Current Concepts of Psoriasis Immunopathogenesis.

Psoriasis is a recurrent, chronic, immune-mediated, systemic inflammatory disease of the skin, joints, and other organic systems. After atopic dermatitis, chronic stationary psoriasis is the most common inflammatory skin disease, affecting an average of 2-4% of the world's population. The disease carries a significant burden due to its numerous comorbidities and the major impact on patients' social and emotional aspects of life. According to current knowledge, psoriasis is a multifactorial disease that occurs in genetically predisposed individuals under various environmental factors, which trigger an immune response disorder with a series of complex inflammatory cascades. The disease is initiated and maintained by mutual interaction of the innate and adaptive immune cells, primarily dendritic cells, T lymphocytes, and keratinocytes, whose leading role alternates at different stages of the disease, consisting mainly in the IL-23/Th17 pathway. Inflammatory events result in consequent epidermal and dermal changes and evolution of the characteristic psoriatic phenotype, respectively. This paper aims to present a comprehensive overview of current knowledge on psoriasis genetic and environmental etiological factors, immunopathogenesis, and the leading cellular and cytokine participants in the inflammatory pathways of this disease.

Impact of antipsychotic medication on IL-6/STAT3 signaling axis in peripheral blood mononuclear cells of drug-naive schizophrenia patients.

AIM: Immunopathogenesis remains a widely appreciated etiopathological model of schizophrenia. Persistent efforts have aimed to identify schizophrenia biomarkers indexing immune system abnormalities and also immuno-dampening effects of antipsychotic medications. Although data arising from published reports are encouraging, such studies are limited to a few immune parameters and not focused on a specific pathway. Th17 cells-mediated immuno-inflammatory responses have emerged as a potential mechanism in various neuropsychiatric conditions, including schizophrenia. The Th17 pathway is distinctly regulated through a coordinated action of multiple cytokines and transcription factors. In this study, we explored whether antipsychotic medication has any effect on the cytokines and transcription factors of the Th17 pathway. METHODS: A total of 27 drug-naive schizophrenia patients were recruited and followed up for 3 months after initiation of antipsychotic medication. Lymphocyte gene expression levels of two transcription factors (STAT3 and RORC) and one of their upstream regulators, IL6, were quantified before and after treatment. Plasma levels of cytokines, such as interleukin (IL)-1ß, IL-6, IL-17A, IL-23, and IL-33, were also analyzed before and after treatment. RESULTS: Treatment with antipsychotic medication for 3 months resulted in significant downregulation of STAT3 gene expression as well as reduction in plasma levels of IL-1ß, IL-6, and IL-17A. Significant reduction in total scores for the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms was also observed in schizophrenia patients after 3 months of antipsychotic treatment. CONCLUSION: Our findings suggest possible immuno-modulatory effects of antipsychotic medication on the critical regulators, such as IL-6 and STAT3, of the Th17 pathway in schizophrenia patients. The IL-6/STAT3 signaling axis involved in the transcriptional regulation of Th17 cells might appear as an important target of antipsychotic treatment in schizophrenia patients. Alternatively, irrespective of the effect of antipsychotic drugs, the IL-6/STAT3 signaling axis might be crucially involved in ameliorating psychotic symptoms.

Pharmacological effects of TAK-828F: an orally available RORγt inverse agonist, in mouse colitis model and human blood cells of inflammatory bowel disease.

