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Introduction: LncRNA LBX2-AS1 drives the development of various cancers, but the exact mechanism whereby LBX2-AS1 affects glioblastoma (GBM) progression is unaddressed. This study intended to delineate the regulatory mechanism of LBX2-AS1 in GBM metastasis and angiogenesis. Material and methods: LBX2-AS1 level in GBM was assessed by bioinformatics methods. The lncRNA-transcription factor (TF)-mRNA trios were predicted using the lncMAP database. Correlation between genes was predicted by Pearson analysis. The binding relationship was predicted by JASPAR. Levels of LBX2-AS1 and its downstream genes were assayed via qRT-PCR. Changes in expressions of VEGF-A, IL4R, and epithelial-mesenchymal transition (EMT)-associated proteins were assessed through western blot. GBM cell proliferation, migration, and invasion were assayed through CCK8, colony formation, and Transwell experiments. In vitro angiogenesis capacity was evaluated via a HUVEC tube formation experiment. The regulatory relationship between various genes was verified through radioimmunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and dual-luciferase assays. Results: LBX2-AS1 was elevated in GBM, and in vitro experiments demonstrated the stimulatory effect of LBX2-AS1 on GBM cell proliferation, invasion, migration, and angiogenesis. We observed that LBX2-AS1 activated IL4R expression by binding the transcription factor NFKB1, thus promoting the progression of GBM. Rescue experiments illustrated that silencing IL4R or NFKB1 reversed the impact of forced LBX2-AS1 expression on GBM cells. Conclusions: This study revealed the mechanism of the LBX2-AS1/NFKB1/IL4R axis in driving GBM metastasis and angiogenesis, which may help to improve the regulatory network of GBM malignant progression and provide potential targets for GBM treatment. [ABSTRACT FROM AUTHOR]

Background: Viral conjunctivitis is an inflammation of the conjunctiva caused by viruses. Interleukin-4 (IL-4) and IL-4R have been reported to associate with the pathogenesis of conjunctivitis; however, the role of IL-4 and IL-4R genetic polymorphisms in conjunctivitis remains unknown. Aim: This study aimed to evaluate the relation between IL-4 gene polymorphisms (rs2243250) and IL-4 gene receptor (rs1805010) with infectious conjunctivitis. Methods: The study was conducted in 92 age-matched volunteers; 50 of viral conjunctivitis patients and 42 of healthy controls. The levels of both IL-4 and total IgE were measured using suitable methods. Genotyping of IL-4 (rs2243250) SNP was performed by Alleles Refractory Mutation Systems PCR (ARMS PCR) method, while the Genotyping of IL-4 receptor (rs1805010) SNP was performed by RFLP PCR method. Results: Our results showed that there is a significant difference in genotype and alleles distributions in IL-4 (rs2243250) SNP between viral conjunctivitis and control. However, no significant difference in genotypes and alleles distribution IL-4 gene receptor (rs1805010) SNP between viral conjunctivitis and control. More ever, there is a significant increase in serum IL-4 and total IgE in viral conjunctivitis than control. Conclusions: the analysis of our results indicates that IL-4 (rs2243250) SNP gene polymorphisms may be an indicator of increasing the incidence of viral conjunctivitis in the Egyptian population. [ABSTRACT FROM AUTHOR]

The IL-4/IL-13 axis is involved in the pathogenesis of allergic rhinitis (AR). In this study, we investigated the serum cytokines levels of IL-4, IL-5, IL-6, and IL-13 in AR patients, and the transcript expression levels of their receptors (i.e. IL4R, IL5RA, IL6R, and IL13RA1) in nasal epithelial cells of AR patients versus non-allergic controls. Nasal epithelial cells and blood samples of non-allergic controls (n = 30) and AR patients (n = 30) were collected to examine mRNA expression and serum cytokines levels, respectively. Bioinformatics analyses of IL-4/IL-13 receptor heterodimer association with tight junction (TJ) and JAK/STAT signaling genes were conducted in a gene expression profiling (GEP) dataset (GSE44037) of AR patients (n = 12) and healthy controls (n = 6). Serum IL-4, IL-5, IL-6 or IL-13 levels, and IL13RA1 transcript expression were significantly higher in AR patients compared with non-allergic controls. IL-4 and IL-13 serum levels were positively correlated with IL13RA1 expression in AR patients but not in non-allergic controls. In the GEP dataset (GSE44037), six TJ (CLDN4, CLDN7, CLDN12, CLDN15, TJP1, and TJP2) genes’ expressions were negatively correlated, respectively, with IL-4Rα/IL-13Rα1 heterodimeric receptor expression in AR patients and not in control samples. These six TJ genes contributed to the significant enrichment of tight junction Gene Ontology (GO ID: 0070160). Lastly, STATs DNA binding motif analysis showed that each of these TJ genes contains STATs binding consensus sequence within intronic and intergenic regions. Our results suggest that increased IL-4/IL-13 serum cytokines levels may contribute to decreased TJs expression via IL-4Rα/IL-13Rα1 heterodimeric receptor in nasal epithelium of AR patients.

