Biologics targeting IL-17 sharply reduce circulating T follicular helper and T peripheral helper cell sub-populations in psoriasis.

Introduction: Circulating T follicular helper (cTfh) cells and circulating T peripheral helper (cTph) cells (which share common characteristics with the cTfh population) are implicated in the pathogenesis of immune-mediated and autoimmune diseases such as psoriasis (Ps). Their close interplay with the interleukin 17 (IL-17) axis and the ex vivo effect of IL-17-targeting biologic agents used to treat Ps on them are elusive. This study aimed to investigate the effect of biologics targeting IL-17 on cTfh and cTph cell subpopulations isolated from the blood of patients with Ps. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with Ps at treatment initiation and three months later. Samples were also collected from controls. Cells were stained using monoclonal antibodies. Flow cytometry assessed the fraction of cTfh (CD3+CD4+CXCR5+) and cTph (CD3+CD4+CXCR5-PD-1hi) cells.. Results: Flow cytometric analysis showed increased fractions of activated cTfh subsets including ICOS+ and ICOS+PD-1+ expressing cells, in patients compared to controls. Biologic blocking of IL-17A diminished the cTfh population. Furthermore, ICOS+ and ICOS+PD-1+ sub-populations were also inhibited. Finally, the cTph cell fraction significantly decreased after three months of successful treatment with biologics. Conclusion: Early anti-IL-17-mediated clinical remission in Ps is associated with decreased cTfh and cTph cell subpopulations.

CD32 (FcγRIIB) expression is low on CD21low B cells from systemic sclerosis patients with digital ulcers, interstitial lung disease, and anti-topoisomerase I autoantibodies.

CD21low B cells have recently been found increased in SSc-associated digital ulcers (DUs) or interstitial lung disease (ILD). To further characterize CD21low B cells which encompass autoreactive cells, we analyzed their expression of the inhibitory CD32 receptor in SSc. Peripheral blood mononuclear cells from 27 patients with SSc and 15 age-and sex-matched healthy controls (HCs) were analyzed with multicolor flow cytometry. CD21low B cells were significantly increased in patients with DUs (51.3%) compared to HCs (28.1%) and in patients with ILD (53.1%) compared to HCs. CD21lowCD32low B cells were significantly increased in patients with DUs (23.8%) compared to HCs (4.4%), in patients with ILD (28.4%) compared to HCs, and in anti-topoisomerase I (+) patients (21.5%) compared to HCs and to anti-topoisomerase I (-) patients (2.4%). Autoreactive B cells recognizing Topoisomerase I were predominantly within CD32low cell fraction. Our study further supports the autoreactive status of CD21lowCD32low B cells in SSc patients.

Cannabidiol Mediates In Vitro Attenuation of Proinflammatory Cytokine Responses in Psoriatic Disease.

Background: Cannabidiol (CBD), a substance that belongs to the phytocannabinoids, appears to exert antioxidant, neuroprotective, antipsychotic, anticonvulsant, and anticancer properties. Recent evidence supports the immunoregulatory effect of CBD on autoimmune and/or inflammatory disease. Psoriasis is a chronic skin disease. The main immune cell population involved in the pathogenesis of the disease is the interleukin- (IL-) 17-producing T helper (Th) 17 subset. Other subpopulations, such as interferon-γ (IFNγ) -producing Th1 and T cytotoxic (Tc) 1, IL-17-producing Tc17, as well as natural killer (NK) and natural killer T cells (NKT) have been implicated in psoriasis development. Purpose: The aim of the present study was to evaluate the in vitro effect of CBD on the aforementioned subpopulations isolated from patients with psoriasis using flow cytometry. Methods: Cells were stimulated in the presence or absence of CBD, stained and examined using surface and intracellular markers. Results: CBD decreased IL-17 production within the CD3, Th, and NKT cell compartments and IFNγ production within the CD3 compartment in cells isolated from patients with psoriasis. Interestingly, CBD supplementation did not inhibit production of proinflammatory cytokines in cells isolated from healthy individuals. On the contrary, IFNγ-producing Th, Tc, and NK cells increased after CBD supplementation. Conclusion: CBD provides anti-inflammatory effects in T cells isolated from patients with psoriasis. Our results could be the impetus for future investigations regarding the immunomodulatory properties of CBD and its utilization for development of CBD-containing antipsoriatic agents.

