Rs-10889677 variant in interleukin-23 receptor may contribute to creating an inflammatory milieu more susceptible to bladder tumourigenesis: report and meta-analysis.

Bladder cancer (BLC) is a recurrent high-risk malignancy typified by an inherent localised chronic inflammation. IL-23-receptor (IL-23R), as a positive regulator in the priming of T helper-17 cells, is regarded a principal coordinator of inflammation-propelled neoplasia. In this article, we indented firstly to scrutinise the influence of rs10889677"A/C" SNP located in IL-23R-gene on BLC development and progression among Egyptians. Findings revealed that the rs10889677"C" allele was significantly associated with the increased BLC risk and its higher frequencies were plainly noticeable in high-grade and invasive tumours when applied the dominant/homozygous/allelic genetic models. Under the same genetic models, elevated serum levels of IL-23R protein in BLC patients were pertinently correlated with the rs10889677"A/C" polymorphism. As a corollary, the frequent up-regulation of IL-23R exerts a subsequent activation of the IL-23/17 inflammatory axis. That is experienced as a drastic increase in IL-23 and IL17 levels under the dominant/homozygous/heterozygous/recessive models. Second, study further described how the rs10889677 variant confers its pro-tumoural influences on IL-23R-bearing immune cells, involving tumour-associated macrophages (TAMs), natural killers (NKs) and CD4+ T-helper cells. When the dominant model was adopted, it was observed that patients bearing the rs10889677 "C" allele had lower counts of IL-23R-positive CD56+NKs and CD4+ T-cells, in tandem with higher levels of IL-23R-positive CD14+ TAMs compared with those with rs10889677 "A" allele. To entrench the idea, we did a meta-analysis on BLC patients from three different ethnicities (Asian, Caucasians and African). We observed that rs10889677"SNP" is significantly correlated with increased risk of BLCs in the overall population using over-dominant model. Consequently, authors suggested that the rs10889677 variant could be directly implicated in developing inflammatory environment more prone to generating malignancy.

Rs-1884444 G/T variant in IL-23 receptor is likely to modify risk of bladder urothelial carcinoma by regulating IL-23/IL-17 inflammatory pathway.

Bladder urothelial carcinoma (BUC) is a chronic relapsing urological malignancy, which poses a serious threat to human life. Non-resolving chronic-inflammation at the neoplastic site is associated consistently with inducing tumor-progression and poor patient outcomes. Interleukin 23 receptor (IL-23R) is a key element in T-helper 17 cell-mediated inflammatory process, that plays a critical role in orchestrating tumor-promoting inflammation. Therefore, we hypothesized that potentially functional genetic variant rs1884444 G/T of IL-23R may modify BUC risk. To validate this hypothesis, our findings demonstrated that the rs1884444 G/T variant was significantly associated with a reduced risk of BUC compared to controls observed under allelic (T vs. G) and dominant (GT + TT vs. GG) models (P < 0.05). In addition, the frequency of the T-allele has dropped to very low values in the case of high-grades and invasive-tumors (P < 0.05). Thus, T-allele has emerged as a reliable genetic marker for good prognosis of BUC. In tumorgenesis, the binding-affinity of the receptor seemed to be distorted by the effect of the non-conservative G/T variation, which in turn caused the IL-23/IL-17 pathway to be disabled. This was recognized by low levels of IL-23 and IL-17 in the serum of patients, under the influence of all the tested genetic models (P < 0.01). Results also indicated that the level of the receptor-bearing immune cells could be altered in response to the G/T protective effect. For example, the median counts of T-helper CD4+ cells and CD56+ natural killers increased significantly in conjunction with the decrease in the median count of CD14+ tumor-associated-macrophages under the dominant model. Nevertheless, the causative link between this subtle polymorphism and the immune-surveillance against BUC needs further in-depth investigation. Overall, we concluded that the rs-1884444 G/T variant is highly-associated with a reduction in the BUC risk, which may occur via deregulation of the IL-23/IL-17 pathway.

Long non-coding RNAs BACE1-AS and BC200 in multiple sclerosis and their relation to cognitive function: A gene expression analysis.

