Association between IL-17 and IgA in the joints of patients with inflammatory arthropathies
© The Author(s). 2017
Received: 18 July 2016
Accepted: 17 January 2017
Published: 6 February 2017
Hyperactive secretion and pathogenic effects of interleukin (IL)-17 and IgA have been detected in different arthropathies. Recent evidence has revealed that TH17 cytokines regulate mucosal IgA secretion. However, it is unknown whether and how IL-17 mediates synovial IgA production. Here we aim to investigate the connection of synovial IL-17 with IgA production in the joint.
In this study we included synovial fluids (SF) from patients with rheumatoid arthritis (RA; n = 66), spondyloarthritis (SpA; n = 18) and osteoarthritis (OA; n = 36). The levels of IL-17, IL-6, transforming growth factor (TGF)-β1, B-cell-activating factor of the TNF family (BAFF) and anti-lipopolyssacharide (LPS) immunoglobulin (Ig)A were investigated by enzyme-linked immunosorbent assay (ELISA). Total IgA was measured by radial immunodiffusion assay. Synovial fluid-derived mononuclear cells (SFMC) were stimulated with bacterial antigens or SF-conditioned media, and cytokines and IgA were analyzed in the supernatants.
IL-17, IL-6 and TGF-β1 were increased in SF from both RA and SpA compared with OA patients. Concentration of IL-17 correlated with the disease activity score (DAS)-28, IL-6 and anti-LPS IgA levels. Bacterial-stimulated SFMCs from RA and SpA patients secreted higher IL-17 than vehicle-stimulated SFMCs. Conditioned media with SF containing IL-17 induced anti-LPS IgA production by SFMCs which was independent of IL-6 activity. Concentrations of synovial TGF-β1 and BAFF correlated with anti-LPS and total IgA levels, respectively. Blockade of IL-17 decreased the production of TGF-β1 and anti-LPS IgA by SF-stimulated SFMCs.
This study reports a connection between IL-17 and IgA secretion in the joint. In addition, it demonstrates that enterobacterial antigens trigger synovial IL-17 production, and that TGF-β1 and BAFF may mediate the effect of IL-17 on IgA production. This circuit may contribute to the pathogenesis of inflammatory joint diseases.
KeywordsInterleukin-17 Immunoglobulin A Synovial fluid Transforming growth factor B-cell activating factor of the TNF family
Mucosal surfaces serve as a protective barrier against most pathogens. These surfaces are protected by a first-line defense mediated by immunoglobulin A (IgA) . Moreover, it is also known that T helper (TH)17 cells are more abundantly present at the mucosal surface of the intestine, compared with other T-cell subsets . Accumulating evidence has demonstrated that TH17 cells contribute to intestinal homeostasis by regulating intestinal IgA secretion supporting a link between intestinal T-cell function and IgA production [3, 4]. Less is known about the potential role of TH17 cells for IgA induction in the joint, though chronic activation of TH17 can cause arthropathies [5, 6] and hyperactive IgA synthesis occurs in many types of inflammatory joint diseases [7–10].
In spite of the long-standing assumption that infectious agents and their products may influence the development of osteoarticular diseases [11, 12], our understanding of the intricate connections linking bacterial components with inflammatory arthropathies is still limited. Rheumatoid arthritis (RA), one of the most common autoimmune osteoarticular diseases, is characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and systemic disorders mainly driven by pro-inflammatory cytokines and matrix-degrading enzymes . Infectious agents and their products have been largely linked with RA although the precise mechanisms implicated in this complex relationship is not fully understood [11, 12, 14]. Elucidation of the pathogenic mechanisms that perpetuate RA will open the possibility of better disease management and rational control of immune dysregulation . Spondyloarthritis (SpA) is the second most prevalent form of chronic inflammatory arthritis (prevalence 0.5-1.5%) that mainly affects young adults . SpA has been traditionally subdivided into subtypes including ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis/spondylitis associated with inflammatory bowel disease (IBD), and undifferentiated SpA (uSpA) . However, evidence suggests that SpA is a single disease with a heterogeneous phenotype . Although the etiology of SpA remains obscure, it has demonstrated a strong association with environmental factors including pathogenic intestinal microbes . However, whether enterobacterial antigens trigger synovial IL-17 in RA and SpA is still uncertain.