Abstract Background Etiologic studies provide evidence that IL-4R and IL-6R receptors may play important roles in the regulatory mechanisms of the development of clinical dengue, especially in children which is a segment of the population with high severe dengue risk. Moreover, the allele frequencies and genetic associations may be influenced by the populational genetic background. Therefore, we performed a case-control study to evaluate possible associations between SNPs in IL4R and IL6R genes and clinical dengue in children from two Colombian populations. Methods We genotyped the rs1805016 (IL4R) and rs8192284 (IL6R) by PCR-RFLP method, in 298 symptomatic children and 648 asymptomatic controls. Three individual genetic ancestral proportions (APs) (European, Amerindian, African) were inferred by genotyping 29 AIMs (Ancestry informative markers). The variables gender, APs, and the population of origin were used like confusion variables. Results We found IL4R -rs1805016 GG genotype and G-allele carriers and IL6R- rs8192284 AA genotype associated with clinical dengue in the pooled and Huila samples. Nevertheless, we found no association of these polymorphisms in the sample of Antioquia. Conclusions For the first time, we report SNPs in IL4R and IL6R genes associated with clinical dengue, which contributes to understanding the genetic susceptibility to dengue disease. Moreover, these results may be influenced by genetic background and must be evaluated through functional analysis. [ABSTRACT FROM AUTHOR]

Background: MDNA55 is an interleukin 4 receptor (IL4R)-targeting toxin in development for recurrent GBM, a universally fatal disease. IL4R is overexpressed in GBM as well as cells of the tumor microenvironment. High expression of IL4R is associated with poor clinical outcomes., Methods: MDNA55-05 is an open-label, single-arm phase IIb study of MDNA55 in recurrent GBM (rGBM) patients with an aggressive form of GBM (de novo GBM, IDH wild-type, and nonresectable at recurrence) on their 1st or 2nd recurrence. MDNA55 was administered intratumorally as a single dose treatment (dose range of 18 to 240 ug) using convection-enhanced delivery (CED) with up to 4 stereo-tactically placed catheters. It was co-infused with a contrast agent (Gd-DTPA, Magnevist®) to assess distribution in and around the tumor margins. The flow rate of each catheter did not exceed 10μL/min to ensure that the infusion duration did not exceed 48 h. The primary endpoint was mOS, with secondary endpoints determining the effects of IL4R status on mOS and PFS., Results: MDNA55 showed an acceptable safety profile at doses up to 240 μg. In all evaluable patients (n = 44) mOS was 11.64 months (80% one-sided CI 8.62, 15.02) and OS-12 was 46%. A subgroup (n = 32) consisting of IL4R High and IL4R Low patients treated with high-dose MDNA55 (>180 ug) showed the best benefit with mOS of 15 months, OS-12 of 55%. Based on mRANO criteria, tumor control was observed in 81% (26/32), including those patients who exhibited pseudo-progression (15/26)., Conclusions: MDNA55 demonstrated tumor control and promising survival and may benefit rGBM patients when treated at high-dose irrespective of IL4R expression level.Trial Registration: Clinicaltrials.gov NCT02858895., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: In patients with asthma, the fungus Aspergillus fumigatus can cause allergic bronchopulmonary aspergillosis (ABPA). Familial ABPA is reported, and some genetic factors have been associated with the disease, however, these are small studies (n ⩽ 38) and do not explain all cases of ABPA. Methods: We analysed SNPs in 95 ABPA patients, comparing frequencies to 152 atopic asthmatic and 279 healthy controls. Twenty two genes were selected from literature, and 195 tagging SNPs were analysed for genetic association with ABPA using logistic regression corrected for multiple testing. We also analysed monocyte-derived macrophage gene expression before and during co-culture with A. fumigatus. Results: Seventeen ABPA-associated SNPs (ABPA v Atopic asthma) were identified. Three remained significant after correction for multiple testing; IL13 rs20541, IL4R rs3024656, TLR3 rs1879026. We also identified minor differences in macrophage gene expression responses in the ABPA group compared to the control groups. Conclusions: Multiple SNPs are now associated with ABPA. Some are novel associations. These associations implicate cytokine pathways and receptors in the aberrant response to A. fumigatus and susceptibility to ABPA, providing insights into the pathogenesis of ABPA and/or its complications. We hope these results will lead to increased understanding and improved treatment and diagnostics for ABPA. [ABSTRACT FROM AUTHOR]