OBJECTIVE AND DESIGN: To evaluate the potency of RORγt blockade for treatment of Inflammatory Bowel Disease (IBD), the efficacy of TAK-828F, a novel RORγt inverse agonist, in anti-TNF-α mAb non-responsive mouse colitis model and effect of TAK-828F on IL-17 production in peripheral mononuclear blood cells (PBMCs) of anti-TNF-α naive and treatment-failure patients of IBD was investigated. METHODS AND RESULTS: The colitis model showed Th17-dependent pathogenicity and response to anti-IL-12/23p40 monoclonal antibody (mAb), but no response to anti-TNF-α mAb. In the model, TAK-828F, at oral dosages of 1 and 3 mg/kg, inhibited progression of colitis and reduced the immune reaction that characterize Th17 cells. Anti-IL-17A mAb showed neither efficacy nor change in the T cell population and colonic gene expression in the model. In the normal mouse, a 4-week treatment of TAK-828F at 30 mg/kg did not severely reduce lymphocyte cell counts in peripheral and intestinal mucosa, which was observed in RORγ-/- mice. TAK-828F strongly inhibited IL-17 gene expression with IC50 values from 21.4 to 34.4 nmol/L in PBMCs from anti-TNF mAb naive and treatment-failure patients of IBD. CONCLUSIONS: These results indicate that RORγt blockade would provide an effective approach for treating refractory patients with IBD by blocking IL-23/Th17 pathway.

Th17 Inhibitors in Active Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.

BACKGROUND: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α antagonists as first-line biologic agents. We determined the overall treatment effect of Th17 pathway inhibitors compared to placebo or active control on American College of Rheumatology (ACR) 20 response at week 12 (primary objective), risk of infections, discontinuation of treatment due to adverse events, and serious adverse events during the placebo-controlled period (12-24 weeks) in adults with active PsA in published randomized controlled trials. METHODS: The SCOPUS database was searched. The Cochrane risk of bias tool was used for assessing quality. The pooled relative risk (RR) was derived from random effects models. RESULTS: Seven randomized controlled trials were included which randomized 1,718 patients to Th17 inhibitors and 840 to placebo. Patients treated with Th17 inhibitors had an RR of 2.04 (95% CI: 1.79-2.33; p < 0.001) for achieving an ACR20 response at week 12 (I2 = 0%; p = 0.89) compared to placebo-treated patients. There was no evidence of publication bias. The result was consistent for study phase and outcome (ACR50/70), mechanism of action and TNF-α naivety. RR of infections was 1.06 (0.91-1.23), that of candida infections was 3.35 (0.75-14.95), that of serious adverse events was 0.82 (0.42-1.59) and that of discontinuation of treatment was 0.54 (0.31-0.93) among treated versus placebo subjects. No incident cases of tuberculosis were reported. CONCLUSION: In patients with active PsA, biologics targeting the Th17 axis produce a clinically significant improvement in joint disease activity with acceptable safety and tolerability for short-term treatment compared to placebo.

The immune microenvironment of the colorectal tumor: Involvement of immunity genes and microRNAs belonging to the TH17 pathway.

Colorectal cancer is a complex and multifactorial disease. Various factors such as genetic, immunological, epigenetic and environmental constitute minor risk factors with their additive effects contributing to the advent of colorectal cancer. In order to evaluate the role of innate and adaptive immunity in the susceptibility, the presentation and the development of colorectal cancer, we considered an immunogenetic approach on polymorphisms in the TLR4 gene and NOD2/CARD15 gene (receptors of innate immunity) as well as in cytokine genes of the TH17 pathway IL17A, IL17F and cytokine receptor IL23R. Then, we evaluated the expression of microRNAs regulated by TLR4 and NOD2/CARD15 or targeting TLR4, IL17 and proinflammatory cytokines (IL-6, TNF) induced by IL17. Through a case-control study, we showed that the polymorphism of IL17A is associated with its susceptibility to colorectal cancer. Considering the tumor location, we found that the mutated alleles of IL17A, IL17F and IL23R are rather associated with colon cancer and not with rectum cancer. This result confirms that the colon and rectum are two different physiological entities. This study shows that TLR4, IL17A/F and IL23R polymorphisms are involved in the presentation of the disease with regard to tumor architecture, histology, and differentiation, advanced stage of the disease and lymph node and metastasis. Overall, these polymorphisms are associated with a poor prognosis of the disease. Furthermore, in order to evaluate the involvement of epigenetic mechanisms in the occurrence of colorectal cancer, we aimed at analyzing the tumor compared to a normal adjacent tissue and the expression of miRNAs (miR21, miR146a, miR135a, miR147b and miR155) that regulate immunity genes especially the cytokines of the TH17 pathway. This research has shown that microRNAs 21, 135a and 146a are associated with colorectal cancer. Indeed, these three miRs are overexpressed in cancer tissue compared to healthy tissue. These results clearly confirm the involvement of epigenetics in colorectal cancer. In other words, this study reveals the importance of immunity and specifically the TH17 pathway in the development and presentation of colorectal cancer. These results suggest that TLR4, IL17A, IL17F and IL23R polymorphisms as well as the expression of microRNAs that regulate inflammation and the TH17 pathway are associated with the evolution and progression of the colorectal tumor that could be considered as biomarkers in colorectal cancer.