Gallic acid diminishes pro-inflammatory interferon-γ- and interleukin-17-producing sub-populations in vitro in patients with psoriasis.

Psoriasis is an inflammation of the skin mediated via the IL-23/Thl17/IL-17 pathway. We have previously demonstrated that the anthocyanin delphinidin diminishes in vitro the IL-17 and IFN-γ production of peripheral monocytes isolated by psoriasis patients (PBMCs). The degradation product of delphinidin is gallic acid (GA). This phenolic acid compound found in fruits, red wine, or green tea exerts pleiotropic antioxidant, anticarcinogenic, antimicrobial, and anti-inflammatory properties. Previous research has demonstrated the inhibitory effect of GA on pro-inflammatory transcription factors, such as STAT3, RORγt, and NF-κB, or cytokines as IL-1ß and TNF, which contribute to psoriasis development. We investigated the effect of GA in vitro on PBMCs, which were stimulated ex vivo, from 40 individuals (28 diagnosed with psoriasis vulgaris and 12 healthy controls (HCs)). In our experiments, PBMCs were cultured untreated or were activated in the presence of phorbol 12-myristate 13-acetate/ionomycin with or without GA. We utilized multicolor flow cytometry to assess the production of inteleukin-17 (IL-17) and interferon-γ (IFN-γ) in T and NK cells. GA did not alter the fractions of IL-17- or IFN-γ-producing T and IFN-γ-producing NK cells in HCs. However, in psoriasis patients, the effect of GA on that cell population was significant. Specifically, GA decreased the frequency of IL-17-producing cells within the CD3+ (T) and CD3+CD4+ (Th) compartment; the frequency of IFN-γ-producing cells within the CD3+, CD3+CD4+, and CD3+CD4- (Tc) compartment, and the frequency of IFN-γ-producing cells within the CD3-CD56+ (NK) compartment. Whether GA's effect also appears in vivo needs to be investigated in future.

A sharp decrease of Th17, CXCR3+-Th17, and Th17.1 in peripheral blood is associated with an early anti-IL-17-mediated clinical remission in psoriasis.

Psoriasis-an immune-mediated skin disease-implicates in its pathophysiology by circulating pro-inflammatory cell populations, cytokines, and their interactions with the epidermis. The direct effect of approved anti-interleukin- (IL-)17A and anti-IL-17R biologic therapy on immunophenotyping of peripheral blood mononuclear lymphocytes' (PBMCs) relative sub-population frequencies in psoriasis patients has not yet been described. Using multiparameter flow cytometry we examined T-cell subpopulations characterized by CCR6, CCR4, and CXCR3 chemokine receptor surface expression at baseline and after initiation of biologic therapy in PBMCs collected from 30 psoriasis patients. Increased CD3+CD4+CXCR3+, CD3+CD4+CCR6+CCR4+CXCR3+(CXCR3+-Th17), and CD3+CD4+CCR6+CCR4-CXCR3+(Th17.1) cell populations were observed in patients with psoriasis in comparison to healthy individuals (n = 10). IL-17 therapeutic blockade decreased CD3+CD4+CCR6+, CD3+CD4+CXCR3+, CD3+CD4+CCR6-CXCR3+(Th1), CD3+CD4+CCR6+CCR4+(Th17), CD3+CD4+CCR6+CCR4+CXCR3+(CXCR3+-Th17), and CD3+CD4+CCR6+CCR4-CXCR3+(Th17.1) cell populations in responding psoriasis patients. Moreover, CD3+CD4-CCR6+, CD3+CD4-CXCR3+, CD3+CD4-CCR6+CCR4+(Tc17), and CD3+CD4-CCR6-CXCR3+(Tc1) percentages were also inhibited. Modulation of the same cell sub-populations was also assessed in patients treated with methotrexate (n = 4), apremilast (n = 4), and anti-IL-23 biologic treatment (n = 4). In our study, the levels and functional capacity of peripheral pro-inflammatory Th1, Th17, and additional CCR6+T cell sub-gated populations from psoriasis patients that were treated with anti-IL-17 or anti-IL-17R targeted biologic therapy were explored for the first time. Our data clearly demonstrate that early anti-IL-17 mediated clinical remission is accompanied by a significant decrease of Th1, Th17, CXCR3+-Th17, and Th17.1 cells.

Tetracyclines Diminish In Vitro IFN-γ and IL-17-Producing Adaptive and Innate Immune Cells in Multiple Sclerosis.

