought to go through different phases. Understanding the underlying events in these phases is crucial to diagnose PsA early. Here, we have characterized the circulating memory T ... ...

Abstract	Background: Psoriasis patients developing psoriatic arthritis (PsA) are thought to go through different phases. Understanding the underlying events in these phases is crucial to diagnose PsA early. Here, we have characterized the circulating memory T helper (Th) cells in psoriasis patients with or without arthralgia, psoriasis patients who developed PsA during follow-up (subclinical PsA), early PsA patients and healthy controls to elucidate their role in PsA development. Methods: We used peripheral blood mononuclear cells of sex and age-matched psoriasis patients included in Rotterdam Joint Skin study (n=22), early PsA patients included in Dutch South West Early Psoriatic Arthritis Cohort (DEPAR) (n=23) and healthy controls (HC; n=17). We profiled memory Th cell subsets with flow cytometry and used the machine learning algorithm FlowSOM to interpret the data. Results: Three of the 22 psoriasis patients developed PsA during 2-year follow-up. FlowSOM identified 12 clusters of memory Th cells, including Th1, Th2, Th17/22, and Th17.1 cells. All psoriasis and PsA patients had higher numbers of Th17/22 than healthy controls. Psoriasis patients without arthralgia had lower numbers of CCR6 Conclusions: Unsupervised clustering analysis revealed differences in circulating memory Th cells between psoriasis and PsA patients compared to HC; however, no specific subset was identified characterizing subclinical PsA patients.
MeSH term(s)	Arthritis, Psoriatic/diagnosis ; Humans ; Leukocytes, Mononuclear ; Machine Learning ; Psoriasis/diagnosis ; Th17 Cells
Language	English
Publishing date	2022-01-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/s13075-021-02714-5
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Zs.A 5490: Show issues

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Article ; Online: The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner.

Dankers, Wendy / den Braanker, Hannah / Paulissen, Sandra M J / van Hamburg, Jan Piet / Davelaar, Nadine / Colin, Edgar M / Lubberts, Erik

Arthritis research & therapy

2021 Volume 23, Issue 1, Page(s) 157

Abstract: Background: Chronic synovial inflammation is an important hallmark of inflammatory arthritis, but the cells and mechanisms involved are incompletely understood. Previously, we have shown that CCR6+ memory T-helper (memTh) cells and synovial fibroblasts ( ...

Abstract	Background: Chronic synovial inflammation is an important hallmark of inflammatory arthritis, but the cells and mechanisms involved are incompletely understood. Previously, we have shown that CCR6+ memory T-helper (memTh) cells and synovial fibroblasts (SF) activate each other in a pro-inflammatory feedforward loop, which potentially drives persistent synovial inflammation in inflammatory arthritis. However, the CCR6+ memTh cells are a heterogeneous population, containing Th17/Th22 and Th17.1 cells. Currently, it is unclear which of these subpopulations drive SF activation and how they should be targeted. In this study, we examined the individual contribution of these CCR6+ memTh subpopulations to SF activation and examined ways to regulate their function. Methods: Th17/Th22 (CXCR3 Results: Th17/Th22, Th17.1, DP, and DN cells equally express RORC but differ in production of TBX21 and cytokines like IL-17A and IFNγ. Despite these differences, all the individual CCR6+ memTh subpopulations, both from healthy individuals and RA patients, were more potent in activating SF than the classical Th1 cells. SF activation was partially inhibited by blocking IL-17A, but not by inhibiting IFNγ or TBX21. However, active vitamin D inhibited the pathogenicity of all subpopulations leading to suppression of SF activation. Conclusions: Human CCR6+ memTh cells contain several subpopulations that equally express RORC but differ in TBX21, IFNγ, and IL-17A expression. All individual Th17 subpopulations are more potent in activating SF than classical Th1 cells in an IFNγ-independent manner. Furthermore, our data suggest that IL-17A is not dominant in this T cell-SF activation loop but that a multiple T cell cytokine inhibitor, such as 1,25(OH)
MeSH term(s)	Cytokines ; Fibroblasts ; Humans ; Leukocytes, Mononuclear ; Receptors, CCR6 ; Th17 Cells
Chemical Substances	CCR6 protein, human ; Cytokines ; Receptors, CCR6
Language	English
Publishing date	2021-06-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/s13075-021-02532-9
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Article ; Online: Discovery of small-molecules targeting the CCL20/CCR6 axis as first-in-class inhibitors for inflammatory bowel diseases.

