IL-17 Axis Research Articles

Role of interleukin-23/interleukin-17 axis in T-cell-mediated actions in hypertension.

Current knowledge suggests that hypertension is in part mediated by immune mechanisms. Both interleukin (IL)-23 and IL-17 are up-regulated in several experimental hypertensive rodent models, as well as in hypertensive humans in observational studies. Recent preclinical studies have shown that either IL-23 or IL-17A treatment induce blood pressure elevation. However, the IL-23/IL-17 axis has not been a major therapeutic target in hypertension, unlike in other autoimmune diseases. In this review, we summarize current knowledge on the role of these cytokines in immune mechanisms contributing to hypertension, and discuss the potential of IL-23/IL-17-targeted therapy for treatment of hypertension.

From genes polymorphisms to mucosal expression of cytokines: evaluating IL-23/IL-17 axis in adult patients with gastritis.

Chronic inflammation is the typical sign of gastritis that may shift into gastric cancer. IL-17A and IL-17F as a novel inflammatory cytokines subset of CD4+Th play the main role in inflammation. A key cytokine receptor in the inflammatory IL-17/IL-23 axis, the interleukin 23 receptor (IL23R), may be related to gastritis. We evaluated the correspondence between IL-17A G197A, IL-17F A7488G and IL23R+2199 A/C polymorphisms with TGF-β1, IL-6, IL-17, IL-21 and IL-23 mucosal mRNAs expression in uninfected H. Pylori (HP) chronic gastritis patients. Total RNA and genomic DNA were separated from gastric biopsies of 44 patients with gastritis. Subsequently, mucosal mRNAs expression of TGF-β1, IL-6, IL-17, IL-21 and IL-23 were assessed by real-time PCR. To polymorphisms determination of IL-17A G197A, IL-17F A7488G and IL-23R +2199A/C the PCR-RFLP was used in gastric biopsies. Results point that IL-17A G197A, IL-17F A7488G and IL23R +2199A/C polymorphisms did not influence the mucosal expression of TGF-β1, IL-6, IL-17 and IL-21 (p> 0.05). In an opposite result, we don't find a correspondence between IL-17A G197A, IL-17F A7488G polymorphisms and mucosal expression of IL-23 (p> 0.05). In a contrary, we found a correlation between IL23R +2199A/C polymorphism and mucosal expression of IL-23 in patients with chronic gastritis (p< 0.05). These findings propose that IL23R +2199A/C polymorphism may change the mucosal expression of IL-23 pattern in patients with gastritis disease in the absence of HP, but to support the conclusion, more research may be required.

Interleukin 23 is elevated in the serum of patients with SLE.

Aim: Interleukin-23 (IL-23) is a cytokine that promotes the differentiation of T cells into pro-inflammatory Th17. We have previously shown that IL-23 is upregulated in systemic lupus erythematosus (SLE) patients and lupus prone mice. As SLE is highly heterogeneous, we asked whether IL-23 production correlates with different manifestations of the disease.Methods: We recruited 56 subjects who fulfilled the ACR criteria for SLE. Interleukin-23 was measured in the serum by ELISA.Results: IL-23 levels were positively correlated with the overall SLE disease activity as measured with the SLEDAI. Moreover, IL-23 correlated with the skin, renal domains of SLEDAI and arthritis but not with cytopenias or serositis. IL-23 did also correlate with anti-dsDNA antibody positivity and inversely correlated with C3 levels. We found no relationship between patients' demographics, prior disease manifestations, medications, or autoantibody profile and IL-23 levels. No immunomodulatory medication seemed to be affecting IL-23 levels suggesting that current medications used in SLE are not as effective in shutting down the IL-23/IL-17 axis. Conclusions: IL-23 levels track SLE disease activity mostly in the renal, skin and musculoskeletal domains. Our data suggest that IL-23 inhibitors may be helpful in combination with current standard of care in alleviating arthritis, renal and cutaneous manifestations of the disease.

Annulation reaction enables the identification of an exocyclic amide tricyclic chemotype as retinoic acid Receptor-Related orphan receptor gamma (RORγ/RORc) inverse agonists

RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.