Cln 3-requiring 9 is a negative regulator of Th17 pathway-driven inflammation in anti-glomerular basement membrane glomerulonephritis.

T helper 17 (Th17) lymphocytes promote renal inflammation in anti-glomerular basement membrane glomerulonephritis (anti-GBM GN), and signal transducer and activator of transcription 3 (STAT3) mediates activation of Th17 lymphocytes by IL-6 and transforming growth factor-ß (TGF-ß). Cln 3-requiring 9 (Ctr9), a subunit of RNA polymerase-associated factor complex (PAFc), regulates the transcription of IL-6/STAT3-dependent genes. Here, we investigated the role of Ctr9 in regulating Th17-driven inflammation in anti-GBM GN. In mice, STAT3ß or IL-17 knockout ameliorated anti-GBM autoantibody-induced renal injury. This phenomenon was associated with decreases in retinoic acid receptor-related orphan receptor γt (RORγt), IL-17, phosphorylated STAT3, and proinflammatory cytokines. Compared with wild-type mice, Ctr9 increased in both STAT3ß(-/-) and IL-17(-/-) mice injected with anti-GBM IgG, showing a negative correlation with Th17-related transcripts. Small interfering RNA (siRNA)-mediated knockdown of Ctr9 in intrarenal lymphocytes further upregulated Th17-related transcripts, consistent with repression of Th17 differentiation by Ctr9. Interestingly, Ctr9 was also expressed in human and mouse mesangial cells and downregulated in response to anti-GBM IgG or to TGF-ß plus IL-17. Ctr9 in mesangial cells was even more repressed in the presence of both anti-GBM IgG and Th17-activating cytokines. Consistent with these findings, renal biopsies obtained from patients with anti-GBM GN showed consistent downregulation of Ctr9 and upregulation of phosphorylated STAT3 and IL-17 in the glomerulus. We conclude that Ctr9 is a negative regulator of Th17 differentiation in anti-GBM GN and repressed by anti-GBM IgG and IL-17 in mesangial cells.

Translating the Science of Psoriasis.

Knowledge about the pathophysiology of psoriasis has evolved substantially in recent years, since the identification of the T helper 17 (Th17) cells. Cytokines produced by these cells appear to play major roles in psoriatic inflammation. The cytokine interleukin (IL)-23 appears to promote regulatory T cells to differentiate into Th17 cells. Available and investigational therapies act on targets within these pathways.

Emerging drugs for the treatment of axial and peripheral spondyloarthritis.

INTRODUCTION: The topic under discussion is of strong relevance to the field of spondyloarthritis (SpA) because, in addition to established biological, there are new promising compounds. The reason for the review is to put all available data together to allow for an overview on recent developments and to especially inform readers about emerging drugs, biologics and small molecules in the field of SpA. AREAS COVERED: This review on new therapies in axial and peripheral SpA comprising psoriatic arthritis (PsA) shows, that, in addition to the established anti-TNF agents infliximab, etanercept, adalimumab, golimumab, certolizumab and the first biosimilar approved in the EU, there are at least two emerging biologics in the field of SpA: ustekinumab, a compound targeting IL12/IL-23 via the p40 subunit of both cytokines works for psoriasis and PsA and probably also for Crohn's disease, and the anti-IL-17 antibody secukinumab which has also been shown to work in psoriasis, both compounds seem to also work in ankylosing spondylitis. In addition, the potential of two small molecules, apremilast a phoshodiesterase4 inhibitor and tofacitinib, a januskinase inhibitor is discussed. EXPERT OPINION: Since, in contrast to rheumatoid arthritis, the therapeutic array in SpA is currently limited to TNF-blockers, and since there is still an unmet need because some patients do not respond to anti-TNF therapy at all or they loose response, new agents with a different mechanism of action are eagerly awaited.