Background: Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. The aim was to assess the genetic connections between the angiogenesis-related NOS3, CD14, MMP3, IL4R, IL4 genes and VEGF expression and plasma levels. Methods: The associations between VEGF plasma levels with the polymorphisms of NOS3, CD14, MMP3, IL4R, and IL4 were assessed in 403 healthy unrelated adults. The epistatic and environmental interactions were explored, including four VEGF-related polymorphisms previously identified. The VEGF expression in peripheral blood mononuclear cells was quantified (n = 65) for the VEGF121, VEGF145, VEGF165, and VEGF189 isoforms. Results: The polymorphism rs1799983 of NOS3 was associated with the sum of all VEGF isoforms mRNA levels (P = 0.032) and VEGF145 (P = 0.033). Rs1800779 of NOS3 interacted with rs3918226 of the same gene and with the rs2569190 of CD14 (P = 0.022, P = 0.042, respectively) for VEGF plasma levels. Other epistatic interactions included the rs1801275 of IL4R with the rs6921438 (VEGF-related variant) and rs3025058 of MMP3 (P = 0.042, P = 0.010 respectively) and the rs2569190 of CD14 with the rs3025058 of MMP3 (P = 0.0119). We also identified an interaction of rs1800779 with obesity, high-density lipoprotein cholesterol and triglycerides (P = 0.018, P = 0.005, P = 0.043, respectively) as well as the interaction of rs6921438 with hypertension (P = 0.028). Conclusions: Our findings indicated that genetic variants of NOS3, CD14, MMP3 and IL4R are implicated in the determination of VEGF expression and plasma levels. Thus, they support the hypothesis that in physiological conditions there are complex biological relationships between pathways (such as angiogenesis and inflammation), which are involved in the development of chronic diseases. [ABSTRACT FROM AUTHOR]

Abstract: We searched for an association between the interleukin 4 receptor gene (IL4R) rs1805015 and interleukin 13 gene (IL13) rs20541 polymorphisms and the development of antibodies to hepatitis B surface antigen (anti-HBs) in the case of hepatitis B virus (HBV) vaccination or infection in hemodialysis (HD) patients. HD patients who failed to respond to HBV vaccination did not differ in genotype frequencies of IL4R (TT 72.7%, CT 22.6%, CC 4.7%) and IL13 (CC 59.0%, CT 34.2%, TT 6.8%) from vaccine responders (IL4R TT 68.0%, CT 27.3%, CC 4.7%; IL13 CC 55.0%, CT 38.5%, TT 6.5%). HD patients who did not develop anti-HBs despite HBV infection also did not differ in genotype frequencies of IL4R (TT 67.8%, CT 26.8%, CC 5.4%) and IL13 (CC 60.7%, CT 33.9%, TT 5.4%) from HD patients who developed an anti-HBs response (IL4R TT 65.4%, CT 30.8%, CC 3.8%; IL13 CC 60.5%, CT 34.6%, TT 4.9%). In HD patients, neither the IL4R nor IL13 polymorphism is associated with anti-HBs development irrespective of whether an immunization is provoked by HBV vaccination or HBV infection. [Copyright &y& Elsevier]

Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma, is typically treated with chemotherapy combined with the immunotherapy rituximab, an antibody targeting the B cell receptor, CD20. Despite the success of this treatment regimen, approximately a third of DLBCL patients experience either relapse or have refractory disease that is resistant to rituximab, indicating the need for alternative therapeutic strategies. Here, we identified that CD74 and IL4R are expressed on the cell surface of both CD20 positive and CD20 negative B cell populations. Moreover, genes encoding CD74 and IL4R are expressed in lymphoma biopsies isolated from all stages of disease. We engineered bispecific antibodies targeting CD74 or IL4R in combination with rituximab anti-CD20 (anti-CD74/anti-CD20 and anti-IL4R/anti-CD20). Bispecific antibody function was evaluated by measuring direct induction of apoptosis, antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity in both rituximab-sensitive and rituximab-resistant DLBCL cell lines. Both anti-CD74/anti-CD20 and anti-IL4R/anti-CD20 were able to mediate ADCC and ADCP, but CD74-targeting therapeutic antibodies could also mediate direct cytotoxicity. Overall, this study strongly indicates that development of bispecific antibodies that target multiple B cell receptors expressed by lymphoma could provide improved defense against relapse and rituximab resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Geanes, Krepel, McLennan, Pierce, Khanal and Bradley.)

Abstract: Introduction: Glioma is one of the most aggressive human tumors; however, little is known about its genetic risk factors. The role of heredity is likely to be explained by combinations of common low-risk variants. Previous studies have indicated that more than 100 single nucleotide polymorphisms (SNPs) are associated with the risk of glioma. Methods: To further investigate how and to what extent these SNPs contribute to glioma susceptibility in a Chinese population, we analyzed 43 SNPs of 226 glioma patients and 254 normal people in order to evaluate the associations between SNPs and the risk of glioma. Results: Overall, we found three protective alleles for glioma in patients: the allele “G” of rs1801275 in the IL4R gene by allele model (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.50–0.99; P =0.04) and dominant model (OR, 0.67; 95% CI, 0.46–0.99; P =0.04) analysis respectively, the allele “T” of rs17748 in the TREH gene by recessive model (OR, 0.48; 95% CI, 0.23–1.01; P =0.05) analysis, and the allele “G” of rs6470745 in CCDC26 gene by recessive model (OR, 0.48; 95% CI, 0.26–0.89; P =0.02) analysis. Conclusion: This study provides evidence for three glioma susceptibility genes – TREH, IL4R and CCDC26 – in a Chinese population; this may shed light on molecular markers of glioma susceptibility and could therefore be used as a diagnostic and prognostic marker for glioma patients in clinical study. [Copyright &y& Elsevier]