799 Acute IL-17A production by a 3D immunocompetent psoriatic skin substitute to study the interaction between epithelial and immune cells

Psoriasis is a chronic inflammatory dermatosis mediated by T cells through the IL-23/IL-17 axis. The hallmark cytokine of the Th17 cells, IL-17A, activates keratinocytes leading to the secretion of various chemokines that also account for leukocytes infiltration, thus producing an activation loop leading to the chronicization of the psoriatic lesions. The lack of suitable preclinical models reflecting the complex phenotype of this skin disease is a major obstacle to the further study of psoriasis pathogenesis. In this study, we aimed to optimize T cell culture methods and their incorporation into a 3D models in order to obtain long-term IL-17A production. To this end, both healthy (HS) and psoriatic (PS) skin substitutes have been produced according to the self-assembly method. T cells were isolated from whole blood by negative selection with the EasySep Direct Human T cell isolation kit and activated with phorbol 12-myristate 13-acetate (PMA, 25ng/ml) and ionomycin (1μg/ml). Activated T cells were then seeded into the 3D skin models. The location of CD3+ T cells within the skin substitutes was demonstrated by immunofluorescence staining. PS displayed a more pronounced leucocyte infiltration than HS. Compared to the previous activation method, the activation with PMA and ionomycin allowed the production of IL-17A. Moreover, a higher production of IL-17A was obtained with the psoriatic skin model than with the healthy one (p<0.001). Overall, these results suggest that the 3D immunocompetent psoriatic skin model is a promising tool for the study of the psoriasis pathogenesis as it allows to further mimic the physiopathological context found in native psoriatic skin.

763 Exosomes derived from human umbilical cord mesenchymal stem cells relieve psoriasis-like skin inflammation

Exosomes are microvesicles secreted from the endosomal membrane and have been shown to act as regulators of cell-cell communication.The immunomodulatory effect of mesenchymal stromal cells (MSCs) is partially mediated by MSC-derived exosomes (MSC-exo).MSC-exo are a very attractive candidate for cell therapy applications in several inflammatory diseases.Psoriasis is a chronic immune-mediated inflammatory skin disease.In recent years,studies have proved that the IL-23/IL-17 axis is closely related to the immunological pathogenesis of psoriasis,and plays a key role in the occurrence and development of psoriasis.Because of the immunomodulatory properties of umbilical cord mesenchymal stem cell-derived exosomes (hucMSCs-Exo),we investigated whether hucMSCs-Exo can ameliorate psoriasis inflammation,and explored the underlying mechanisms.

880 Targeted IL-17RA antagonism ameliorates histological and transcriptomic features of hidradenitis suppurativa: A proof of concept study

Hidradenitis Suppurativa is an autoinflammatory disorder of keratinization with a major inflammatory contribution from the Th17 axis. We have previously shown that in addition to previously described IL-17A & IL-17F; IL-17C is found at higher levels by both IHC and rt-PCR in lesional HS skin. We asked whether the IL-17 axis mediates disease activity by using an IL-17RA antagonist Brodalumab to examine histological and transcriptomic features of disease in 10 individuals with HS. Biopsies as per previously published consensus criteria were taken at Baseline and at Weeks 4 and 12 after treatment with an IL-17RA antagonist. Elevated levels keratinocyte derived genes (S100A9: logFCH =10.19; CXCL1: logFCH=5.46; CXCL8: logFCH=5.2), B-cell associated genes (IGHG3: logFCH=14.49) and cell trafficking chemokines (CXCl13: logFCH=7.62) were significantly elevated compared to normal site matched controls. IL-17RA antagonism resulted in statistically significant reductions in CXCL1, CXCL8, IL-36a to the level of unaffected HS patient tissue as confirmed by rt-PCR by Week 4. Histology demonstrates a significant reduction in CD11+ and CD3+ dermal cells (measured by quantitative IHC) by week 4 (p<0.01) continuing on to Week 12. Significant reductions in transepithelial neutrophil trafficking (measured by quantitative IHC) into dermal epithelialized tunnels was also noted. Morphological changes in epidermal psoriasiform hyperplasia were seen by Week 12 of therapy. Epidermal psoriasiform hyperplasia and trans-epithelial neutrophil migration in HS epidermis and epithelialized tunnels have parallels with Psoriasis Vulgaris and Generalized Pustular Psoriasis. IL17RA antagonism demonstrates rapid (by week 4) reduction in expression of B and T cell trafficking chemokines as measured by RT-PCR and significant alterations in epidermal morphology by Week 12. This highlights the role of IL-17 mediated feed-forward inflammation as in psoriasis and transepithelial neutrophil trafficking in dermal tunnels in HS.