Correlation of changes in inflammatory and collagen biomarkers with durable guselkumab efficacy through 2 years in participants with active psoriatic arthritis: results from a phase III randomized controlled trial.

Background: Guselkumab (human monoclonal antibody) selectively inhibits the interleukin (IL)-23p19 subunit. Objectives: Assess the longer-term pharmacodynamic effects of guselkumab and explore associations between such effects and clinical responses in patients with active psoriatic arthritis (PsA). Design: DISCOVER-2 randomized 739 biologic-naïve patients with active PsA (swollen/tender joint counts each ⩾5, C-reactive protein (CRP) ⩾0.6 mg/dL) to guselkumab (100 mg every 4 weeks (Q4W) or at Weeks 0, 4, and then Q8W) or placebo. Guselkumab-randomized participants with available serum biomarker data (randomly selected to reflect demographic and disease characteristics of the DISCOVER-2 population) comprised inflammatory (N = 100) and collagen (N = 178) biomarker cohorts. Methods: Pharmacodynamic effects of guselkumab through 2 years on inflammatory and collagen biomarker levels (general linear model) and associations between biomarkers and improvements in composite measures of joint, skin, and overall disease activity (Spearman linear regression) through 2 years were assessed. The relationship between the pharmacodynamic effects of guselkumab and achieving ⩾50% improvement in the American College of Rheumatology response criteria (ACR50) was assessed using a general linear model. Results: With guselkumab, pharmacodynamic effects on inflammatory (CRP, IL-6, serum amyloid A (SAA), IL-17A, IL-17F, IL-22, and beta-defensin 2 (BD-2)) and collagen (matrix metalloproteinase-degradation type I, III, IV, and VI collagen (C1M, C3M, C4M, and C6M)) biomarker levels were sustained or enhanced through Week 100. Throughout follow-up timepoints (Week 24/52/100), decreases in CRP, IL-6, C1M, and C6M levels correlated (r = 0.26-0.30; p < 0.05) with improved joint disease activity (Disease Activity in Psoriatic Arthritis); decreases in IL-17A, IL-17F, IL-22, and BD-2 levels correlated (r = 0.34-0.58; p < 0.05) with improved skin disease (Psoriasis Area and Severity Index); and decreases in C1M, C3M, C4M, and C6M correlated (r = 0.27-0.31; p < 0.05) with improved overall disease activity (Psoriatic Arthritis Disease Activity Score). Significantly (p < 0.05) greater reductions from baseline at Week 100 in CRP, IL-6, SAA, and C1M levels were observed in participants improving from Week 24 ACR50 nonresponse to Week 100 ACR50 response and were accompanied by a significant decrease in C1M from Week 24 to Week 100 versus nonresponders at both Weeks 24 and 100. Conclusion: In biologic-naïve participants with active PsA, guselkumab elicited substantial and enduring reductions in biomarkers that were associated with durable improvements in joint, skin, and overall disease activity through 2 years of DISCOVER-2. Trial registration: NCT03158285 (clinicaltrials.gov identifier).

Shared Pathophysiology of Inflammatory Bowel Disease and Psoriasis: Unraveling the Connection.