Background: Malaria is among the most prevalent parasitic diseases worldwide. In Brazil, malaria is concentrated in the northern region, where Plasmodium vivax accounts for 85% disease incidence. The role of genetic factors in host immune system conferring resistance/susceptibility against P. vivax infections is still poorly understood. Methods: The present study investigates the influence of polymorphisms in 18 genes related to the immune system in patients with malaria caused by P. vivax. A total of 263 healthy individuals (control group) and 216 individuals infected by P. vivax (malaria group) were genotyped for 33 single nucleotide polymorphisms (SNPs) in IL1B, IL2, IL4, IL4R, IL6, IL8, IL10, IL12A, IL12B, IL12RB1, SP110, TNF, TNFRSF1A, IFNG, IFNGR1, VDR, PTPN22 and P2X7 genes. All subjects were genotyped with 48 ancestry informative insertion-deletion polymorphisms to determine the proportion of African, European and Amerindian ancestry. Only 13 SNPs in 10 genes with differences lower than 20% between cases and controls in a Poisson Regression model with age as covariate were further investigated with a structured population association test. Results: The IL1B gene -5839C > T and IL4R 1902A > G polymorphisms and IL12RB1 -1094A/-641C and TNF -1031 T/-863A/-857 T/-308 G/-238 G haplotypes were associated with malaria susceptibility after population structure correction (p = 0.04, p = 0.02, p = 0.01 and p = 0.01, respectively). Conclusion: Plasmodium vivax malaria pathophysiology is still poorly understood. The present findings reinforce and increase our understanding about the role of the immune system in malaria susceptibility. [ABSTRACT FROM AUTHOR]

Background: Asthma and rhinitis may represent two manifestations of the same airway disease. Genetic research can increase our understanding of their common or distinct pathogenesis. IL13 and IL4R polymorphisms are associated with asthma and show gene-gene interaction in asthma. Their role in rhinitis has not been extensively studied. Methods: Association of IL13 and IL4R polymorphisms in relation to rhinitis, asthma, serum IgE and skin test response was studied in: (1) 188 trios ascertained through a proband with rhinitis who were clinically not affected by asthma; (2) 407 trios with an asthmatic proband, and (3) 118 asthma cases and 102 unrelated healthy controls using family-based association testing, logistic regression, and analysis of variance as appropriate. Gene-gene interaction was evaluated using logistic regression analysis. Results: IL13 C-1111T (rs1800925) was significantly associated with rhinitis and atopic phenotypes in rhinitis trios that were not affected by clinical asthma. IL13 Arg130Gln (rs20541) and G870A (rs1295685) were consistently associated with asthma and serum IgE in both asthma populations. IL4R Glu375Ala (rs1805011) and Ser411Leu (rs1805013) were associated with asthma in the asthma case-control population. Combining risk genotypes of IL13 Arg130Gln with IL4R Glu375Ala, and IL13 C-1111T with IL4R Ser478Pro yielded increased risks for asthma compared to their separate effects. Conclusion:IL13 polymorphisms were associated with asthma and rhinitis without clinical asthma; thus, these polymorphisms may constitute a common etiologic pathway for their development. In addition, the study replicates a previously reported interaction of IL13 and IL4R polymorphisms in asthma. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: Inheritance and genetic factors are supposed to influence susceptibility to asthma and allergy. We tested if single nucleotide polymorphisms (SNPs) in the IL4R gene were associated with susceptibility to such diseases, or if they were related to the phenotypic presentation of asthma and allergic rhinoconjunctivitis (ARC). Methods: Three hundred and nine 12- to 13-year-old children were included. Six SNPs in the IL4R were analysed in response to current allergic disease, and to presentation of specific asthma and ARC phenotypes. Questionnaires were used to determine allergic disease status, and skin prick tests to evaluate sensitization to common airborne allergens. Results: Less eczema was seen in individuals with the AA-genotype of rs2057768, and less ARC among those with the AA-genotype of rs2107356, especially ARC associated with sensitization to pollen. The AA-genotype of rs2057768 and the TT genotype of rs3024632 were associated with a specific asthma phenotype. Conclusion: Variations within the IL4R gene are associated with allergic diseases in children, preferably with eczema and disease phenotypes of ARC and asthma. [ABSTRACT FROM AUTHOR]

