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The combination of anti-angiogenic treatment and immunotherapy presents a promising strategy against colon cancer. Interleukin-17F (IL-17F) emerges as a critical immune cell cytokine expressed in colonic epithelial cells, demonstrating potential in inhibiting angiogenesis. In order to clarify the roles of IL-17F in the colon cancer microenvironment and elucidate its mechanism, we established a mouse colon carcinoma cell line CT26 overexpressing IL-17F and transplanted it subcutaneously into syngeneic BALB/c mice. We also analyzed induced colon tumor in IL-17F knockout and wild type mice. Our results demonstrated that IL-17F could suppress colon tumor growth in vivo with inhibited angiogenesis and enhanced recruitment of cysteine-cysteine motif chemokine receptor 6 (CCR6) positive immune cells. Additionally, IL-17F suppressed the tube formation, cell growth and migration of endothelial cells EOMA in vitro. Comprehensive bioinformatics analysis of transcriptome profiles between EOMA cells and those treated with three different concentrations of IL-17F identified 109 differentially expressed genes. Notably, a potential new target, Caspase 4, showed increased expressions after IL-17F treatment in endothelial cells. Further molecular validation revealed a novel downstream signaling for IL-17F: IL-17F enhanced Caspase 4/GSDMD signaling of endothelial cells, CT26 cells and CT26 transplanted tumors, while IL-17F knockout colon tumors exhibited decreased Caspase 4/GSDMD signaling. The heightened expression of the GSDMD N-terminus, coupled with increased cellular propidium iodide (PI) uptake and lactate dehydrogenase (LDH) release, revealed that IL-17F promoted pyroptosis of endothelial cells. Altogether, IL-17F could modulate the colon tumor microenvironment with inhibited angiogenesis, underscoring its potential as a therapeutic target for colon cancer.

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Background: In current literature there are only scarce data on the host inflammatory response during Burkholderia cepacia complex (Bcc) persistence. The primary objective of the present research was to carry out cross-sectional analyses of biomarkers and evaluate disease progression in cystic fibrosis (CF) patients with chronic Bcc infection and pathogen-free ones. The secondary aim was to assess prospectively overall survival of the study participants during up to 8 years of follow-up. Methods: The study included 116 paediatric patients with CF; 47 CF patients were chronically infected with Bcc, and 69 individuals were Bcc free. Plasma and sputum biomarkers (neutrophil elastase, MMP-8, MMP-9, MMP-12, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IL-22, IL-23, IL-17, IFN-γ, TGFß1, TNF-α) were analysed using commercially available kits. Besides, inhibitory effect of dexamethasone on proliferative response of PHA-stimulated peripheral blood lymphocytes had been assessed. Results: Bcc infected patients did not differ from Bcc free ones in demographic and clinical parameters, but demonstrated an increased rate of glucose metabolism disturbances and survival disadvantage during prolong follow-up period. Biomarkers analyses revealed elevated TNF-α and reduced IL-17F levels in sputum samples of Bcc infected patients. These patients also demonstrated improvement of peripheral blood lymphocyte sensitivity to steroid treatment and reduction in plasma pro-inflammatory (IL-17F and IL-18) and anti-inflammatory (TGFß1 and IL-10) cytokine concentrations. Conclusions: Reduction in IL-17F levels may have several important consequences including increase in steroid sensitivity and glycemic control disturbances. Further investigations are needed to clarify the role of IL-17 cytokines in CF complication development. Low plasma TGFß1 and IL-10 levels in Bcc infected group may be a sign of subverted activity of regulatory T cells. Such immune alterations may be one of the factors contributing to the development of the cepacia syndrome.