Inflammatory bowel disease (IBD) and psoriasis are both chronic autoimmune diseases with a unique set of characteristics. Interestingly, both conditions share considerable overlap in their pathophysiological mechanisms and immune dysregulation. Epidemiological studies validate the relationship by showing a greater prevalence of co-occurrence of the two disorders. At the genetic level, there is a confirmation of a link between shared susceptibility loci and DNA polymorphism, particularly interleukin-23 receptor (IL23R), interleukin-12 subunit beta (IL12B), tumor necrosis factor (ligand) superfamily member 15 (TNFSF15), and signal transducer and activator of transcription 3 (STAT3). In addition, epigenetic factors have a role in genetic predisposition in the development and progression through processes such as DNA methylation and histone modification adding another layer of genetic susceptibility. The relationship between psoriasis and IBD is emphasized by a comparable immunopathogenesis, which involves delicate relationships between the innate and adaptive immune responses. The primary interest is on the T-helper 17 (Th17) cell pathway and the cytokines interleukin-17 (IL-17), interleukin-23 (IL-23), and tumor necrosis factor-alpha (TNF-α). Consequently, both disorders exhibit chronic inflammation and tissue restructuring, resulting from similar cellular and molecular processes. The presence of overlapping pathophysiology highlights the significance of implementing integrated management strategies and employing multidisciplinary techniques for both diagnosis and therapy. Hence, understanding the mutual processes might facilitate the advancement of precise biologic treatments that aim at these commonly shared inflammatory pathways.

Exploring the association between Th17 pathway gene polymorphisms and pulmonary tuberculosis.

Th17 cells play a key role in immunity against Mycobacterium tuberculosis (MTB), and this study aimed to explore the association of Th17 pathway gene polymorphisms with pulmonary tuberculosis (PTB) susceptibility in a Chinese population. A total of 10 single nucleotide polymorphisms in Th17 pathway genes (IL-17A gene rs2275913, rs3748067, rs8193036, rs3819024, IL-17F gene rs7741835, rs763780, IL-21 gene rs907715, rs2055979, IL-23R gene rs11805303, and rs7518660) were genotyped in 456 PTB patients and 466 controls using SNPscan technique. The IL-23R rs11805303 CC genotype, C allele frequencies were significantly lower in PTB patients than in controls, and the rs11805303 variant was significantly associated with the reduced risk of PTB in a recessive model. There were no significant associations between IL-17A, IL-17F, and IL-21 gene variations and PTB risk. In IL-17A gene, rs2275913, rs3748067, and rs3819024 variants were associated with drug resistance in PTB patients. In IL-17F gene, rs7741835 variant affected drug resistance, and rs763780 variant was associated with hypoproteinemia in PTB patients. In addition, the lower frequencies of the TT genotype, T allele of rs2055979 were found in PTB patients with drug-induced liver injury. Haplotype analysis showed that IL-23R CG haplotype frequency was significantly lower in PTB patients than in controls, while the TG haplotype frequency was higher. In conclusion, IL-23R rs11805303 polymorphism may contribute to the genetic underpinnings of PTB in the Chinese population, and the IL-17A, IL-17F, and IL-21 genetic variations are associated with several clinical manifestations of PTB patients.

Immunomodulatory role of Th17 pathway in experimental visceral leishmaniasis.

Visceral leishmaniasis (VL) or Kala-azar is a vector borne protozoan infection caused by Leishmania donovani in the Indian subcontinent mainly India, Nepal and Bangladesh. It is a major public health problem in these countries mostly affecting the socio-economically poor population. Leishmaniasis ranks the third most important disease after malaria and filariasis but is still considered as one of the neglected tropical diseases of the world. For development of better therapeutic agents and effective vaccine against VL, there is a need to understand host immunological changes that play a vital role during course of infection. Therefore, we investigated the role of Th17 pathway in Balb/c mice during Leishmania donovani infection and treatment with amphotericin B. Mice were divided in four groups i.e. Control, Infected, Uninfected treated and Infected treated. The cytokine levels were estimated in the spleen of Balb/c mice on days 1, 3, 7, 14, 17, 21, 28, 35, 45 and 60 post infection and during course of treatment. The mRNA levels of the Th17 pathway during active Leishmania donovani infection and after treatment were determined by real time polymerase chain reaction (RT-PCR) and protein levels by flow cytometry and ELISA. Results of our study revealed that active infection was associated with low levels of Th17 cytokines IL-17, IL-22 and IL-23 and elevated levels of IL-6, IL-1ß and TGF-ß. Amphotericin B treatment restored production of pro-inflammatory cytokines IL-17 and IL-22. The levels of transcription factor RORγt were found to correlate with the levels of IL-17 during infection and also after chemotherapy whereas STAT3 levels were elevated during infection and vice versa after treatment. The findings of this study suggest that Th17 cytokines IL-17 and IL-22 are associated with protection against VL infection and development of any interventions or chemotherapeutic agents targeting Th17 pathway could be an important approach for VL treatment.