Dithranol targets keratinocytes, their crosstalk with neutrophils and inhibits the IL-36 inflammatory loop in psoriasis.

Despite the introduction of biologics, topical dithranol (anthralin) has remained one of the most effective anti-psoriatic agents. Serial biopsies from human psoriatic lesions and both the c-Jun/JunB and imiquimod psoriasis mouse model allowed us to study the therapeutic mechanism of this drug. Top differentially expressed genes in the early response to dithranol belonged to keratinocyte and epidermal differentiation pathways and IL-1 family members (i.e. IL36RN) but not elements of the IL-17/IL-23 axis. In human psoriatic response to dithranol, rapid decrease in expression of keratinocyte differentiation regulators (e.g. involucrin, SERPINB7 and SERPINB13), antimicrobial peptides (e.g. ß-defensins like DEFB4A, DEFB4B, DEFB103A, S100 proteins like S100A7, S100A12), chemotactic factors for neutrophils (e.g. CXCL5, CXCL8) and neutrophilic infiltration was followed with much delay by reduction in T cell infiltration. Targeting keratinocytes rather than immune cells may be an alternative approach in particular for topical anti-psoriatic treatment, an area with high need for new drugs.

Frontline Science: Activation of metabolic nuclear receptors restores periodontal tissue homeostasis in mice with leukocyte adhesion deficiency-1.

β2 Integrins mediate neutrophil-endothelial adhesion and recruitment of neutrophils to sites of inflammation. The diminished expression of β2 integrins in patients with mutations in the ITGB2 (CD18) gene (leukocyte adhesion deficiency-Type 1; LAD1) results in few or no neutrophils in peripheral tissues. In the periodontium, neutrophil paucity is associated with up-regulation of IL-23 and IL-17, which drive inflammatory bone loss. Using a relevant mouse model, we investigated whether diminished efferocytosis (owing to neutrophil scarcity) is associated with LAD1 periodontitis pathogenesis and aimed to develop approaches to restore the missing efferocytosis signals. We first showed that CD18-/- mice phenocopied human LAD1 in terms of IL-23/IL-17-driven inflammatory bone loss. Ab-mediated blockade of c-Mer tyrosine kinase (Mer), a major efferocytic receptor, mimicked LAD1-associated up-regulation of gingival IL-23 and IL-17 mRNA expression in wild-type (WT) mice. Consistently, soluble Mer-Fc reversed the inhibitory effect of efferocytosis on IL-23 expression in LPS-activated Mϕs. Adoptive transfer of WT neutrophils to CD18-/- mice down-regulated IL-23 and IL-17 expression to normal levels, but not when CD18-/- mice were treated with blocking anti-Mer Ab. Synthetic agonist-induced activation of liver X receptors (LXR) and peroxisome proliferator-activated receptors (PPAR), which link efferocytosis to generation of homeostatic signals, inhibited the expression of IL-23 and IL-17 and favorably affected the bone levels of CD18-/- mice. Therefore, our data link diminished efferocytosis-associated signaling due to impaired neutrophil recruitment to dysregulation of the IL-23-IL-17 axis and, moreover, suggest LXR and PPAR as potential therapeutic targets for treating LAD1 periodontitis.