Background: Recently published data indicate that host germline variations in immune genes can influence the outcome of lymphoma patients. Interleukin (IL)-4 and IL13 are crucial immune factors and may influence the course of the disease. Both cytokines signal through the interleukin-4 receptor (IL4R). Therefore, we investigated whether polymorphisms of IL4, IL13 and IL4R genes could predict the outcome of diffuse large B-cell lymphoma (DLBCL) patients. Methods: In 228 DLBCL samples of the German High-Grade Non-Hodgkin's Lymphoma Study Group, the polymorphisms of IL4 (-524CT, rs2243250), IL13 (-1069CT, rs1800925) and IL4R (I75V, rs1805010; S503P, rs1805015; Q576R, rs1801275) were analyzed and the soluble interleukin-4 receptor (sIL4R) serum level was measured before the start of chemotherapy. Results: Patients harboring IL4R V75 (IL4RI75V-AG and IL4RI75V-GG) had shorter overall survival (OS) (P = 0.044) and event-free survival (EFS) (P = 0.056) periods compared with I75 carriers (IL4RI75V-AA). Multivariate analysis adjusted to the International Prognostic Index revealed a relative risk of 1.9 for carriers of the IL4R V75 (P = 0.011) in relation to OS. DLBCL patients homozygous for the IL4R I75 and low sIL4R serum levels have the most favorable OS and EFS. Conclusions: These data support the role for host germline gene variations of immunologically important factors like the IL4R I75V gene variation to predict the survival in DLBCL patients. [ABSTRACT FROM PUBLISHER]

Abstract: A body of evidence indicates obesity is an inflammatory state with chronic activation of the immune system. The interleukin 4 receptor (IL4R) single nucleotide polymorphism (SNP), rs 180275 (1902A>G) is well recognized for its association with atopy and other inflammatory diseases. We assessed the possible association of rs 180275 and rs 1805010 with obesity in Korean population. Study subject consisting of 876 Koreans were divided into three groups: subjects with 1) BMI<25, 2) BMI between 25 and 27, and 3) BMI>27. Analyses of genotype distributions and allele frequencies of study subjects revealed that rs 180275 polymorphism was associated with an increase in BMI in Korean population (P =0.009 and 0.011, respectively) while no association was found between rs 1805010 and obesity. We observed significantly lower percentage of rs 180275 G allele in subjects with BMI>27 than in subjects with BMI≤27 (9.9% vs. 16.0%). Logistic regression analysis revealed that the odds ratio (OR) for an increase in BMI associated with the G vs. A allele was 0.57 [95% Confidence interval (CI)=0.39–0.85, p =0.002], which strongly implicates the protective role of rs 180275 G allele against an increase in BMI. Haplotype analysis revealed no association was present between rs 180275 and rs 1805010 polymorphisms. The frequency of rs 180275 G allele is significantly lower in subjects with BMI>27, suggesting the protective role of IL4R rs 180275 G allele against an increase in BMI in Korean population. [Copyright &y& Elsevier]

Background: IL4R, the gene encoding the α chain of the IL-4 and IL-13 receptors, has received extensive attention as a candidate gene for asthma risk. However, the results from studies testing for associations of the I50V and Q551R IL4R genetic variants are conflicting. Objective: We sought to determine the average risk of asthma associated with the I50V and Q551R IL4R variants based on the results of case-control studies reported in the literature. Methods: Meta-analyses were performed with data from case-control association studies that met specified inclusion criteria (9 and 8 studies for I50V and Q551R, respectively). Random-effects models were used to calculate combined odds ratios (ORs) and significance of associations. Analyses were performed for asthma in general and for subgroups based on the atopy status of the asthma population. Results: The R551 IL4R variant was significantly associated with increased risk of asthma, most notably atopic asthma (combined OR, 1.6; P = .004). Exclusion of the outlier study reporting an OR of less than 1 greatly increased the significance of association (OR, 1.8; P = 3 × 10−9). I50V variants were not significantly associated with asthma. Conclusions: A meta-analysis of results from case-control studies strongly supports the conclusion that the R551 IL4R variant imparts a modest yet significant risk for atopic asthma. Clinical implications: Knowledge that the R551 IL4R variant is associated with increased asthma risk should provide a basis for understanding the heterogeneity of asthma pathogenesis and for pharmacogenetic approaches to treat individuals carrying this variant. [Copyright &y& Elsevier]