Martina, Maria Grazia / Giorgio, Carmine / Allodi, Marika / Palese, Simone / Barocelli, Elisabetta / Ballabeni, Vigilio / Szpakowska, Martyna / Chevigné, Andy / Piet van Hamburg, Jan / Davelaar, Nadine / Lubberts, Erik / Bertoni, Simona / Radi, Marco

European journal of medicinal chemistry

2022 Volume 243, Page(s) 114703

Abstract: The CCL20/CCR6 axis is implicated in the migration of CCR6+ immune cells towards CCL20, its sole ligand, whose expression is increased during inflammatory processes and is known to play a pivotal role in triggering different autoimmune-mediated ... ...

Abstract	The CCL20/CCR6 axis is implicated in the migration of CCR6+ immune cells towards CCL20, its sole ligand, whose expression is increased during inflammatory processes and is known to play a pivotal role in triggering different autoimmune-mediated inflammatory diseases. Herein, we report a drug discovery effort focused on the development of a new pharmacological approach for the treatment of inflammatory bowel diseases (IBDs) based on small-molecule CCR6 antagonists. The most promising compound 1b was identified by combining in silico studies, sustainable chemistry and in vitro functional/targeted assays, and its efficacy was finally validated in a classic murine model of colitis (TNBS-induced) and in a model of peritonitis (zymosan-induced). These data provide the proof of principle that a pharmacological modulation of the CCL20/CCR6 axis may indeed represent the first step for the development of an orally bioavailable drug candidate for the treatment of IBD and, potentially, other diseases regulated by the CCL20/CCR6 axis.
MeSH term(s)	Mice ; Humans ; Animals ; Receptors, CCR6/metabolism ; Chemokine CCL20/metabolism ; Inflammatory Bowel Diseases/drug therapy ; Autoimmune Diseases
Chemical Substances	Receptors, CCR6 ; Chemokine CCL20 ; CCR6 protein, human ; CCL20 protein, human ; CCR6 protein, mouse
Language	English
Publishing date	2022-08-29
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2022.114703
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Article ; Online: Human Memory Th17 Cell Populations Change Into Anti-inflammatory Cells With Regulatory Capacity Upon Exposure to Active Vitamin D.

Dankers, Wendy / Davelaar, Nadine / van Hamburg, Jan Piet / van de Peppel, Jeroen / Colin, Edgar M / Lubberts, Erik

Frontiers in immunology

2019 Volume 10, Page(s) 1504

Abstract: Autoimmune diseases are characterized by an aberrantly activated immune system, resulting in tissue damage and functional disability in patients. An important therapeutic goal is to restore the deregulated immunological balance between pro- and anti- ... ...