Introduction: Limited data from clinical trials in multiple sclerosis (MS) reported that minocycline, a widely used antibiotic belonging to the family of tetracyclines (TCs), exerts a beneficial short-lived clinical effect A similar anti-inflammatory effect of minocycline attributed to a deviation from Th1 to Th2 immune response has been reported in experimental models of MS. Whether such an immunomodulatory mechanism is operated in the human disease remains largely unknown. Aim: To assess the in vitro immunomodulatory effect of tetracyclines, and in particular minocycline and doxycycline, in naïve and treated patients with MS. Material and Methods: Peripheral blood mononuclear cells from 45 individuals (35 MS patients, amongst which 15 naïve patients and 10 healthy controls, HCs) were cultured with minocycline or doxycycline and conventional stimulants (PMA/Ionomycin or IL-12/IL-18). IFN-γ and IL-17 producing T-, NK- and NKT cells were assessed by flow cytometry. The effect of TCs on cell viability and apoptosis was further assessed by flow cytometry with Annexin V staining. Results: Both tetracyclines significantly decreased, in a dose dependent manner, IFN-γ production in NKT and CD4+ T lymphocytes from MS patients (naïve or treated) stimulated with IL-12/IL-18 but did not decrease IFN-γ producing CD8+ T cells from naive MS or treated RRMS patients. They also decreased IL-17+ T and NKT cells following PMA and Ionomycin-stimulation. Tetracyclines did not affect the viability of cell subsets. Conclusion: Tetracyclines can in vitro suppress IFN-γ and IL-17- producing cells from MS patients, and this may explain their potential therapeutic effect in vivo.

In Mixed Lymphocyte Reaction, the Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat Suppresses Cellular and Humoral Alloimmunity.

Hypoxia-inducible factor (HIF) prolyl-hydroxylase inhibitors are currently used for the treatment of renal anemia. Since HIF affects immune cells, we evaluated the effect of such a drug, the roxadustat, on adaptive immunity. Cell proliferation was assessed in a two-way mixed lymphocyte reaction (MLR) with BrdU assay. In CD4+ T cells isolated from the two-way MLRs, western blotting was performed to detect the impact of roxadustat on HIF-1α and HIF-2α, the apoptotic marker cleaved caspase-3, and the master transcription factors of CD4+ T cells differentiation towards Th1, Th2, Th17, Treg and Tfh subsets. The signature cytokines of the above CD4+ T-cell subsets IFN-γ, IL-4, IL-17, IL-10, and IL-21 were measured in the supernatants. For assessing humoral immunity, we developed a suitable antibody-mediated complement-dependent cytotoxicity assay. Roxadustat stabilized HIF-1α and HIF-2α, suppressed cell proliferation, inhibited CD4+ T-cell differentiation into Th1 and Th17 subsets, while it favored differentiation towards Th2, Treg and Tfh. Roxadustat suppressed humoral immunity too. These immunosuppressive properties of roxadustat indicate that the recently introduced HIF prolyl-hydroxylase inhibitors in medical therapeutics may render the patients vulnerable to infections. This possibility should be further evaluated in clinical trials.

Autoantibodies against specific nuclear antigens are present in psoriatic disease and are diminished by secukinumab.

Anti-nuclear antibodies (ANA) are frequently detected in patients with psoriasis (Ps) and psoriatic arthritis (PsA), but their target autoantigens remain unknown. We assessed antibody (ab) reactivity against 23 known nuclear antigens in patients with Ps and PsA and assess the effects of secukinumab (anti-IL17A) treatment on ANA levels. A total of 201 patients, 101 with Ps and 100 with PsA, and 50 ANA-negative healthy controls (HCs) were tested for ANAs by a line immunoassay testing reactivity to 23 nuclear antigens. Ab reactivity to at least 1 antigen was found in 20.4% psoriatic disease patients (25.7% Ps and 15% PsA) compared to 8% HCs (p = ns), the most frequent being against dense fine speckled 70 (DFS70) (6.5%). In Ps and PsA patients with secukinumab-induced remission, anti-DFS70 and other antigen-specific autoantibodies were diminished over time. No decline was noted for IgG abs against antigens from pathogens such as cytomegalovirus, Epstein-Barr virus and Helicobacter pylori. Autoantibody decrease was associated with significant reduction of plasmablasts, follicular B and follicular T cells. In conclusion, one third of antigen-specific ANA patients with psoriatic disease recognize DFS70. Secukinumab decreases nuclear antigen autoreactivity, plasmablasts, follicular B and follicular T cells, highlighting a new mechanism of its action.