It is known that transforming growth factor (TGF)-β1 has a unique role in driving IgA isotype switching , and is also critical for TH17-cell differentiation . It is also known that IL-6, a major factor for the differentiation of naïve CD4 T cells into Th17 cells , plays a key role in B-cell proliferation and antibody secretion . However, there is no evidence indicating that TGF-β1 or IL-6 together with IL-17 have a role for IgA generation in joint. Ultimately, B- cell-activating factor of the TNF family (BAFF) has been recognized as a cytokine that induces IgA class switching by activating B cells . Interestingly, IL-17 has also been recently shown to synergize with BAFF to increase the frequency of autoantibodies, and high BAFF levels have been considered a measurement of B-cell dysfunction in autoimmune diseases .
In the present study, we aimed to examine the role of IL-17 in IgA production in the joint. We used synovial fluids (SF) containing different cytokines rather recombinant cytokines in order to recreate the pathophysiologic microenvironment of the joints during ongoing inflammatory diseases. These findings identify pathways by which IL-17 mediates induction of synovial IgA responses during inflammatory arthropathies.
Demographic characteristics of the patients
Medium age, years
Medium duration of disease, years (range)
8 (3 months-30 years)
85% chronic phase (>1 year)
4 (2 months-17 years)
55% chronic phase (>6 months)
The study was approved by the Ethics Committee of the National University of Cuyo, Mendoza, Argentina. Informed consent was obtained from all patients included in the study. The principles of Helsinki Declaration 1975/83 were followed.
Synovial fluid preparation
SF was aspirated from knee joints and mixed immediately with 50 IU/ml heparin. The volumes of aspired fluids were 5–30 ml. SF of RA and SpA patients were classified as inflammatory since all of them had more than 2000 cells/mm3; in contrast, OA patients had non-inflammatory SF (less than 2000 cells/mm3) [28, 29]. For cytokine and antibody analysis, samples were centrifuged at 250 x xg for 10 min and the supernatants were stored at -20 °C.
Cytokine determination by enzyme-linked immunosorbent assay (ELISA)
IL-17, TGF-β1 and IL-6 were determined in SF using commercial capture ELISA kits (eBioscience, San Diego, CA, USA), according to the manufacturer’s instructions. The limits of detection for the above-mentioned assays were 4 pg/ml for IL-17, 2 pg/ml for IL-6 and 8 pg/ml for TGF-β1. The SF with levels of these cytokines higher than the limit of detection was considered positive in the frequency analysis. BAFF was determined by ELISA kit (Antigenic America, Huntington Station, NY, USA) which was kindly provided by Dr. Adriana Gruppi (National University of Córdoba, Argentina).
Enterobacterial antigen preparations
Yersinia enterocolitica O:8, strain WA-314 (kindly provided by Dr Kapperud, Department of Bacteriology, Oslo, Norway) was used for heat killed Yersinia (HKY) preparation, which consisted in a twice autoclaved bacterial suspension (1 × 1010 bacteria/ml). The absence of bacterial growth in HKY was tested by plating on Mueller-Hinton agar and incubation at 26 °C for 48 h. Lipopolysaccharide (LPS) was obtained as previously described .
Synovial anti-enterobacterial IgA and total IgA
Multiwell plates were coated with 100 μl per well of 10 μg/ml LPS in 0.15 M phosphate-buffered saline (PBS) pH 7.2 at 4 °C overnight. After incubation with 1:50 diluted SF, bound antibodies were demonstrated by reaction with goat anti-human IgA and peroxidase-conjugated rabbit anti-goat IgG (Sigma, St. Louis, MO, USA) followed by the addition of the enzyme substrate (H2O2) and chromogen O-phenylendiamine (Sigma). Optical density (OD) was measured at 490 nm in an ELISA reader (Bio-Rad, Hercules, CA, USA). Total IgA levels in SF were determined by radial immunodiffusion assay (Diffu-Plate kit, Biocientífica, Buenos Aires, Argentina)
Assessment of IL-17, TGF-β1 and anti-LPS IgA in stimulated mononuclear cells from SF
SF mononuclear cells (SFMC) were obtained using Ficoll-Hypaque (Histopaque 1077, Sigma). Cells (2 × 106 cells/well) were cultured in RPMI 1640 medium (Hyclone, Logan, UT, USA) with 10% fetal bovine serum (FBS) (Sigma), and stimulated with 107 or 108 bacteria/ml of HKY and incubated at 37 °C in 5% CO2. Supernatants were collected after 72 h for determination of IL-17 using a commercial ELISA kit (eBioscience). In addition, SFMC were incubated for 96 h with media conditioned with different dilutions of SF containing IL-17; then, TGF-β1 or anti-LPS IgA were measured by ELISA. To analyze the role of IL-6 in this effect, cells were incubated in vitro with pharmacologically relevant concentrations of the anti-IL-6 receptor antagonist tocilizumab (TCZ) (200 μg/ml, Roche Pharma, Grenzach-Wyhlen, Germany) . To analyze the effect of synovial IL-17, the cells were stimulated with SF in presence of the anti-IL-17 (100 μg/ml, Secukinumab, Novartis Argentina SA, Buenos Aires, Argentina).