Evidence of altered Th17 pathway signatures in the cerebrospinal fluid of patients with Guillain Barré Syndrome.

Data indexing the contribution of various immuno-inflammatory components in the cerebrospinal fluid (CSF) towards the pathophysiology of Guillain Barré Syndrome (GBS) are limited. Th17 pathway plays crucial role in many immune mediated disorders of the nervous system. This study was aimed at exploring the role of Th17 pathway related cytokines in the CSF of patients with GBS. Levels of multiple key cytokines of Th17 pathway in CSF of patients with GBS (N = 37) and controls (N = 37) were examined in this prospective study using Bio-plex Pro Human Th17 cytokine assays in a Multiplex Suspension Array platform. The findings were correlated with clinical features and electrophysiological subtypes. Three key cytokines of Th17 pathway (IL-6, IL-17A and IL-22) were significantly elevated in CSF of patients with GBS as compared to controls. There was a positive correlation between the levels of IL-6 and IL-17A as well as between the levels of IL-17A and IL-22 in the CSF of patients with GBS. The CSF levels of IL-6 and IL-22 were negatively correlated with the duration of symptoms of GBS. None of the studied cytokines correlated with functional disability scores at admission to hospital or with the electrophysiological subtypes. Identification of Th17 pathway signatures in CSF sheds more insights into the pathogenic role of Th17 cells in GBS. These findings complement the contemporary knowledge and tender further support towards the involvement of Th17 pathway in GBS.

IL-17A is not a treatment target in progressive vitiligo.

Multiple reports confirm elevated circulating IL-17 levels and increased numbers of Th17 lymphocytes in patients with non-segmental vitiligo. Additionally, melanocyte damaging characteristics have been ascribed to IL-17. A single-arm pilot study using secukinumab in active non-segmental vitiligo was conducted. The large majority of patients developed additional skin depigmentations limiting further enrollment. Overall, laboratory analysis revealed no change in secreted chemokines or Th subsets. Th17 lymphocytes correlated with Th2, Th9, and Th22 cells while an inverse link with Th1 cells and serum sCD25 levels was observed. In contrast, Th17.1 cells correlated positively with Th1 lymphocytes. Confirmatory results were found in an independent group of patients with vitiligo showing a significant increase in Th17.1 and Th1 lymphocytes in progressive vitiligo patients compared to healthy controls, which was not found for Th17 cells. These results do not support a direct pathogenic role of IL-17 or Th17 cells in vitiligo. Nonetheless, a delicate Th17/Th17.1/Th1 balance seems evident which changes markedly according to disease activity. This may offer new treatment options by interfering with cytokines that drive differentiation of Th17 cells toward Th1.

Th17 pathway signatures in a large Indian cohort of Guillain Barré syndrome.

The etiopathogenesis of Guillain Barré Syndrome (GBS) is inadequately understood. The role of immuno-inflammatory Th17 pathway was examined in GBS patients by genetic, gene expression and biochemical studies. Genotyping of G197A single nucleotide polymorphism within IL17 gene was carried out by PCR-RFLP method in 220 GBS patients. Quantification of gene expression of STAT3 and RORC and estimation of plasma level of IL-17A were carried out in a subset of patients. Significantly increased STAT3 gene expression in lymphocytes and plasma IL-17A levels were observed in GBS patients. This study adds new dimension and reinforces important implications of Th17 pathway in GBS.