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Biological antibodies targeting key cytokines such as IL-17 and IL-23 have revolutionized psoriasis outcome. However, the recurrence remains an urgent challenge to be addressed. Currently, most of the descriptions of skin T-cell characteristics in psoriasis are derived from lesional and non-lesional skin, and their characteristics in resolved lesions (clinically healed lesions) remain vague. In order to further elucidate the cellular mechanism of recurrence, we performed single-cell sequencing and multiplexed immunohistochemical staining of T-cell subsets in autologous resolved lesion (RL), on-site recurrent psoriatic lesion (PL), and adjacent normal-appearing skin (NS) of psoriasis. By comparing with PL and NS tissues, we identified three potential cellular candidates for recurrence in clinically healed lesions: IL-17A/F double producing T cells, unstable Tregs and quiescent TRMs. Our results provide research clues for elucidating the immunological recurrence mechanism of psoriasis, and further work is needed to deepen our findings.

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IL-17F single nucleotide polymorphism (SNP) can affect IL-17F expression and activity and this can lead to the increased susceptibility to several autoimmune diseases. The aim was to investigate the association of IL-17F (rs763780) SNP with the development of multiple sclerosis (MS) in a cohort of Egyptian patients and to evaluate the effect of this polymorphism on the disease course. IL-17F (rs763780) gene polymorphisms was typed by TaqMan genotyping assay for 231 Egyptians divided into 102 MS patients and 129 healthy controls with matched age and sex. The IL-17F rs763780 C containing genotypes (CT+CC) and C allele have statistically significant increased frequency in MS patients when compared with controls (p = 0.005 and 0.004 respectively) especially in females' patients (p = 0.005 and 0.006 respectively). The heterozygous CT genotype was associated with the presence of optic neuritis (p = 0.038). The multivariable regression analysis revealed significant associations between smoking, the higher frequency of attacks and the prediction of higher EDSS score (p = 0.032, 0.049 respectively). It can be concluded that the IL-17F rs763780 C containing genotypes (CT and CC) and C allele may be risk factors for the development of MS in the studied Egyptian cohort by a gender-dependent mechanism that contributes to tendency for predisposition in females and optic neuritis is more common in patients carrying the CT heterozygous genotype.

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Significant research advances in our understanding of psoriatic disease have led to the development of several highly selective, effective, and safe topical and systemic treatments. These treatments have led to unprecedented levels of disease clearance and control for most patients with psoriasis with cutaneous disease. However, there remains a need for improved treatments for those patients with recalcitrant disease, psoriatic arthritis, or nonplaque disease variants. Recently approved therapies and investigational products in ongoing clinical development programs that target IL-17A/F, IL-23, TYK2, PDE4, AhR or IL-36 cytokine signaling are improving the clinician's ability to care for a broader range of patients affected by psoriasis.

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BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic inflammation. Its pathogenesis involves immunological, genetic, and environmental factors. We investigate the association between Tumor Necrosis Factor α Protein 3 (TNFAIP3), Interleukin 10 (IL10), Tumor Necrosis Factor α (TNF α), and Interleukin 17 F (IL17F) polymorphisms with susceptibility to RA. METHODS AND RESULTS: 191 patients with RA diagnosed according to the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) classification and 190 healthy subjects were recruited. Rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), and C-reactive protein (CRP) were measured. Genotyping of the polymorphisms was performed by real-time PCR. Analysis of the allelic frequencies of TNFAIP3 showed a positive association OR (95% CI) = 1.46 (1.01-2.09); p = 0.04, but failed to meet the criteria of significance after Bonferroni Correction. The genotypic and allelic distribution of the IL10, IL17F, and TNFα showed no significant difference when comparing the RA group with controls. Furthermore, the genotype codominant model shows a moderate positive association in the presence of ACPA (OR (95% CI) = 2.82 (1.22-6.24); p = 0.01. None of the polymorphisms studied was associated with RF and CRP production. CONCLUSION: Our results show that there is a tendency for the AG genotype of IL10-1082 to be associated with the production of ACPA in patients with RA. None of the variants studied were associated with RA susceptibility in Algerians.