Osteoarthritis (OA) is a common disease characterised by the degeneration of the cartilage of synovial joints such as the hip and knee. In the past ten years a large number of twin-pair, sibling-risk and segregation studies have been conducted on the disease, and these have revealed a major genetic component that is transmitted in a nonmendelian manner. OA therefore fits best into the complex, multifactorial class of common diseases. With a genetic component established, genome-wide linkage scans were performed, and these uncovered several genomic intervals likely to harbour OA susceptibility. In the past few years these intervals have started to yield genes containing OA-associated variants. This is therefore a very exciting period in the molecular genetic analysis of this common disease. The genes that have so far been implicated in susceptibility include the interleukin 1 gene (IL1) cluster at chromosome 2q11.2-q13, the matrilin 3 gene (MATN3) at 2p24.1, the IL-4 receptor ±-chain gene (IL4R) at 16p12.1, the secreted frizzled-related protein 3 gene (FRZB) at 2q32.1, the metalloproteinase gene ADAM12 at 10q26.2 and, most recently, the asporin gene (ASPN) at 9q22.31. The evidence for involvement of these genes in OA is more compelling for some than others, with the IL1 and ASPN associations being the most convincing to date. It is imperative that the veracity of each of the associations be tested by genotyping additional cohorts and that their global relevance be assessed by genotyping OA cohorts from different ethnic backgrounds. The gene products of IL1, IL4R, FRZB and ASPN regulate cartilage chondrocyte differentiation and survival, and their effects on the chondrocyte are potentially amenable to therapeutic intervention. The latest genetics is therefore providing new insights for the development of novel OA treatments. [ABSTRACT FROM PUBLISHER]

Development of asthma is likely to depend on a complex interaction between environmental and genetic factors. Several groups have suggested the gene of the IL-4 receptorα chain (IL4R) as a candidate gene for the development of asthma, although association with single polymorphisms has shown contradicting results.We chose to analyse IL4R gene haplotypes and assess their possible relevance in susceptibility to asthma and to certain clinical phenotypes.IL4R gene haplotypes were analysed, based on the three markers C-3223T, Q551R and I50V, using the expectation–maximization algorithm, in 170 atopic asthma patients and 350 controls, all adult Swedish Caucasians.Our data showed significantly higher levels of soluble IL-4R (sIL-4R) in asthma patients compared with controls (P<0.0001). Furthermore, we showed a significant association between the IL4R haplotype containing the alleles T-3223, V50 and R551 (TVR) of the IL4R gene, and susceptibility to atopic asthma, with a frequency of 6.5% in the patients compared with 1% in the controls (P<0.0005). A subgroup of patients with heterozygous or homozygous state for the T-3223, V50 and R551 alleles, also had lower levels of sIL-4R in their circulation compared with patients with homozygous state in the C-3223, I50 and Q551 alleles (P<0.05) and showed less severe asthma according to lung function test (P<0.05). Analysis of single markers showed the T-3223 IL4R allele to associate with lower serum levels of sIL-4 receptor (P<0.0001) and patients carrying the T allele also had more symptoms of active asthma (wheezing,P<0.01; coughing,P<0.05 and breathing difficulties,P<0.01).Our data suggest that asthmatic patients with low levels of sIL-4 receptor may represent a genetically distinct subgroup of atopic asthma. TVR haplotype analyses confirm the importance of IL4R as a candidate gene for susceptibility to asthma. This finding may have implications for the understanding of the pathogenesis of asthma and possibly for the development of more specific therapies. [ABSTRACT FROM AUTHOR]

Three overlapping fragments of the equine interleukin-4 receptor alpha chain gene (IL4R) were cloned and sequenced. The resulting 3553 bp cDNA sequence exhibited homology to human, murine and bovine IL4R. The equine IL4R exhibits many conserved features when compared to other species, including intron–exon boundary positions and amino acid sequence motifs characteristic of type I cytokine receptors. The IL4R gene was localized to horse chromosome ECA13 by synteny mapping on a somatic cell hybrid panel. Evidence for an alternative splice variant of IL4R was found in the genomic sequence and subsequently verified using RT-PCR on equine monocyte RNA. A polymorphism screen of the largest exon, homologous to exon 12 of the human IL4R gene, was performed using DNA from 60 horses of various breeds which yielded 11 coding-region single nucleotide polymorphisms (SNPs), 7 synonymous and 4 non-synonymous. Three of the four non-synonymous SNPs occur at high frequencies and are found very near a conserved tyrosine residue. [Copyright &y& Elsevier]