Curcumin mediates attenuation of pro-inflammatory interferon γ and interleukin 17 cytokine responses in psoriatic disease, strengthening its role as a dietary immunosuppressant.

Curcumin exhibits anti-inflammatory properties and has been used for centuries in traditional medicine and as dietary supplement. Data from clinical trials has strengthened the notion that curcumin may exert an anti-inflammatory and immunosuppressive role in patients with psoriatic disease, but its mode of action has remained elusive. We hypothesized that curcumin could inhibit interferon (IFN)-γ and interleukin (IL)-17 production in peripheral blood mononuclear cells from patients with psoriasis and psoriatic arthritis (PsA). To this end, we assessed the in vitro effect of curcumin on IFN-γ production by cluster differentiation (CD)4(+), CD8(+) T cells, natural killer (NK) and NKT cells and on IL-17 production by CD4(+) T cells from 34 patients with psoriatic disease (22 with psoriasis and 12 with PsA); 15 normal subjects were included as healthy controls. We also assessed the effect of curcumin on signal transducer and activator of transcription (STAT)3 activation. Curcumin significantly decreased, in a dose dependent manner, IFNγ-production by CD4(+) and CD8(+) T cells, and NK and NKT cells in patients with psoriatic disease and healthy controls. It also decreased IL-17 production by CD4(+) T cells (Th17). At the molecular level, curcumin increased STAT3 serine 727 phosphorylation intensity and p-STAT3(+) CD4(+) T cells in patients with PsA and psoriasis. In conclusion, curcumin in vitro inhibits pro-inflammatory IFN-γ and IL-17 production in psoriatic disease, and this may strengthen its role as a dietary immunosuppressant in patients with this disease.

p38 mitogen-activated protein kinase impairment of innate immune cells is a characteristic feature of HBeAg-negative chronic hepatitis B.

The mitogen-activated protein kinase p38 (MAPK) is implicated in the induction of immune responses by regulating the differentiation of T lymphocytes and production of cytokines. Our aim was to investigate p38MAPK phosphorylation in different stages of the natural history of hepatitis B virus (HBV) infection. Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Hypaque density-based centrifugation from 10 patients with HBeAg-negative chronic hepatitis B [HBeAg(-) CHB;HBV-DNA>2000IU/mL], eight patients with HBeAg-negative chronic HBV infection [HBeAg(-) CI;undetectable HBV-DNA] and 8 healthy controls (HCs). p38MAPK phosphorylation was assessed by phospho-specific flow cytometry in PBMCs and cell subsets (CD3+,CD3-,CD56+,CD56-) after stimulation with cytokines (IL-12+IL-2 and IL-12+IL-18) or nonspecific stimuli [arsenite, phorbol 12-myristate 13-acetate (PMA) and ionomycin] at 0,30,60,120 and 240 minutes using p38 phospho-specific conjugated antibodies. ΙFN-γ was determined by ELISA in PBMCs culture supernatants after stimulation with rhIL-2, rhIL-12 and rhIL-18, with and without pre-treatment with the p38 MAPK inhibitor, SB203580. HBeAg(-) CI patients showed the highest expression of phosphor-p38 MAPK in total PBMCs and subpopulations compared to HBeAg(-) CHB and HCs. A striking impairment in p38 phosphorylation was noted in CD56+ cells and in especially in NK cells (CD3-CD56+). SB203580-induced inhibition of p38MAPK phosphorylation was associated with suppression of IFN-γ production in all groups. The universal lack of p38 MAPK activation in CD56+ and in particular in NK cells from HBeAg(-) CHB patients during viremia suggests a potential cell-dependent implication of this pathway in the natural history of HBV infection.

On the immunoregulatory role of statins in multiple sclerosis: the effects on Th17 cells.

Statins, the cholesterol-lowering drugs, also possess immunomodulatory properties, affecting among others T cell activation and differentiation, antigen presentation, and regulatory T cell (Tregs) maintenance and differentiation. Their effects on autoagression have led investigators to assess their clinical significance in autoimmune disease, such as multiple sclerosis (MS), a chronic progressive demyelinating disease of autoimmune nature. The dysregulated immunity noted in MS features a profound shift from Tregs dominance to Th17 cell superiority. In this review, we discuss the immunobiological basis of statins, their role in autoimmunity related to MS, and the data from experimental models and human studies on their effect on Th17 cells.