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INTRODUCTION: Bimekizumab is a humanized monoclonal IgG1 antibody with a unique mechanism of action, as it inhibits both IL17A and IL17F molecules. This dual inhibition is thought to be responsible for its high efficacy in treating chronic plaque psoriasis with rapid onset of action in Randomized Controlled Trials (RCTs). Concerning safety, oral candidiasis was one of the most common drug-related adverse events, commonly mild-to-moderate in severity. Although data from RCTs supporting this efficacy and safety profile of bimekizumab is numerous, results from the real-world setting concerning short- and mid-term treatment effectiveness and safety profile are limited. MATERIALS AND METHODS: An observational, retrospective, monocentric study was conducted at the Psoriasis Outpatient Unit of "A. Sygros" Hospital for Skin and Venereal Diseases, in Athens, Greece, which included 61 adult patients with moderate-to-severe skin psoriasis, who received at least one dosage of bimekizumab. RESULTS: At week 4, 65.7% achieved PASI75, 45.7% PASI90, and 32.4% PASI100. After 16 weeks of treatment, 92.3/76.9/66.7% of the patients achieved PASI75/90/100, respectively. Increased BMI, previous treatment with another IL-17 inhibitor, or previous exposure to another biologic did not seem to influence the possibility of achieving PASI90 and PASI100 at week 16 of bimekizumab treatment in this cohort. Six (9.8%) cases of possibly drug-related AEs were reported, from which four incidences of oral candidiasis. CONCLUSION: Our results confirm that this IL17A/F inhibitor is highly effective, with a tolerability profile similar to the one expected from RCTs.

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Background: Atopic dermatitis (AD) is a chronic, recurrent inflammatory disease associated with an unbalanced immune response in the upper layers of the skin tissue, mostly starting in childhood. As important factors in gene expression regulation, polymorphisms in interleukin (IL)-17A and IL-17F may be associated with the susceptibility and severity of AD. Methods: Blood samples and clinical information were obtained from 132 patients with AD and 100 healthy children. Using multiplex polymerase chain reaction and next-generation sequencing, five potential single-nucleotide polymorphisms (SNPs) of IL-17A and IL-17F were genotyped in all participants. The relationship between SNPs and susceptibility to or severity of AD was examined by analyzing haplotypes and genetic models. Results: The IL-17A rs3819025 polymorphism was substantially associated with higher AD risk in both the allele model (p = 0.03; odds ratio [OR] = 1.76; confidence interval [CI]: 1.05-2.95) and the dominant model (p = 0.04, OR = 1.85; CI: 1.03-3.33). There was no correlation between AD susceptibility and the IL-17A (rs2275913 and rs4711998) or IL-17F (rs763780 and rs12203736) SNPs (all p > 0.05). Additionally, the five IL-17A and IL-17F SNPs did not significantly differ across the mild-to-moderate and severe subgroups (all p > 0.05). Conclusions: The IL-17A/rs3819025 polymorphism was linked to the development of AD, whereas the IL-17F polymorphism was unrelated to the susceptibility to and severity of AD. The IL-17A polymorphism may provide valuable information to speculate on the susceptibility to AD in Chinese Han children.

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Ischemic stroke is a serious neurological disease with limited therapeutic options; thus, it is particularly important to find effective treatments. Restoration of gut microflora diversity is an important factor in the treatment of ischemic stroke, but the mechanism remains unclear. Cornuside is known for its unique anti-inflammatory and circulation-promoting effects; however, whether it can effectively treat ischemic stroke and its therapeutic mechanisms remain unknown. In this study, we used a rat middle cerebral artery occlusion-reperfusion model (MCAO/R) to mimic ischemic stroke in humans and to assess the cerebral protective effects of cornuside in rats with ischemic stroke. Using 16S rRNA sequencing and RNA sequencing, we explored the cornuside mechanism in the brain-gut axis that confers protection against ischemic stroke. In conclusion, cornuside can inhibit the IL-17F/TRAF6/NF-κB pathway by improving the dysregulation of intestinal microflora, and reduce intestinal inflammation and neuroinflammation, which treated ischemic stroke rats.