IL4 pathway is known to upregulate IgE mediated immune responses and responsible for the manifestation of Atopic disorders. The current study was aimed to elucidate the genetic variations of Interleukin 4 (IL4) and Interleukin 4 receptor alpha (IL4R) genes and their possible association with atopic subjects. The well-designed questionnaire was used to collect the subject demographic and clinical details. Biochemical parameters were analysed using Chemiluminescent Immunoassay (CLIA) technique. The genotyping was performed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). We observed a statistically significant difference of serum Immunoglobulin-E (IgE) levels among cases and controls (P <0.05). Subjects harbouring the variant genotypes of I50V and Q576R single nucleotide polymorphisms (SNPs) in IL4R gene showed statistically differential risk towards atopic disorders. However, the variants genotype of 70 bp VNTR polymorphism in IL4 gene showed a protective role towards in predisposition to Atopy. On stratification, the above genetic variants had a significant impact on modifiable and non-modifiable factors associated with the disease. Our study demonstrates that increased IgE levels and IL4 gene variants (I50V and Q576R) are significantly associated towards predisposition to allergic disorders in this study population. • Our study results infer that immunoglobulin E and interleukins play an important role in the pathogenesis of allergic disorders as reported throughout the globe. • The studied genotypes do have a significant role as modifiers of environmental exposure and life style factors in determining the risk of atopic disorders in Kashmiri population. • One of the important observations of our study was a protective association of one of the variants of IL4VNTR70bp repeat gene. The subjects harboring variant genotype (homozygous mutant + Heterozygous) of above gene showed an inverse association towards atopic disorders. • Kashmiri population is considered to be a non-migrant pure ethnic Muslim-dominated population with common consanguineous marriages, hence the less chances of frequent admixture of genetic markers. • The differential risk, opposite to what has been observed in other populations has been already reported in some genetic variants for other than allergic diseases in our population. The diversity of pollens, which happens to be substrates for above studied genes, could have different effects in IL4VNTR70bp repeat gene. Additionally, the peak-allergy seasons in Kashmir suit to variety of allergens, which are helped by cotton fluff from Russian poplars to reach to the people. Such carriers are not so common in other parts of India as well as major part of the world. [ABSTRACT FROM AUTHOR]

The central pathogen-immune interface in tuberculosis is the granuloma, a complex host immune structure that dictates infection trajectory and physiology. Granuloma macrophages undergo a dramatic transition in which entire epithelial modules are induced and define granuloma architecture. In tuberculosis, relatively little is known about the host signals that trigger this transition. Using the zebrafish- Mycobacterium marinum model, we identify the basis of granuloma macrophage transformation. Single-cell RNA-sequencing analysis of zebrafish granulomas and analysis of Mycobacterium tuberculosis- infected macaques reveal that, even in the presence of robust type 1 immune responses, countervailing type 2 signals associate with macrophage epithelialization. We find that type 2 immune signaling, mediated via stat6 , is absolutely required for epithelialization and granuloma formation. In mixed chimeras, stat6 acts cell autonomously within macrophages, where it is required for epithelioid transformation and incorporation into necrotic granulomas. These findings establish the signaling pathway that produces the hallmark structure of mycobacterial infection. [Display omitted] • Diverse cell populations and inflammatory cues characterize tuberculous granulomas • Granuloma macrophages that express E-cadherin display type 2 immune signatures • stat6 functions cell autonomously in granuloma macrophage epithelioid transformation • A type 2/Stat6 axis coordinates necrotic granuloma formation and epithelialization During mycobacterial infections, a non-canonical type 2 immune response underlies the formation and epithelial architecture of the granuloma, the hallmark structure of tuberculosis. [ABSTRACT FROM AUTHOR]

Neutrophils constitute the body's first line of defense against invading pathogens. Equipped with a large array of tools, these immune cells are highly efficient in eliminating bacterial and viral infections, yet their activity can at the same time be detrimental to the host itself - this is the broad consensus on these granulocytes. However, the last decade has proven that neutrophils are a much more sophisticated cell type with unexpected and underappreciated functions in health and disease. In this review, we look at the latest discoveries in neutrophil biology with a focus on their role during the hallmark setting of type 2 immunity – helminth infection. We discuss the involvement of neutrophils in various helminth infection models and summarize the latest findings regarding neutrophil regulation and effector function. We will show that neutrophils have much more to offer than previously thought and while studies of neutrophils in helminth infections are still in its infancy, recent discoveries highlight more than ever that these cells are a key cog of the immune system, even during type 2 responses. [ABSTRACT FROM AUTHOR]

Abstract: Autoimmune myasthenia gravis is a T-cell–dependent, antibody-mediated, rare neuromuscular disorder. Interleukin-4, acting via interleukin-4 receptor alpha, plays a pivotal role in B-cell differentiation and antibody production and has been implicated to influence disease progression in experimental autoimmune myasthenia gravis. Polymorphisms of the interleukin-4 receptor alpha gene have been shown to be associated with various autoimmune diseases. We compared the distribution of three polymorphisms of the interleukin-4 receptor alpha gene (S503P, rs1805015, Q576R, rs1801275, I75V, rs1805010), all affecting interleukin-4 signaling, in two cohorts of myasthenia gravis patients with ethnically matched controls. Although the distribution of the S503P and Q576R polymorphisms did not differ significantly between the groups, the frequency of the GG rare homozygote genotype of the I75V polymorphism was significantly higher in patients with myasthenia gravis. Our data suggest that the reduced responsiveness to interleukin-4 because the I75V polymorphism may contribute to the pathogenesis of myasthenia gravis. [Copyright &y& Elsevier]