Apremilast increases IL-10-producing regulatory B cells and decreases proinflammatory T cells and innate cells in psoriatic arthritis and psoriasis.

OBJECTIVES: Psoriatic arthritis (PsA) and psoriasis are immune-mediated inflammatory diseases sharing common immunological mechanisms. Regulatory B cells (Breg cells) producing IL-10 (B10 cells), a critical anti-inflammatory B-cell subset, were found to be decreased in both PsA and psoriasis. Apremilast, a phosphodiesterase-4(PDE4) inhibitor, increases IL-10 and therefore, we examined the effect of apremilast on Breg cells. METHODS: Fifty patients, including 20 with PsA and 30 with psoriasis, were included in the study. The effect of apremilast on Breg cells at 3, 6 and 12 months post-treatment, was examined by flow cytometry in ODN2006 (TLR9)-stimulated peripheral blood mononuclear cells and magnetically-isolated cells. Th1 cells, Th17 cells and NKT were also measured. RESULTS: Ex vivo stimulated cell analysis identified that post-apremilast (IL-10+CD19+) B10 cells were increased in all PsA and psoriasis patients and correlated with psoriatic skin and joint clinical improvement. Apremilast decreased IFNγ(+) T and NKT cells and IL-17(+)NKT cells. B10 cells also inversely correlated with Th1 cells, and IFNγ(+)NKT cells. CONCLUSION: These results suggest that Breg cells are a major target of apremilast in PsA and psoriasis and that apremilast-induced increase of Breg cells is associated with a decrease of Th1 cells, IFNγ-producing NKT cells and IL-17-producing NKT cells.

Regulatory B cells: New players in inflammatory and autoimmune rheumatic diseases.

OBJECTIVE: Regulatory B cells (Bregs) are a new subset of B cells with immunoregulatory functions, mainly through IL-10 production. Bregs suppress inflammatory Th1 and Th17 differentiation and induce Tregs suppressing autoimmune diseases. The aim of the study was to review the literature related to Bregs in autoimmune rheumatic diseases (ARDs). METHODS: A literature review of publications in PUBMED published in English was performed using the relevant combinations of terms. RESULTS: All relevant publications are discussed. Overall, recent studies in rheumatic diseases found Bregs to be decreased in ANCA-associated vasculitides (AAV) and in systemic sclerosis (SSc), particularly in SSc-associated lung fibrosis. In AAV Bregs levels are negatively correlated with autoantibody levels whereas in SSc this association is less clear but there is an inverse association with Th1 and Th17 cells. In rheumatoid arthritis (RA), Bregs were decreased, particularly in RA-associated lung fibrosis. In psoriatic arthritis IL-10 + Bregs are decreased and inversely associated with Th1 and Th17 cells. In systemic lupus erythematosus (SLE), the role of Bregs is unclear. In experimental diseases, when Bregs were expanded ex-vivo, they ameliorated established disease. CONCLUSION: Bregs appear to be a new player in the pathogenesis of ARDs, and may offer a new strategy for therapeutic intervention.

Regulatory B and T lymphocytes in multiple sclerosis: friends or foes?

Current clinical experience with immunomodulatory agents and monoclonal antibodies in principle has established the benefit of depleting lymphocytic populations in relapsing-remitting multiple sclerosis (RRMS). B and T cells may exert multiple pro-inflammatory actions, but also possess regulatory functions making their role in RRMS pathogenesis much more complex. There is no clear correlation of Tregs and Bregs with clinical features of the disease. Herein, we discuss the emerging data on regulatory T and B cell subset distributions in MS and their roles in the pathophysiology of MS and its murine model, experimental autoimmune encephalomyelitis (EAE). In addition, we summarize the immunomodulatory properties of certain MS therapeutic agents through their effect on such regulatory cell subsets and their relevance to clinical outcomes.

Curcumin for the Management of Periodontitis and Early ACPA-Positive Rheumatoid Arthritis: Killing Two Birds with One Stone.