Abstract	Autoimmune diseases are characterized by an aberrantly activated immune system, resulting in tissue damage and functional disability in patients. An important therapeutic goal is to restore the deregulated immunological balance between pro- and anti-inflammatory T cells. This imbalance is illustrated by elevated levels and activity of memory Th17 cell populations, such as Th17, Th1/Th17, and Th17.1 cells, in various autoimmune diseases. These cells are characterized by the chemokine receptor CCR6, RORC expression and production of IL-17A, IFNγ, and TNFα. Using rheumatoid arthritis (RA) as a model of autoimmune disease, we here demonstrate that pro-inflammatory memory CCR6+ Th cells can switch into anti-inflammatory cells with regulatory capacity using the active vitamin D metabolite 1,25(OH)
MeSH term(s)	Adult ; Anti-Inflammatory Agents/immunology ; Arthritis, Rheumatoid/immunology ; Autoimmune Diseases/immunology ; CD3 Complex/immunology ; Cells, Cultured ; Female ; Humans ; Immunologic Memory/immunology ; Interleukins/immunology ; Male ; Middle Aged ; Receptors, CCR6/immunology ; Th17 Cells/immunology ; Tumor Necrosis Factor-alpha/immunology ; Vitamin D/immunology
Chemical Substances	Anti-Inflammatory Agents ; CD3 Complex ; Interleukins ; Receptors, CCR6 ; Tumor Necrosis Factor-alpha ; Vitamin D (1406-16-2)
Language	English
Publishing date	2019-07-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.01504
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Article ; Online: CD4

Razawy, Wida / Asmawidjaja, Patrick S / Mus, Anne-Marie / Salioska, Nazike / Davelaar, Nadine / Kops, Nicole / Oukka, Mohamed / Alves, C Henrique / Lubberts, Erik

European journal of immunology

2019 Volume 50, Issue 2, Page(s) 245–255

Abstract: IL-23 plays an important role in the development of arthritis and the IL-23 receptor (IL-23R) is expressed on different types of T cells. However, it is not fully clear which IL- ... ...

Abstract	IL-23 plays an important role in the development of arthritis and the IL-23 receptor (IL-23R) is expressed on different types of T cells. However, it is not fully clear which IL-23R
MeSH term(s)	Adoptive Transfer/methods ; Animals ; Arthritis/immunology ; CD4-Positive T-Lymphocytes/immunology ; Disease Models, Animal ; Female ; Inflammation/immunology ; Interleukin-17/immunology ; Interleukin-23/immunology ; Lymphoid Tissue/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, Antigen, T-Cell, gamma-delta/immunology ; Receptors, CCR6/immunology ; Receptors, Interleukin/immunology ; Th17 Cells/immunology
Chemical Substances	CCR6 protein, mouse ; Interleukin-17 ; Interleukin-23 ; Receptors, Antigen, T-Cell, gamma-delta ; Receptors, CCR6 ; Receptors, Interleukin ; interleukin-23 receptor, mouse
Language	English
Publishing date	2019-11-28
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201948112
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: 1,25(OH)

Dankers, Wendy / González-Leal, Claudia / Davelaar, Nadine / Asmawidjaja, Patrick S / Mus, Adriana M C / Hazes, Johanna M W / Colin, Edgar M / Lubberts, Erik

Arthritis research & therapy

2018 Volume 20, Issue 1, Page(s) 212

Abstract: Background: Despite recent improvements in the treatment of rheumatoid arthritis (RA), an insufficient treatment response and the development of treatment resistance in many patients illustrates the need for new therapeutic strategies. Chronic synovial ... ...

Abstract	Background: Despite recent improvements in the treatment of rheumatoid arthritis (RA), an insufficient treatment response and the development of treatment resistance in many patients illustrates the need for new therapeutic strategies. Chronic synovial inflammation could be suppressed by targeting RA synovial fibroblast (RASF) activation by, for example, interleukin (IL)-17A-producing CCR6 Methods: CCR6 Results: 1,25(OH) Conclusion: This study suggests that 1,25(OH)
MeSH term(s)	Calcitriol/administration & dosage ; Coculture Techniques ; Dexamethasone/administration & dosage ; Drug Synergism ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Humans ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/metabolism ; Receptors, CCR6/biosynthesis ; Synovial Membrane/drug effects ; Synovial Membrane/metabolism ; T-Lymphocytes, Helper-Inducer/drug effects ; T-Lymphocytes, Helper-Inducer/metabolism ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	CCR6 protein, human ; Receptors, CCR6 ; Tumor Necrosis Factor-alpha ; Dexamethasone (7S5I7G3JQL) ; Calcitriol (FXC9231JVH)
Language	English
Publishing date	2018-09-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/s13075-018-1706-9
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Article ; Online: Achieving sustained minimal disease activity with methotrexate in early interleukin 23-driven early psoriatic arthritis.