Ixekizumab: an anti- IL-17A monoclonal antibody for the treatment of psoriatic arthritis.

INTRODUCTION: Psoriatic arthritis (PsA) is an inflammatory rheumatic disease that manifests itself with synovitis, dactylitis, enthesitis and also axial involvement. Interleukin-17A has been identified as a master cytokine in the inflammatory response and pathogenesis of PsA and spondyloarthritis in general. Ixekizumab is a new humanized monoclonal antibody that blocks the biological activity of IL-17A. This biological agent has previously demonstrated a high level of efficacy in psoriasis. Areas covered: This review discusses the basic immunology of the IL-17 cytokine family, the contribution of IL-17A to the immunopathogenesis of PsA, the clinical trials that evaluated ixekizumab in patients with PsA (SPIRIT program) and the safety of this agent. Expert opinion: Ixekizumab demonstrated its efficacy in different aspects of PsA including peripheral joint involvement, dactylitis, skin symptoms and patient reported outcomes in the 2 phase III trials from the SPIRIT program. Its safety profile was consistent with previous observations in patients with psoriasis. The role of IL-17A in the management of patients with PsA needs further clarification. According to EULAR recommendations for the management of PsA, IL-17A inhibitors may be used as second line biological DMARDs after TNF inhibitors.

Identification and Characterization of a Novel Association between Dietary Potassium and Risk of Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Recent animal studies have identified that dietary salt intake may modify the risk and progression of autoimmune disorders through modulation of the IL-23/TH17 pathway, which is critical in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD). METHODS: We conducted a prospective study of U.S. women enrolled in the Nurses' Health Study (NHS) and NHSII who provided detailed and validated information on diet and lifestyle beginning in 1984 in NHS and 1991 in NHSII. We confirmed incident cases of UC and CD reported through 2010 in NHS and 2011 in NHSII. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. In a case-control study nested within these cohorts, we evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes involved in TH17 pathway and dietary potassium on risk of CD and UC. In a cohort of healthy volunteers, we also assessed the effect of supplemental potassium on development of naïve and memory T cells, differentiated with TGFß1 or TH17 conditions. RESULTS: Among a total of 194,711 women over a follow-up of 3,220,247 person-years, we documented 273 cases of CD and 335 cases of UC. Dietary intake of potassium (Ptrend = 0.005) but not sodium (Ptrend = 0.44) was inversely associated with risk of CD. Although, both dietary potassium and sodium were not significantly associated with risk of UC, there was a suggestion of an inverse association with dietary potassium (Ptrend = 0.08). The association of potassium with risk of CD and UC appeared to be modified by loci involved in the TH17 pathway that have previously been associated with susceptibility to CD, particularly SNP rs7657746 (IL21) (Pinteraction = 0.004 and 0.01, respectively). In vitro, potassium enhanced the expression of Foxp3 in both naïve and memory CD4+ T cells via activating Smad2/3 and inhibiting Smad7 in TH17 cells. CONCLUSION: Dietary potassium is inversely associated with risk of CD with both in vitro and gene-environment interaction data suggesting a potential role for potassium in regulating immune tolerance through its effect on Tregs and TH17 pathway.

GM-CSF as a therapeutic target in inflammatory diseases.

GM-CSF is a well-known haemopoietic growth factor that is used in the clinic to correct neutropaenia, usually as a result of chemotherapy. GM-CSF also has many pro-inflammatory functions and recent data implicates GM-CSF as a key factor in Th17 driven autoimmune inflammatory conditions. In this review we summarize the findings that have led to the development of GM-CSF antagonists for the treatment of autoimmune diseases like rheumatoid arthritis (RA) and discuss some results of recent clinical trials of these agents.