Differences in the amounts of cytokines or IgA in RA, SpA and OA patients were compared by using one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison test. Two variables were compared by unpaired Student´s t test. Differences in the frequencies of SF with detectable level of cytokine (positive SF) in each group of patients were analyzed by Fisher´s exact test. Correlations between two variables were examined by Spearman’s analysis. A P value less than 0.05 was considered as statistically significant. All analyses were performed using GraphPad Prism 5 software (GraphPad Software, San Diego, CA, USA).
Synovial IL-17, IL-6 and TGF-β1 production in patients with RA and SpA
Secretion of IL-17 by SFMCs from patients with RA and SpA after stimulation with enterobacterial antigens and anti-enterobacterial IgA response
Interaction of IL-17, TGF-β1 and BAFF in synovial IgA production
The role of IL-17 in the induction of IgA in the joint is poorly understood. Most of the available information on the association between Th17 and IgA comes from studies of intestinal immunity. In this regard, recent studies have demonstrated that TH17 cells are the T helper subset responsible for promoting the B cell switch toward the production of high-affinity T cell-dependent IgA responses . Moreover, microbial-specific Th17 cells contribute to intestinal homeostasis by regulating intestinal pIgR expression and IgA secretion . In the present work we focused on IL-17-mediated induction of IgA production in the joint.
First, we detected elevated IL-17 concentrations in SF from both RA and SpA patients compared with control OA patients. These observations are in accordance with previous studies in RA and in SpA [6, 32, 33] patients. Furthermore, differences in SF concentrations of IL-6 and TGF-β1 were similar to those found for IL-17, and positive correlation was also observed between SF concentrations of IL-17 and IL-6. These results are consistent with the role of IL-6 and TGF-β1 in the differentiation of IL-17-producing CD4+ T cells [20, 21, 37] and support the involvement of IL-17 in the pathogenesis of the inflammatory arthritis (RA and SpA) but not in OA. Noteworthy, we detected a positive association between IL-17 and disease activity evaluated by DAS28 in RA. In accordance, in other study, Th17 cells positively correlated with both CRP levels and DAS28 in RA patients . Although this correlation was more difficult to assess in SpA, accumulating evidence firmly implicates IL-17 in the pathogenesis of SpA [33, 38].
In spite of considerable progress in the elucidation of the relationship between bacterial infection and rheumatologic disorders [11, 12, 14], the precise mechanism by which bacterial enteroantigens modulate the local inflammatory microenvironment and influence clinical course of inflammatory arthropathies are poorly understood. Here, we found that stimulation with Yersinia antigens promotes robust IL-17 production by SFMC of RA and SpA patients. This induction was IL-6-dependent in line with the well-established role of IL-6 as a potent inducer of TH17 differentiation [21, 37], and the major role of IL-6 in the pathophysiology of arthritis . Additionally, we demonstrated an IL-17-IgA link in the joint since SFMC secreted anti-LPS IgA in response to stimulation with medium conditioned with SF containing different IL-17 concentrations (Fig. 2d). In line with this finding, a relationship between TH17 and B-cell differentiation has been identified . In addition, it has been recently reported that lung IgA response is dependent on TH17 cells since depletion of IL-17 ablates IgA responses in the lung . Moreover, IL-17 has been involved simultaneously in both aggravating intestinal inflammation and promoting the development of rapidly progressive IgA nephropathy in patients with Crohn’s disease . These findings demonstrate a connection between bacterial stimulation, IL-17 and promotion of local IgA response in arthropathies. We found that IL-6 was not essential for IL-17 effects. In line, IL-6 was not required for IgA+ B cell development or specific mucosal IgA responses in other in vivo systems [43, 44].