Noncoding RNAs modify GATA3-driven transcription, leading to the immune profiles seen in psoriasis and atopic dermatitis

Abstract Atopic dermatitis (AD) and psoriasis are clinical manifestations of immune dysregulation in the skin. Psoriasis is generally classified as a T cell-mediated, IFN-γ dependent disease, while AD is skewed toward interleukin (IL)-4 dependence. Consistent with these classifications are clinical observations that IL-4 improves psoriasis disease score and an IL-4 receptor blocking antibody is approved for treatment of severe AD. However, the immunobiology is far more complex, as IL-13, often produced by IL-4 dependent T cells, can be elevated in psoriasis. Since GATA3 controls both IL-4 and IL-13 expression, we propose that regulation of GATA3 differs between the two diseases, resulting in overlapping yet distinct cytokine profiles. Our meta-analysis of two RNA sequencing profiles for each disease identified a noncoding RNA of unknown function (NRUF) in all four datasets (p&amp;lt;1×10−10). Upon analyzing 48 datasets of immune responses to viral infection in epithelial cells and leukocytes, we found IL-13 and NRUF expression levels are most strongly correlated in lymphocytes. In T cell lines, we found elevated expression of the NRUF noncoding RNA associates with IL-4 and IL-13. However, IL-31, which is elevated in AD independently from the GATA3/IL-4/IL-13 axis, is not correlated to NRUF expression, supporting our hypothesis that NRUF drives disease pathology via the GATA3/IL-4/IL-13-dependent inflammatory response. Using overexpression or silencing approaches, we have characterized the ability of this NRUF to direct cytokine polarization of T cells from healthy control and donors with AD or psoriasis. We propose this NRUF modulates these two cutaneous diseases by regulating GATA3-based IL-4/IL-13 balance in T cells.

Treating Autoimmune Diseases by Targeting IL-23 with Gene-Silencing Pyrrole-Imidazole Polyamide.

Autoimmune diseases are a physiological state that immune responses are directed against and damage the body's own tissues. Numerous studies have demonstrated promising therapeutic effects in certain autoimmune diseases by targeting IL-23/IL-17 axis, mostly through using Abs against IL-23 or IL-17A. Pyrrole-imidazole polyamides are nuclease-resistant compounds that inhibit gene expression through binding to the minor groove of DNA. To develop a novel gene-silencing agent that targets IL-23/IL-17 axis, we designed polyamide that specifically binds to the transcription factor c-Rel-binding site located in the promoter of IL-23p19 subunit. Our study showed that this polyamide is capable of entering into nucleus with high efficiency in dendritic cells and macrophage. In addition, it prevented the binding of c-Rel to the promoter of IL-23p19 in vivo and specifically inhibited the expression of IL-23. More importantly, we demonstrated that this polyamide is therapeutically effective using both the imiquimod-induced psoriasis and experimental autoimmune uveitis mouse models. Taken together, these results indicate that pyrrole-imidazole polyamide targeting IL-23p19 could be a novel and feasible therapeutic strategy for patients with autoimmune diseases.

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience

BackgroundSystemic inflammation is an important feature of post-cardiac arrest syndrome (PCAS). This study was designed to determine whether the plasma concentrations of some circulating pro-inflammatory cytokines (interleukin-17 [IL-8], IL-22, IL-23 and IL-33) are of value in predicting the outcome of patients after return of spontaneous circulation (ROSC) during the post–cardiac arrest period.MethodsThis was a prospective observational clinical study. In total, 21 patients (survivors, n = 10; non-survivors, n = 11) who experienced cardiac arrest and successful ROSC with expected survival of at least 7 days were consecutively enrolled from January 2016 to December 2017. Of the 21 enrolled patients, ten survived were designated “survivors”. The other eleven patients died between 2 days and 1 months post ROSC. Venous blood was drawn at three time-points: baseline (< 1 h post ROSC), 2 days post ROSC and 7 days post ROSC. Plasma IL-8, IL-22, IL-23 and IL-33 were determined using commercial enzyme-linked immunosorbent assays.ResultsPlasma creatinine levels, but aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were elevated in non-survivors compared with survivors. Plasma levels of IL-17, IL-22, IL-23 and IL-33 of the 21 total patients did not change at 2 or 7 days post ROSC compared to baseline. In survivors, the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were lower than baseline. In non-survivors, plasma levels of IL-17 increased compared with baseline. Receiver operating characteristic curve analysis showed that the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were able to predict the mortality of PCAS patients, and positively correlated with Acute Physiology and Chronic Health Evaluation (APACHE)-II score and time to ROSC.ConclusionThese results provide the first evidence that the elevated plasma IL-17 and IL-23 levels are associated with poor outcome in PCAS patients. The role of IL-17/IL-23 axis post ROSC is worth paying attention to in PCAS patients.Trial registrationClinicaltrial.govNCT02297776, 2014-11-21.