den Braanker, Hannah / Wervers, Kim / Mus, Adriana M C / Bangoer, Priyanka S / Davelaar, Nadine / Luime, Jolanda / Tchetverikov, Ilja / Hazes, J M W / Vis, Marijn / Lubberts, Erik / Kok, Marc R

RMD open

2020 Volume 6, Issue 2

Abstract: Objectives: Methotrexate (MTX) is currently the recommended first-line therapy for treating psoriatic arthritis (PsA), despite lacking clear evidence. No estimates of efficacy of MTX in usual care and no clear MTX responsive clinical or laboratory ... ...

Abstract	Objectives: Methotrexate (MTX) is currently the recommended first-line therapy for treating psoriatic arthritis (PsA), despite lacking clear evidence. No estimates of efficacy of MTX in usual care and no clear MTX responsive clinical or laboratory variables are currently available. This study describes the response to MTX monotherapy in newly diagnosed patients with PsA in usual care. Second, we compared clinical variables and cytokine profiles in patients responding and not responding to MTX monotherapy. Methods: We used data collected in the Dutch southwest Early Psoriatic Arthritis cohoRt study to select patients with PsA with oligoarthritis or polyarthritis, and at least 1 year follow-up. We analysed disease activity at 6 months of patients who started MTX monotherapy and still used MTX monotherapy 1 year after diagnosis. Cytokine profiles were determined at baseline and after 3 and 6 months with a bead-based multi-immunoassay. Results: We identified 219 patients of which 183 (84%) patients started MTX monotherapy within 6 months after diagnosis. 90 patients used MTX monotherapy throughout the first year of which 44 patients (24%) reached minimal disease activity(MDA) at 6 months, decreasing to 33 patients (18%) after 1 year. Non-responders had significantly higher concentrations of interleukin (IL) 23 and IL-10 before and during MTX therapy. Conclusions: Our results showed that only 18% of patients with PsA are in sustained MDA after 1 year of MTX monotherapy and non-responders more often had IL-23-driven disease. Our results indicate the need for more treat-to-target and personalised therapy strategies in PsA.
MeSH term(s)	Adult ; Aged ; Antirheumatic Agents/administration & dosage ; Antirheumatic Agents/therapeutic use ; Arthritis, Psoriatic/blood ; Arthritis, Psoriatic/diagnosis ; Arthritis, Psoriatic/drug therapy ; Biomarkers ; Cytokines/blood ; Female ; Humans ; Inflammation Mediators/blood ; Interleukin-23/blood ; Male ; Methotrexate/administration & dosage ; Methotrexate/therapeutic use ; Middle Aged ; Prognosis ; Severity of Illness Index ; Treatment Outcome
Chemical Substances	Antirheumatic Agents ; Biomarkers ; Cytokines ; Inflammation Mediators ; Interleukin-23 ; Methotrexate (YL5FZ2Y5U1)
Language	English
Publishing date	2020-07-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2812592-7
ISSN	2056-5933 ; 2056-5933
ISSN (online)	2056-5933
ISSN	2056-5933
DOI	10.1136/rmdopen-2020-001175
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Article ; Online: Interleukin-17A Is Produced by CD4+ but Not CD8+ T Cells in Synovial Fluid Following T Cell Receptor Activation and Regulates Different Inflammatory Mediators Compared to Tumor Necrosis Factor in a Model of Psoriatic Arthritis Synovitis.

Xu, Xiaofei / Davelaar, Nadine / Mus, Anne-Marie / Asmawidjaja, Patrick S / Hazes, Johanna M W / Baeten, Dominique L P / Vis, Marijn / Bisoendial, Radjesh J / Prens, Errol P / Lubberts, Erik

Arthritis & rheumatology (Hoboken, N.J.)