We demonstrated that SF with elevated IL-17 and TGF-β1 levels had higher anti-LPS IgA levels reinforcing TH17-IgA connection in arthritis. TGF-β1 is a direct regulator of class switching to IgA [19, 45, 46]. Therefore, to investigate whether IL-17 works indirectly for helping the synovial IgA response, we analyzed the relationship between IL-17 and TGF-β1. Our data indicated that medium conditioned with SF containing IL-17 induced TGF-β1 production by SFMC. Accordingly, the SF with both cytokines showed the higher levels of IgA in SF. Interestingly, SF containing TGF-β1 but lacking IL-17 showed low IgA concentration suggesting that IL-17 or TH17 cytokines may play an essential role for synovial IgA generation. A recent report further demonstrated that TH17 cells may convert into T follicular helper (TFH) cells in Peyer’s patches and induce intestinal IgA . It has been shown that IL-21 can modulate B cell differentiation by enhancing TGF-β1-driven IgA production . Moreover, Cao et al have recently demonstrated that IL-21, produced by both TH17 and TFH cells, can augment IgA responses mediated by TGF-β1 and retinoic acid in the intestine, and intestinal sources of IL-21 directly induce IgA production . Therefore, the role of IL-21 in IgA generation in the joint will require further investigation. However, it has been also demonstrated that TH17 cell cytokines, IL-17 and IL-21 are able to function indirectly to induce IgA production by promoting the expression of BAFF . In line, our data showed that SF with detectable levels of IL-17 but lacking TGF-β1 had elevated levels of IgA (Fig. 3d) and BAFF (Fig. 4b). These results indicate alternative promotion of TGF-β1 and BAFF by IL-17 for synovial IgA generation. Moreover, blockade of IL-17 functions using a specific monoclonal antibody reduced the induction of TGF-β1 and anti-LPS IgA in SF-stimulated SFMCs. We assume that these findings support again the IL-17 effects on the induction of synovial TGF-β1 and IgA. Remarkably, IgA concentration has been related with active arthritis [9, 10], and in the last decade it has become clear that IgA is a very potent stimulus to initiate pro-inflammatory cellular processes . Our study demonstrates the association between IL-17 and IgA responses in the microenvironment of the joint.
Taken together, our results revealed that combined secretion of IL-17, IL-6 and TGF-β1 is a hallmark of inflammatory arthropathies. Moreover, our findings sustain the notion that synovial IL-17 is sensitive to bacterial enteroantigens derived from intestinal infections. These data support an association between IL-17 and IgA responses in the joint, and the involvement of TGF-β1 and BAFF in the mechanisms of IgA-induction by IL-17.
American College of Rheumatology
analysis of variance
28-joints disease activity score
the European Spondyloarthopathy Study Group
enzyme-linked immunosorbent assay
heat killed Yersinia
inflammatory bowel disease
synovial fluid-derived mononuclear cells
- TGF-β1 :
transforming growth factor-β1
B-cell-activating factor of the TNF family
The authors thank Dr Kapperud (Department of Bacteriology, Oslo, Norway) who kindly provided Yersinia enterocolitica O:8, strain WA-314, and Dr. Adriana Gruppi (National University of Córdoba, Argentina) who provided kindly ELISA kit for BAFF determination.
This work was supported by grants from the National Agency for Promotion of Science and Technology (PICT-2008-763, PICT-2011-732), the National University of San Luis (PROICO-2-1114) and Sales Foundation. RJE, MGL, GAR and MSG are members of the Scientific Career of the National Council of Scientific and Technical Investigations (CONICET); JES and MND are postgraduate fellows of CONICET.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article.
RJE, JES and MGL performed ELISA, cell culture and data analysis; MND performed ELISA, radial immunodiffusion assay and data analysis; HT, AM and RB collected synovial fluids and performed clinical data gathering; GAR contributed to manuscript preparation and comments; MSDG designed the project, performed ELISA, statistical analysis, data interpretation and manuscript preparation. All authors read and approved the final manuscript.
The authors declare they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The study was approved by the Ethics Committee of the National University of Cuyo, Mendoza, Argentina. Informed consent was obtained from all patients included in the study. The principles of Helsinki Declaration 1975/83were followed.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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