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INTRODUCTION: Toxoplasma gondii infection is considered as one of the most important opportunistic infections and cause of death in HIV patients. METHODS: In this cross-sectional study, 334 HIV positive patients were included. The molecular test was performed by the restriction fragment length polymorphism-polymerase chain reaction method. Allelic frequency, haplotype analyses, and linkage disequilibrium were calculated. The odds ratio was calculated. The linear regression model was used to analysis of interleukin (IL)-17A, IL-17F, and IL-6 single-nucleotide polymorphism genotypes in HIV patients with and without toxoplasmosis. RESULTS: In total, 95 tested'patients (28.4%) were positive for toxoplasmosis. The risk of toxoplasma infection in the current study did not correlate with IL-17 and IL-6 polymorphism and the risk of contracting toxoplasma was also not significantly correlated in this study. There was no association between the frequency of alleles and the risk of toxoplasma infection in IL-17 haplotype analysis. CONCLUSION: The findings of this study revealed that there were significant differences in the serum levels of IL-6 and IL-17A, but not IL-17F, between the case and control groups in various genetic models. However, these polymorphisms did not show a significant relationship with toxoplasma infection in HIV-positive patients. This study represents the first investigation in Iran to explore the role of IL-6 and IL-17 polymorphisms in toxoplasma infection among HIV-positive patients.

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Biomass exposure is a significant environmental risk factor for COPD, but the underlying mechanisms have not yet been fully elucidated. Inflammatory microenvironment has been shown to drive the development of many chronic diseases. Pollution exposure can cause increased levels of inflammatory factors in the lungs, leading to an inflammatory microenvironment which is prevalent in COPD. Our findings revealed that IL-17F was elevated in COPD, while exposure to biomass led to increased expression of IL-17F in both alveolar epithelial and macrophage cells in mice. Blocking IL-17F could alleviate the lung inflammation induced by seven days of biomass exposure in mice. We employed a transwell co-culture system to simulate the microenvironment and investigate the interactions between MLE-12 and MH-S cells. We demonstrated that anti-IL-17F antibody attenuated the inflammatory responses induced by BRPM2.5 in MLE-12 and MH-S co-cultured with BRPM2.5-MLE-12, which reduced inflammatory changes in microenvironment. We found that IL-17RC, an important receptor for IL-17F, played a key role in the interactions. Knockout of IL-17RC in MH-S resulted in inhibited IL-17F signaling and attenuated inflammatory response after MH-S co-culture with BRPM2.5-MLE-12. Our investigation suggests that BRPM2.5 induces lung epithelial-macrophage interactions via IL-17F/IL-17RC axis regulating the inflammatory response. These results may provide a novel strategy for effective prevention and treatment of biomass-related COPD.

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[This corrects the article DOI: 10.3389/fimmu.2023.1191782.].

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Interleukin-17 family (IL-17s) comprises six structurally related members (IL-17A to IL-17F); sequence homology is highest between IL-17A and IL-17F, displaying certain overlapping functions. In general, IL-17A and IL-17F play important roles in chronic inflammation and autoimmunity, controlling bacterial and fungal infections, and signaling mainly through activation of the nuclear factor-kappa B (NF-κB) pathway. The role of IL-17A and IL-17F has been established in chronic immune-mediated inflammatory diseases (IMIDs), such as psoriasis (PsO), psoriatic arthritis (PsA), axial spondylarthritis (axSpA), hidradenitis suppurativa (HS), inflammatory bowel disease (IBD), multiple sclerosis (MS), and asthma. CD4+ helper T cells (Th17) activated by IL-23 are well-studied sources of IL-17A and IL-17F. However, other cellular subtypes can also produce IL-17A and IL-17F, including gamma delta (γδ) T cells, alpha beta (αß) T cells, type 3 innate lymphoid cells (ILC3), natural killer T cells (NKT), or mucosal associated invariant T cells (MAIT). Interestingly, the production of IL-17A and IL-17F by innate and innate-like lymphocytes can take place in an IL-23 independent manner in addition to IL-23 classical pathway. This would explain the limitations of the inhibition of IL-23 in the treatment of patients with certain rheumatic immune-mediated conditions such as axSpA. Despite their coincident functions, IL-17A and IL-17F contribute independently to chronic tissue inflammation having somehow non-redundant roles. Although IL-17A has been more widely studied, both IL-17A and IL-17F are overexpressed in PsO, PsA, axSpA and HS. Therefore, dual inhibition of IL-17A and IL-17F could provide better outcomes than IL-23 or IL-17A blockade.