2020 Volume 72, Issue 8, Page(s) 1303–1313

Abstract: Objective: Interleukin-17A (IL-17A) and tumor necrosis factor (TNF) contribute to the pathogenesis of psoriatic arthritis (PsA). However, their functional relationship in PsA synovitis has not been fully elucidated. Additionally, although CD8+ T cells ... ...

Abstract	Objective: Interleukin-17A (IL-17A) and tumor necrosis factor (TNF) contribute to the pathogenesis of psoriatic arthritis (PsA). However, their functional relationship in PsA synovitis has not been fully elucidated. Additionally, although CD8+ T cells in PsA have been recognized via flow cytometry as a source of IL-17A production, it is not clear whether CD8+ T cells secrete IL-17A under more physiologically relevant conditions in the context from PsA synovitis. This study was undertaken to clarify the roles of IL-17A and TNF in the synovial fluid (SF) from patients with PsA and investigate the impact of CD8+ T cells on IL-17A production. Methods: IL-17A+ T cells were identified by flow cytometry in SF samples from 20 patients with active PsA, blood samples from 22 treatment-naive patients with PsA, and blood samples from 22 healthy donors. IL-17A+ T cells were sorted from 12 PsA SF samples and stimulated using anti-CD3/anti-CD28 or phorbol myristate acetate (PMA) and ionomycin ex vivo, alone (n = 3) or together with autologous monocytes (n = 3) or PsA fibroblast-like synoviocytes (FLS) (n = 5-6). To evaluate the differential allogeneic effects of neutralizing IL-17A and TNF, SF CD4+ T cells and PsA FLS cocultures were also used (n = 5-6). Results: Flow cytometry analyses of SF samples from patients with PsA showed IL-17A positivity for CD4+ and CD8+ T cells (IL-17A, median 0.71% [interquartile range 0.35-1.50%] in CD4+ cells; median 0.44% [interquartile range 0.17-1.86%] in CD8+ T cells). However, only CD4+ T cells secreted IL-17A after anti-CD3/anti-CD28 activation, when cultured alone and in cocultures with PsA monocytes or PsA FLS (each P < 0.05). Remarkably, CD8+ T cells only secreted IL-17A after 4- or 72-hour stimulation with PMA/ionomycin. Anti-IL-17A and anti-TNF treatments both inhibited PsA synovitis ex vivo. Neutralizing IL-17A strongly inhibited IL-6 (P < 0.05) and IL-1β (P < 0.01), while anti-TNF treatment was more potent in reducing matrix metalloproteinase 3 (MMP-3) (P < 0.05) and MMP-13. Conclusion: CD8+ T cells, in contrast to CD4+ T cells, in SF specimens obtained from PsA patients did not secrete IL-17A following T cell receptor activation. Overlapping, but distinct, effects at the level of inflammatory cytokines and MMPs were found after neutralizing IL-17A or TNF ex vivo in a human model of PsA synovitis.
MeSH term(s)	Adult ; Arthritis, Psoriatic/drug therapy ; Arthritis, Psoriatic/immunology ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; Cell Culture Techniques ; Female ; Flow Cytometry ; Humans ; Inflammation Mediators/metabolism ; Interleukin-17/biosynthesis ; Ionomycin/pharmacology ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Male ; Receptors, Antigen, T-Cell/administration & dosage ; Receptors, Antigen, T-Cell/immunology ; Synovial Fluid ; Synoviocytes/drug effects ; Synoviocytes/immunology ; Synovitis/drug therapy ; Synovitis/immunology ; Tetradecanoylphorbol Acetate/pharmacology ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	IL17A protein, human ; Inflammation Mediators ; Interleukin-17 ; Receptors, Antigen, T-Cell ; Tumor Necrosis Factor-alpha ; Ionomycin (56092-81-0) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
Language	English
Publishing date	2020-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2756371-6
ISSN	2326-5205 ; 2326-5191
ISSN (online)	2326-5205
ISSN	2326-5191
DOI	10.1002/art.41271
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Article ; Online: CCR6(+) Th cell populations distinguish ACPA positive from ACPA negative rheumatoid arthritis.