Therapeutic Potential of Ixekizumab in the Treatment of Ankylosing Spondylitis: A Review on the Emerging Clinical Data.

Over the last 20 years, the greatly improved knowledges of underlying pathogenic mechanisms of AS, including the role of tumor necrosis factor (TNF), the interleukin 23/Th17 axis, and interleukin-17 (Il-17), constituted the rationale to develop biologics selectively inhibiting these pathways. For more than 10 years, anti-TNF biologics were successfully employed to treat AS, with marked improvement of signs and symptoms in around 60% of the patients. Recent knowledge of the pathophysiology of spondyloarthritis has highlighted the emerging role of the IL-17/IL-23 axis. New therapies with selective biological drugs have emerged in the treatment of this pathology. In this review, we evaluated the effects of ixekizumab, a new anti–IL-17A, that was licensed both by EMA and FDA in August 2019 for the treatment of ankylosing spondylitis. The review highlights the efficacy and safety data of the 3 randomized controlled trials (COAST V-COAST W-COAST X) and those of the extension to 52 weeks of COAST V and COAST W.

O31 IL-27 regulates the magnitude of ectopic germinal centres in experimental sialadenitis but fails to modulate IL-17 and IFNg production in CD4 T cells from patients with Sjögren's syndrome

Abstract Background A third of Sjögren’s syndrome (SS) patients develop ectopic lymphoid structures (ELS) in their salivary glands (SG). ELS play an active role in autoimmunity and contribute to the development of MALT lymphoma. Interleukin 27 (IL-27) exerts key immunomodulatory actions on numerous immune cells but its role in the formation and regulation of ELS in the SG of SS is unknown. Here we used a murine model of SG ELS to elucidate the role of IL-27 and its interaction with IL-17 in the development, regulation and function of ELS. We extended our observations on a cohort of SS patients to identify IL-27 cellular source, target cells and functional properties in modulating CD4 T cells function. Methods A single dose of reporter-encoding adenovirus was delivered directly to the SG of wild-type (WT) and IL-27RA-deficient (KO) mice to trigger ELS formation. For IL-17 blockade, anti-mouse IL-17A antibody was used. ELS development and peripheral immune responses were tracked by immuno-histopathology, FACS, and qPCR. Minor SG biopsies were collected from SS and non-specific sialadenitis (sicca) patients. Peripheral blood mononuclear cells (PBMC) isolated from SS and rheumatoid arthritis (RA) patients and age/sex-matched healthy donors (HD). For in vitro experiments PBMCs were incubated with IL-27 and analysed by FACS and cytokines levels were measured in culture supernatants. Tissue IL-27 was assessed by multicolour immunofluorescence. Results In WT mice, SG ELS formation was preceded by upregulation of IL-27p28 and infiltration of IL-27 producing cells. KO mice displayed larger, more abundant ELS in the SG. Higher expression levels of ELS-related genes (Cxcl13, Ccl19, Ltb, Aid) compared to WT mice were measured. KO mice showed an uncontrolled SG Th17 response and systemic IL-17A blockade caused a reduction in ELS size and in the expression of ELS-related genes. In SS patients SG and serum, we observed higher expression levels of IL-27 transcripts and protein, compared to sicca. SG IL-27 was selectively increased in ELS+ patients. IL-27 staining was detected in the T cell-rich areas of SG ELS often co-localizing with DC-LAMP+ dendritic cells. While IL-27 was able to significantly downregulate IL-17 production in HD and RA, CD4 T cells from patients with SS failed to downregulate IL-17 but showed an aberrant IFNγ release upon IL-27 incubation. Conclusion The IL-27-mediated restriction of Th17 expansion plays a critical role in the regulation of germinal centre response. Both in murine inducible ELS and in patients with SS, dendritic cells appear as the main cellular source of IL-27. IL-27 consistently failed to downregulate IL-17 release in CD4 T cells from SS patients, albeit its expression was increased in the ELS+ subset of SS, suggesting that a profound dysregulation of the IL-27/IL-17 axis play an important role in ELS formation in this condition. Disclosures D. Lucchesi None. R. Coleby None. E. Pontarini None. E. Prediletto None. F. Rivellese None. D. Hill None. A. Derrac Soria None. S. Jones None. I. Humphreys None. N. Sutcliffe None. A. Tappuni None. C. Pitzalis None. G. Jones None. M. Bombardieri None.