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Septic gut damage is critical in the progression of sepsis and multiple organ failure, characterized by gut microbiota dysbiosis and epithelium deficiency in the gut barrier. Recent studies highlight the protective effects of Erythropoietin (EPO) on multiple organs. The present study found that EPO treatment significantly alleviated the survival rate, suppressed inflammatory responses, and ameliorated intestine damage in mice with sepsis. EPO treatment also reversed sepsis-induced gut microbiota dysbiosis. The protective role of EPO in the gut barrier and microbiota was impaired after EPOR knockout. Notably, we innovatively demonstrated that IL-17 F screened by transcriptome sequencing could ameliorate sepsis and septic gut damage including gut microbiota dysbiosis and barrier dysfunction, which was verified by IL-17 F-treated fecal microbiota transplantation (FMT) as well. Our findings highlight the protection effects of EPO-mediated IL-17 F in sepsis-induced gut damage by alleviating gut barrier dysfunction and restoring gut microbiota dysbiosis. EPO and IL-17 F may be potential therapeutic targets in septic patients.

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IL-17A+ CD8+ T-cells, termed Tc17 cells, have been identified at sites of inflammation in several immune-mediated inflammatory diseases. However, the biological function of human IL-17A+ CD8+ T-cells is not well characterized, likely due in part to the relative scarcity of these cells. Here, we expanded IL-17A+ CD8+ T-cells from healthy donor PBMC or bulk CD8+ T-cell populations using an in vitro polarization protocol. We show that T-cell activation in the presence of IL-1ß and IL-23 significantly increased the frequencies of IL-17A+ CD8+ T-cells, which was not further enhanced by IL-6, IL-2, or anti-IFNγ mAb addition. In vitro-generated IL-17A+ CD8+ T-cells displayed a distinct type-17 profile compared with IL-17A- CD8+ T-cells, as defined by transcriptional signature (IL17A, IL17F, RORC, RORA, MAF, IL23R, CCR6), high surface expression of CCR6 and CD161, and polyfunctional production of IL-17A, IL-17F, IL-22, IFNγ, TNFα, and GM-CSF. A significant proportion of in vitro-induced IL-17A+ CD8+ T-cells expressed TCRVα7.2 and bound MR1 tetramers indicative of MAIT cells, indicating that our protocol expanded both conventional and unconventional IL-17A+ CD8+ T-cells. Using an IL-17A secretion assay, we sorted the in vitro-generated IL-17A+ CD8+ T-cells for functional analysis. Both conventional and unconventional IL-17A+ CD8+ T-cells were able to induce pro-inflammatory IL-6 and IL-8 production by synovial fibroblasts from patients with psoriatic arthritis, which was reduced upon addition of anti-TNFα and anti-IL-17A neutralizing antibodies. Collectively, these data demonstrate that human in vitro-generated IL-17A+ CD8+ T-cells are biologically functional and that their pro-inflammatory function can be targeted, at least in vitro, using existing immunotherapy.