Paulissen, Sandra M J / van Hamburg, Jan Piet / Davelaar, Nadine / Vroman, Heleen / Hazes, Johanna M W / de Jong, Pascal H P / Lubberts, Erik

Arthritis research & therapy

2015 Volume 17, Page(s) 344

Abstract: Introduction: Patients with rheumatoid arthritis (RA) can be separated into two major subpopulations based on the absence or presence of serum anti-citrullinated protein antibodies (ACPAs). The more severe disease course in ACPA(+) RA and differences in ...

Abstract	Introduction: Patients with rheumatoid arthritis (RA) can be separated into two major subpopulations based on the absence or presence of serum anti-citrullinated protein antibodies (ACPAs). The more severe disease course in ACPA(+) RA and differences in treatment outcome between these subpopulations suggest that ACPA(+) and ACPA(-) RA are different disease subsets. The identification of T-helper (Th) cells specifically recognizing citrullinated peptides, combined with the strong association between HLA-DRB1 and ACPA positivity, point toward a pathogenic role of Th cells in ACPA(+) RA. In this context we recently identified a potential pathogenic role for CCR6(+) Th cells in RA. Therefore, we examined whether Th cell population distributions differ by ACPA status. Methods: We performed a nested matched case-control study including 27 ACPA(+) and 27 ACPA(-) treatment-naive early RA patients matched for disease activity score in 44 joints, presence of rheumatoid factor, sex, age, duration of complaints and presence of erosions. CD4(+)CD45RO(+) (memory) Th cell distribution profiles from these patients were generated based on differential chemokine receptor expression and related with disease duration. Results: ACPA status was not related to differences in total CD4(+) T cell or memory Th cell proportions. However, ACPA(+) patients had significantly higher proportions of Th cells expressing the chemokine receptors CCR6 and CXCR3. Similar proportions of CCR4(+) and CCR10(+) Th cells were found. Within the CCR6(+) cell population, four Th subpopulations were distinguished based on differential chemokine receptor expression: Th17 (CCR4(+)CCR10(-)), Th17.1 (CXCR3(+)), Th22 (CCR4(+)CCR10(+)) and CCR4/CXCR3 double-positive (DP) cells. In particular, higher proportions of Th22 (p = 0.02), Th17.1 (p = 0.03) and CCR4/CXCR3 DP (p = 0.01) cells were present in ACPA(+) patients. In contrast, ACPA status was not associated with differences in Th1 (CCR6(-)CXCR3(+); p = 0.90), Th2 (CCR6(-)CCR4(+); p = 0.27) and T-regulatory (CD25(hi)FOXP3(+); p = 0.06) cell proportions. Interestingly, CCR6(+) Th cells were inversely correlated with disease duration in ACPA(-) patients (R(2) = -0.35; p < 0.01) but not in ACPA(+) (R(2) < 0.01; p = 0.94) patients. Conclusions: These findings demonstrate that increased peripheral blood CCR6(+) Th cells proportions distinguish ACPA(+) RA from ACPA(-) RA. This suggests that CCR6(+) Th cells are involved in the differences in disease severity and treatment outcome between ACPA(+) and ACPA(-) RA.
MeSH term(s)	Arthritis, Rheumatoid/blood ; Arthritis, Rheumatoid/immunology ; Autoantibodies/blood ; Autoantibodies/immunology ; Autoantigens/immunology ; Case-Control Studies ; Cell Separation ; Female ; Flow Cytometry ; Humans ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Receptors, CCR6/immunology ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes, Helper-Inducer/immunology
Chemical Substances	Autoantibodies ; Autoantigens ; CCR6 protein, human ; Receptors, CCR6
Language	English
Publishing date	2015-11-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/s13075-015-0800-5
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Article ; Online: IL-17/Th17 mediated synovial inflammation is IL-22 independent.