• Cervical cancer (CC) is the second leading female malignancy in Bangladesh. • IL1β , IL4 , and IL6 are considered to be involved in cancer progression. • ARMS-PCR methods were developed to evaluate the role of IL1β , IL4R , IL6 in CC. • An association of IL1β , IL4R , IL6 gene polymorphisms with high CC risk was found. • GAA and GAG haplotypes significantly decreased the risk of CC. • AAA AAG, AGA, and AGG haplotypes significantly increased CC risk. • The IL1β mRNA, up-regulated in CC, was associated with poor prognosis in silico. • Proinflammatory cytokines can be a potential therapeutic target for CC treatment. Cervical cancer (CC) is the main cause of cancer-related deaths among women in developing countries. It is the second leading female malignancy in Bangladesh in terms of incidence and mortality. Our present study aimed to investigate the association of IL1β (rs16944), IL4R (rs1801275), and IL6 (rs1800797) gene polymorphisms with the susceptibility of cervical cancer. This case-control study was conducted on 252 cervical cancer patients and 228 healthy volunteers, using tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). In the case of rs16944 polymorphism, GG genotype (OR = 2.10, 95%CI = 1.24–3.56), dominant model (OR = 1.71, 95% CI = 1.11–2.63), recessive model (OR = 1.54, 95% CI = 1.01–2.35), and G allele (OR = 1.30, 95% CI = 1.005–1.68) were significantly associated with increased cervical cancer risk. Among these, GG genotype and dominant model remained significant after the Bonferroni correction (p < 0.017). For rs1801275 polymorphism, GG genotype (OR = 2.66, 95% CI = 1.49–4.75), dominant model (OR = 1.49, 95% CI = 1.04–2.14), recessive model (OR = 2.45, 95% CI = 1.40–4.27), and G allele (OR = 1.59, 95% CI = 1.21–2.10) significantly elevated the risk of cervical cancer but significance did not exist for dominant model after the Bonferroni correction. rs1800797 variant showed significantly increased risk in all genetic models including, AG genotype (OR = 8.13, 95% CI = 5.27–12.55), AA genotype (OR = 9.86, 95% CI = 2.76–35.21), dominant model (OR = 8.25, 95% CI = 5.40–12.60), recessive model (OR = 4.41, 95% CI = 1.25–15.56), and A allele (OR = 4.99, 95% CI = 3.49–7.13) and the significances were consistent with the Bonferroni correction except recessive model. Haplotyping analysis indicates that GAA (p = 5.15x10−5) and GAG haplotypes (p = 4.72x10−9) significantly decreased the risk of CC, whereas AAA (p = 3.89x10-9), AAG (p = 0.0003), AGA (p = 3.98x10-5) and AGG haplotypes (p = 0.002) significantly increased the risk of CC. The IL1β mRNA level was up-regulated, which was associated with poor prognosis in silico. Our results conclude that rs16944 (IL1β), rs1801275 (IL4R), and rs1800797 (IL6) polymorphisms are associated with cervical cancer in Bangladeshi women. [ABSTRACT FROM AUTHOR]

Background: Asthma and rhinitis have a complex etiology, depending on multiple genetic and environmental risk factors. An increasing number of susceptibility genes are currently being identified, but the majority of reported associations have not been consistently replicated across populations of different genetic backgrounds., Purpose: To evaluate whether polymorphisms of IL4R (rs1805015), IL13 (rs20541), IL17A (rs2275913) and GSTP1 (rs1695) genes are associated with rhinitis and/or asthma in adults of Portuguese ancestry., Methods: 192 unrelated healthy individuals and 232 patients, 83 with rhinitis and 149 with asthma, were studied. All polymorphisms were detected by real time polymerase chain reaction (PCR) using TaqMan assays., Results: Comparing to controls, significant association with asthma was observed for GSTP1 rs1695 AA genotype (odds ratio (OR) - 1.96; 95% CI - 1.18 to 3.25; p=0.010). The association sustains for allergic asthma (OR - 2.17; 95% CI - 1.23 to 3.80; p=0.007). IL13 rs20541 GG genotype was associated with less susceptibility to asthma (OR - 0.55, 95% CI - 0.33 to 0.94, p=0.028). Among patients, IL17A rs2275913 AA genotype was less associated with asthma than with rhinitis (OR - 0.20; 95% CI of 0.07 to 0.56; p=0.002). A similar association was found for IL13 rs20541 GG genotype (OR - 0.48; 95% CI of 0.25 to 0.93; p=0.031). There were no significant differences in the distribution of allelic and genotypic frequencies between patients and controls for the IL4R polymorphism' analyzed., Conclusion: These results support the existence of a significant association between GSTP1 rs1695 and IL13 rs20541 SNPs, with susceptibility to asthma, in the population studied. Different genotype profiles of IL17A and IL13 genes seem to influence the clinical pattern of disease expression mainly confined to the upper airways, as rhinitis, or including the lower airways, as asthma., (Copyright © 2016 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)