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Interleukin 17 (IL-17) plays an important role in the inflammation of the gastric mucosa and, in severe cases, the development of gastric cancer. Thus, the authors aimed to evaluate the IL-17F A7488G polymorphism in Helicobacter pylori (H. pylori) patients. Patients and methods: A total of 86 adults (in two H. pylori-positive and H. pylori-negative groups) were included in the study. To identify the infection, rapid urease test and polymerase chain reaction (PCR) were performed. The cagA gene was also evaluated as a bacterial virulence factor. PCR-restriction fragment length polymorphism was used to investigate the IL-17F A7488G polymorphism in gastric biopsies using the NlaIII enzyme. Results: 96.5% of patients in both groups did not show any mutation and had AA genotype, and only three patients infected with cagA-carrying H. pylori strains had polymorphism in the IL-17F A7488G gene, which included AG (one case) and GG (two cases) patterns. No significant relationship was found between these polymorphisms in the two groups of H. pylori-positive and H. pylori-negative patients, while, interestingly, a significant difference was observed between the polymorphisms and the presence of the cagA gene. Conclusion: This report is one of the first to demonstrate the association of IL-17F A7488G polymorphism with H. pylori infection and the presence of the cagA gene. Although no significant association between IL-17F polymorphism and H. pylori infection was found in the population of this study, the patients with mutated genotypes were positive for the cagA gene, which was statistically significant. Therefore, the possibility of the role of pathogenic strains in causing mutations in cytokine genes is more conceivable.

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Background: Chronic periodontitis (CP) is triggered by periodontal pathogens influenced by genetic and environmental factors. Recent studies have suggested that anti-inflammatory cytokines such as interleukin 17 (IL-17) play a prominent role in the pathogenesis of CP.Aim: This study aimed to investigate the association between eight sub-gingival pathogens and interleukin 17F (IL-17F) gene single nucleotide polymorphisms with CP among Libyans.Materials and Methods: A case-control study was conducted on 100 individuals between the ages of 25-65 years. Species-specific 16S rRNA primers for each pathogen were used in a multiplex PCR reaction to detect sub-gingival pathogens from a paper point sample. DNA was also extracted from buccal swab samples and IL-17F polymorphisms were detected by Sanger sequencing.Results: A highly significant association between the seven sub-gingival pathogens and CP, (p-value 0.0001) and a high prevalence of P. intermedia (100%), T. forsythia (96%), T. denticola and E. corrodens (92%), P. gingivalis (82%), C. rectus (74%), P. nigrescens (72%), A. actinomvcetcmcomitans (40%) were found in the case group compared with control group. A novel variant in the c. *34 G>A in IL-17F gene caused a change in glutamic amino acid to lysine amino acid, position on chromosome number (6) in the third exon, mRNA/genomic position 597, found in 14.6% of CP patients (p-value = 0.010) while the IL-17F (rs763780) SNP showed no association with CP (p-value = 0.334).Conclusion: P. intermedia appear as keystone pathogen for CP in the Libyan population. A novel variant in the IL-7F gene may be related to the severity of CP.

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BACKGROUND: On the basis of the mounting evidence that type 17 T (T17) cells and increased IL-17 play a key role in driving hidradenitis suppurativa (HS) lesion development, biologic agents used previously in psoriasis that block signaling of IL-17A and/or IL-17F isoforms have been repurposed to treat HS. OBJECTIVE: Our research aimed to characterize the transcriptome of HS T17 cells compared to the transcriptome of psoriasis T17 cells, along with their ligand-receptor interactions with neighborhood immune cell subsets. METHODS: Single-cell data of 12,300 cutaneous immune cells from 8 deroofing surgical HS skin samples including dermal tunnels were compared to single-cell data of psoriasis skin (19,525 cells from 11 samples) and control skin (11,920 cells from 10 samples). All single-cell data were generated by the same protocol. RESULTS: HS T17 cells expressed lower levels of IL23R and higher levels of IL1R1 and IL17F compared to psoriasis T17 cells (P < .05). HS Treg cells expressed higher levels of IL1R1 and IL17F compared to psoriasis Treg cells (P < .05). Semimature dendritic cells were the major immune cell subsets expressing IL1B in HS, and IL-1ß ligand-receptor interactions between semimature dendritic cells and T17 cells were increased in HS compared to psoriasis (P < .05). HS dermal tunnel keratinocytes expressed inflammatory cytokines (IL17C, IL1A, IL1B, and IL6) that differed from the HS epidermis keratinocytes (IL36G) (P < .05). IL6, which synergizes with IL1B to maintain cytokine expression in T17 cells, was mainly expressed by fibroblasts in HS, which also expressed IL11+ inflammatory fibroblast genes (IL11, IL24, IL6, and POSTN) involved in the paracrine IL-1/IL-6 loop. CONCLUSION: The IL-1ß-T17 cell cytokine axis is likely a dominant pathway in HS with HS T17 cells activated by IL-1ß signaling, unlike psoriasis T17 cells, which are activated by IL-23 signaling.