Keratinocyte: A trigger or an executor of psoriasis?

Psoriasis is a common chronic inflammatory skin disease characterized by abnormal proliferation/differentiation of keratinocytes and excessive immune cell infiltration in the dermis and epidermis. Over the past 2 decades, immune cells have been considered as the main driver of psoriasis because the neutralizing antibodies targeting the IL-23/IL-17 axis that regulates cross-talk between dendritic cells and T cells achieve tremendous success in the treatment of psoriasis. However, whether keratinocyte would be a driver of psoriasis or just an executor in response to immune cells is still under debate. In this review, we focus on the recent advances in the identification of keratinocyte as a trigger of psoriasis, summarize on the role of keratinocytes in self-perpetuating loop to maintain inflammation in psoriasis, and then discuss the possible roles of keratinocytes in the relapse of psoriasis.

Effect of biologics targeting interleukin-23/-17 axis on subclinical atherosclerosis: results of a pilot study.

Psoriasis is associated with an increased risk of developing atherosclerotic vascular disease. The hypothesis that treatment of the skin inflammation may decrease the risk of developing atherosclerosis and consequently, cardiovascular disease, is currently a focus of significant attention. To assess the effect of biologic drugs targeting the interleukin (IL)-23/IL-17 axis on selected subclinical atherosclerosis parameters in patients with psoriatic disease. In a series of patients with moderate to severe psoriasis who were eligible for biologic therapy, pulse wave velocity (PWV) and intima-media thickness (IMT) were determined before therapy and after 6months of treatment with biologics (ustekinumab, secukinumab, ixekizumab). After 6months of treatment, a marked clinical improvement of skin lesions was observed in all patients. No significant changes in PWV or IMT values were observed before (8.59±1.96mm and 0.54±0.9mm, respectively) and after 6months (8.89±2.02mm and 0.53±0.9mm) of therapy (P=0.16 and P=0.74). Systemic treatment of patients with a psoriatic disease with biologics targeting theIL-23/IL-17 axis has a possibly neutral effect on atherosclerosis. Additional studies are needed to assess the impact of newer biologic treatments on atherosclerosis.

Pregnancy status alters IL-21-mediated effects on murine B lymphocytes

A favorable outcome of pregnancy depends greatly on an adequate balance of immune protection and fetal tolerance at the fetomaternal interface. IL-21 is a pro-inflammatory cytokine associated to altered immune responses in auto-immune diseases. IL-21 has pleiotropic functions, including induction of Th17 T cells, inhibition of Treg development, and modulation antibody responses of B lymphocytes. Genetic polymorphisms of IL21 have been associated to poor pregnancy outcomes. However, the mechanism of IL-21 actions needs further evaluation. Here, we postulate that IL-21 affects splenic B cell function during pregnancy and shapes immune responses. We show that splenic B cells from CBA/J × BALB/c mice with favorable pregnancy outcome expressed lower IL21R levels than in CBA/J × DBA/2J mice, a mouse model for immune-induced bad pregnancy outcome. As a consequence, B cells from CBA/J × BALB/c mice reacted less sensitively to IL-21 than B cells from non-pregnant mice (NPM) or from CBA/J × DBA/2J mice. Also, LPS-induced apoptotic rates were altered in NPM and CBA/J × DBA/2J but not in CBA/J × BALB/c mice. This is accompanied by improved survival of B cells that produce the anti-inflammatory cytokine IL-10 upon stimulation with LPS. We also observed lower numbers of CD4+CXCR5+Bcl-6+ follicular T-helper cells (Tfh) in normal pregnant mice, compared to non-pregnant and mice with disturbed pregnancies. Our data indicates that alterations of the Tfh/IL-21/IL-10 axis may have important influence on pregnancy outcome.