van Hamburg, Jan Piet / Corneth, Odilia B J / Paulissen, Sandra M J / Davelaar, Nadine / Asmawidjaja, Patrick S / Mus, Adriana M C / Lubberts, Erik

Annals of the rheumatic diseases

2013 Volume 72, Issue 10, Page(s) 1700–1707

Abstract: Background: Interleukin (IL)-17A and Th17 cells are critically involved in T cell-mediated synovial inflammation. Besides IL-17A, Th17 cells produce IL-22. Recently, Th22 cells were discovered, which produce IL-22 in the absence of IL-17. However, it ... ...

Abstract	Background: Interleukin (IL)-17A and Th17 cells are critically involved in T cell-mediated synovial inflammation. Besides IL-17A, Th17 cells produce IL-22. Recently, Th22 cells were discovered, which produce IL-22 in the absence of IL-17. However, it remains unclear whether IL-22 and Th22 cells contribute to T cell-mediated synovial inflammation. Therefore, we examined the potential of IL-22 and Th22 cells to induce synovial inflammation and whether IL-22 is required for T cell-mediated experimental arthritis. Methods: Peripheral and synovial Th17 and Th22 cells were identified and sorted from patients with rheumatoid arthritis (RA). Co-culture experiments of these primary T cell populations with RA synovial fibroblasts (RASF) were performed. The in vivo IL-22 contribution to synovial inflammation was investigated by inducing T cell-mediated arthritis in IL-22 deficient mice and wild-type mice. Results: Peripheral Th17 and Th22 cell populations were increased in patients with RA and present in RA synovial fluid. In T cell-RASF co-cultures, IL-22 in the presence of IL-17A had limited effects on IL-6, IL-8, matrix metalloproteinase-1 (MMP-1) and MMP-3 production. Furthermore, primary peripheral blood and synovial Th17 cells were more potent in the induction of these factors by RASF compared with Th22 cells. In line with this, similar synovial inflammation and disease severity was found between IL-22 deficient and wild-type mice in T cell-mediated experimental arthritis. Conclusions: These findings show that IL-17A/Th17 cell-mediated synovial inflammation is independent of IL-22 and Th22 cells. This implies that targeting IL-17A/Th17 cells, rather than IL-22/Th22 cells, should be the focus for treatment of T cell-mediated synovial inflammation.
MeSH term(s)	Adult ; Aged ; Animals ; Arthritis, Experimental/immunology ; Arthritis, Rheumatoid/immunology ; Coculture Techniques ; Female ; Humans ; Interleukin-17/biosynthesis ; Interleukin-17/immunology ; Interleukin-6/biosynthesis ; Interleukin-8/biosynthesis ; Interleukins/biosynthesis ; Interleukins/immunology ; Male ; Matrix Metalloproteinase 1/biosynthesis ; Matrix Metalloproteinase 3/biosynthesis ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Receptors, CCR6/analysis ; Synovitis/immunology ; Th17 Cells/immunology ; Up-Regulation/immunology ; Young Adult ; Interleukin-22
Chemical Substances	CCR6 protein, human ; IL17A protein, human ; Interleukin-17 ; Interleukin-6 ; Interleukin-8 ; Interleukins ; Receptors, CCR6 ; Matrix Metalloproteinase 3 (EC 3.4.24.17) ; Matrix Metalloproteinase 1 (EC 3.4.24.7)
Language	English
Publishing date	2013-01-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	7090-7
ISSN	1468-2060 ; 0003-4967
ISSN (online)	1468-2060
ISSN	0003-4967
DOI	10.1136/annrheumdis-2012-202373
Database	MEDical Literature Analysis and Retrieval System OnLINE

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