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BACKGROUND: IL-17A plays a pivotal pathogenic role in several immune-mediated inflammatory diseases. Despite sharing 50% sequence homology with IL-17A, the role of IL-17F remains less clear. Clinical findings suggest that dual inhibition of IL-17A and IL-17F in psoriatic disease is more efficacious than IL-17A inhibition alone, positing a pathogenic role for IL-17F. OBJECTIVE: We characterized the regulation of IL-17A and IL-17F in psoriatic disease. METHODS: Using both in vitro systems and lesional skin tissue from patients, we interrogated the chromosomal, transcriptional, and protein expression landscape of IL-17A+ and IL-17F+ TH17 cells. Alongside established assays such as single-cell RNA sequencing, we developed a novel cytokine-capture technique that was combined with chromatin immunoprecipitation sequencing and RNA sequencing. RESULTS: We confirm a preferential elevation of IL-17F over IL-17A in psoriatic disease and show that expression of each isoform predominantly occurs in distinct cell populations. The expression of both IL-17A and IL-17F exhibited a high degree of plasticity, with the balance between the 2 isoforms influenced by proinflammatory signaling and by anti-inflammatory drugs such as methylprednisolone. This plasticity was reflected in a broad H3K4me3 region at the IL17A-F locus, while opposing effects of STAT5/IL-2 signaling were observed for each of the 2 genes. Functionally, higher IL17F expression was linked to greater cell proliferation. CONCLUSION: There are key differences in the regulation of IL-17A and IL-17F in psoriatic disease, leading to distinct inflammatory cell populations. As such, we propose that both IL-17A and IL-17F neutralization may be required to maximally inhibit IL-17-driven pathology.

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Psoriasis is a systemic inflammatory disease that associates with multiple comorbidities. It involves complex interactions between environmental factors and polygenic predisposition. The IL-17 family is one of the main actors in the pathogenesis of psoriasis. Secondary nonresponse is common, especially during the long-term use of TNF-α inhibitors, but it is not uncommon even for newer biologics, such as IL-17 inhibitors. Identification of clinically useful biomarkers of treatment efficacy and safety would enable optimal treatment selection, improve patient quality of life and outcome, and reduce healthcare costs. To our knowledge, this is the first study to evaluate the relationship between genetic polymorphism of IL-17F (rs763780) and IL-17RA (rs4819554) and response to biological treatment and other clinical data in bio-naive and secondary non-responders psoriasis patients in Romania and Southeastern Europe. We performed a prospective, longitudinal, analytical cohort study of 81 patients diagnosed with moderate-to-severe chronic plaque psoriasis who received biological treatments for the first time. Of the 79 patients treated with TNF-α inhibitors, 44 experienced secondary nonresponse. All patients were genotyped for the two SNPs in IL-17F and IL-17RA genes. The rs763780 polymorphism in the IL-17F gene could be an attractive candidate biomarker for predicting which patients will respond to anti-TNF-α therapies. Another emergent association of rs4819554 in IL-17RA with the risk of nail psoriasis and a higher BMI in moderate-to-severe plaque psoriasis patients is described.

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