Phenotypic switch to eczema in patients receiving biologics for plaque psoriasis: a systematic review.

The use of biologic therapies for the treatment of chronic plaque psoriasis has been linked to the development of atopic eczema, amongst other cutaneous adverse events. This can cause diagnostic confusion and create difficulty in the management of patients with plaque psoriasis. The main objective of this systematic review was to review all cases of eczema, including atopic eczema, reported in patients treated with biologics for chronic plaque psoriasis. PubMed, Medline and Embase databases were used to identify studies reporting eczema in patients treated with biologic therapy for chronic plaque psoriasis. A total of 92 patients were identified from 24 studies, with patients treated with either: adalimumab; etanercept; infliximab; ixekizumab; secukinumab; or ustekinumab. Factors common to some reported cases include: a prior history of atopy; eosinophilia; raised serum immunoglobulin E. Twenty-three had documented treatment outcomes; 14 had biologic therapy discontinued or switched. Management strategies included topical or oral corticosteroids, and treatment with alternative systemic agents such as ciclosporin or apremilast. This adverse event occurred in 1.0-12.1% of patients within trial data and observational studies. This review demonstrates that there are consistent reports of a switch to an atopic eczema phenotype from psoriasis in patients taking biologics inhibiting tumour necrosis factor alpha and the interleukin (IL)-17/IL-23 axis. The majority stopped the implicated biologic, but conservative management was successful in some cases. Those with an atopic diathesis may be more at risk. Elucidation of mechanisms and risk factors would contribute to optimal therapy selection for individual patients.

Introduction: Evolution of inflammatory arthritis from innate to adaptive immune mechanisms.

Introduction: Evolution of inflammatory arthritis from innate to adaptive immune mechanisms.

Leukemia inhibitory factor regulates the activation of inflammatory signals in macrophages and trophoblast cells

The pleiotropic cytokine leukemia inhibitory factor (LIF) is a key gestational factor known to establish dynamic cellular and molecular cross talk at the feto–maternal interface. Previously, we described the regulatory role of the LIF–trophoblast–IL10 axis in the process of macrophage deactivation in response to pro-inflammatory cytokines. However, the direct regulatory effects of LIF in macrophage and trophoblast cell function remains elusive. In this study, we aimed to examine whether and how LIF regulates the behavior of macrophages and trophoblast cells in response to pro-inflammatory stress factors. We found that LIF modulated the activating effects of interferon-gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in macrophages and trophoblast cells by reducing the phosphorylation levels of signal transducer and activator of transcription-1 (Stat1) and -5 (Stat5). Cell activation with IFNγ inhibited cell invasion and migration but this immobilizing effect was abrogated when macrophages and trophoblast cells were deactivated with LIF; macrophage cell motility restitution could in part be explained by the positive effects of LIF in Stat3 activation and matrix metalloproteinase 9 (MMP-9) expression. Pharmacological inhibition of Stat1 and Stat3 indicated that IFNγ-induced Stat1 activation mediated macrophage motility inhibition, and that cell motility in IFNγ-activated macrophages is restored via LIF-induced Stat3 activation and Stat1 inhibition. Moreover, IFNγ-induced TNFα gene expression was also abrogated by LIF through Stat1 inhibition and Stat3 activation. Finally, we have found that cell invasion of trophoblast cells is inhibited when they were cocultured with GM-CSF-differentiated, IFNγ-stimulated macrophages. This effect, however, was inhibited when macrophages were exposed to LIF. Overall, this in vitro study reveals for the first time the anti-inflammatory and pro-gestational activities of LIF by acting directly on macrophages and trophoblast cells.