We propose curcumin as a preventive measure to avoid/manage periodontitis (PD), and as a natural immunosuppressant for rheumatoid arthritis (RA). PD, mainly caused by Porphyromonas gingivalis forming biofilm and leading to tooth decay, is a major public health issue and a risk factor for the development of RA in humans. P. gingivalis is able to trigger experimental autoimmune arthritis in animal models and in humans can induce citrullinated peptides, which not only are a source of anti-citrullinated antibodies (ACPAs), but also participate in autoreactive responses and disease development. Curcumin appears to have efficient anti-bacterial activity against P. gingivalis infection and biofilm formation. In addition to antibacterial, anti-oxidant, and anti-inflammatory action, curcumin exerts unique immunosuppressant properties via the inhibition of Th17 pro-inflammatory responses and promotion of regulatory T cells, thus suppressing autoimmunity. We introduce curcumin as a natural product for the management of both PD and RA-related autoreactivity, possibly also as a preventive measure in early RA or individuals at high risk to develop RA.

The Role of Invariant NKT in Autoimmune Liver Disease: Can Vitamin D Act as an Immunomodulator?

Natural killer T (NKT) cells are a distinct lineage of T cells which express both the T cell receptor (TCR) and natural killer (NK) cell markers. Invariant NKT (iNKT) cells bear an invariant TCR and recognize a small variety of glycolipid antigens presented by CD1d (nonclassical MHC-I). CD1d-restricted iNKT cells are regulators of immune responses and produce cytokines that may be proinflammatory (such as interferon-gamma (IFN-γ)) or anti-inflammatory (such as IL-4). iNKT cells also appear to play a role in B cell regulation and antibody production. Alpha-galactosylceramide (α-GalCer), a derivative of the marine sponge, is a potent stimulator of iNKT cells and has been proposed as a therapeutic iNKT cell activator. Invariant NKT cells have been implicated in the development and perpetuation of several autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (SLE). Animal models of SLE have shown abnormalities in iNKT cells numbers and function, and an inverse correlation between the frequency of NKT cells and IgG levels has also been observed. The role of iNKT cells in autoimmune liver disease (AiLD) has not been extensively studied. This review discusses the current data with regard to iNKT cells function in AiLD, in addition to providing an overview of iNKT cells function in other autoimmune conditions and animal models. We also discuss data regarding the immunomodulatory effects of vitamin D on iNKT cells, which may serve as a potential therapeutic target, given that deficiencies in vitamin D have been reported in various autoimmune disorders.

IL-35: a new immunomodulator in autoimmune rheumatic diseases.

IL-35 is a relatively new cytokine that emerges as an important immunomodulator. IL-35 belongs to IL-12 cytokine family that includes IL-12, IL-23, IL-27, and IL-35. These cytokines are heterodimers that share subunits and their receptors also share subunits. Whereas IL-12 and IL-23 are clearly proinflammatory cytokines, the role of IL-35 is less clear. In mice, IL-35 appears to be anti-inflammatory and to protect from autoimmune inflammatory diseases. IL-35 induces the expansion of a subset of regulatory T cells (Tregs) and Bregs and mediates their suppressive function and inhibits Th17 cells. It also upregulates osteoprotegerin and suppresses RANKL, thus inhibiting bone resorption. In autoimmune rheumatic diseases, findings are conflicting, although in systemic lupus erythematosus, there is reduced function of IL-35. In psoriatic arthritis, a disease characterized by bone erosion and bone formation in peripheral joints and bone formation in spinal joints, serum levels of IL-35 were found increased in one study. Further data are required to define the exact role of IL-35 in human autoimmune rheumatic diseases.

The Role of Flavonoids in Inhibiting Th17 Responses in Inflammatory Arthritis.

Flavonoids have been considered powerful anti-inflammatory agents, and their exact immunomodulatory action as therapeutic agents in autoimmune diseases has started to emerge. Their role in the manipulation of immunoregulation is less understood. Several studies attempted to investigate the role of various flavonoids mainly in experimental models of autoimmune diseases, especially in the context of their potential effect on the increase of regulatory T cells (Tregs) and their ability to stimulate an overexpression of anti-inflammatory cytokines, in particular that of IL-10. The emergence of IL-17, a cytokine largely produced by Th17 cells, as a powerful proinflammatory stimulus which attenuates the induction of Tregs has prompted a series of studies investigating the role of flavonoids on Th17 cells in experimental models as well as human autoimmune diseases. This review thoroughly discusses accumulated data on the role of flavonoids on Th17 in rheumatoid arthritis and experimental autoimmune arthritis.