Cognitive impairment is a common and debilitating feature of multiple sclerosis (MS), and the dysregulation of synaptic plasticity is one of its direct causes. Long non-coding RNAs (lncRNAs) have been shown to play a role in synaptic plasticity, but their role in cognitive impairment in MS has not been fully explored. In this study, using quantitative real-time PCR, we examined the relative expression of two specific lncRNAs, BACE1-AS and BC200, in the serum of two cohorts of MS patients with and without cognitive impairment. Both lncRNAs were overexpressed in both cognitively impaired and non-cognitively impaired MS patients, with consistently higher levels in the cohort with cognitive impairment. We also found a strong positive correlation between the expression levels of these two lncRNAs. Notably, BACE1-AS was consistently higher in the remitting cases of both relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) groups than in the respective relapse cases of the same subtype, with the SPMS-Remitting group of cognitively impaired MS patients showing the highest expression of BACE1-AS among all MS groups. Additionally, we observed that the primary progressive MS (PPMS) group had the highest expression of BC200 in both cohorts of MS. Furthermore, we developed a model called Neuro_Lnc-2, which showed better diagnostic performance than either BACE1-AS or BC200 alone in predicting MS. Our findings suggest that these two lncRNAs may have a significant impact on the pathogenesis of the progressive types of MS and on the cognitive function of the patients. Future research is required to confirm these findings.

Micro-RNA-96 and interleukin-10 are independent biomarkers for multiple sclerosis activity.

BACKGROUND: Micro-RNAs (miRNAs) are evolving as biological markers for multiple sclerosis (MS) both in activity and remission. miR-96 is associated with remission, however, the exact mechanism through which it contributes to the anti-inflammatory pathway is not clear. OBJECTIVE: To study the expression of miR-96 and IL-10 (anti-inflammatory mediator) in relapsing remitting (RR) MS. SUBJECTS AND METHODS: A case control study including 32 RRMS patients from Kasr Al-Ainy MS clinic, Cairo University, Egypt, and 26 healthy controls (HC). Assessment of serum IL-10 by ELISA, and miR-96 via real time PCR was done during relapse and remission in patients, and in HC. RESULTS: IL-10 was higher in RRMS patients during remission and in HC compared with relapse (P ˂ 0.001). miR-96 expression was higher in RRMS patients during remission compared with relapse and HC, and was higher in HC than in relapse (P ˂ 0.001). IL-10 level in remission correlated positively with disease duration (r = 0.41; P = 0.02). Otherwise, no correlation was found between IL-10 and relapse number or EDSS (P>0.05). miR-96 in relapse negatively correlated with EDSS in relapse (r=-0.47; P=0.007), but no correlation was found with disease duration or relapse number, whereas, miR-96 in remission did not correlate with any clinical parameters (P>0.05). No correlation was found between IL-10 and miR-96 either in relapse or remission (P>0.05). CONCLUSION: IL-10 and miR-96 are associated with MS quiescence, however, the lack of a significant correlation between them implicates that the influence of miR-96 may be exhibited through some pathway other than IL-10.

Role of interleukin-23 as a biomarker in rheumatoid arthritis patients and its correlation with disease activity.

BACKGROUND: IL-23 is a pro-inflammatory cytokine belonging to the IL-12 cytokine family. IL-23 is essential for the differentiation of Th17 lymphocytes, a subtype of T lymphocyte implicated in chronic inflammatory/autoimmune mediated diseases. Experimental models of arthritis and clinical indications have highlighted an important role for Th17 lymphocytes in the pathogenesis of RA. However the role and mechanism of action of IL-23 in the pathogenesis of RA are still not fully understood. OBJECTIVE: This study was conducted to assess the level of IL-23 in patients with RA as well as the relationship between the IL-23 level and disease activity. METHODS: The study includes 77 patients with RA fulfilling the American College of Rheumatology (ACR) revised criteria for diagnosis of RA as well as 25 age and sex matched healthy subjects as controls. Patients were divided according to disease activity into four groups: DAS 28 score (˂ 2.6), 10 patients in remission, DAS 28 score between 2.6-3.2, 10 patients with low disease activity, DAS 28 score ranges between (3.2-5.1), 30 patients with moderate disease activity and DAS 28 score (˂ 5.1), 27 patients with High disease activity. Disease activity were determined by the 28-joint disease activity score (DAS 28). Anti-citrullinated protein antibodies (ACPA) was done. The levels of IL-23 were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum level of IL-23 was significantly elevated in RA patients (78.92±52.47) compared to control group (33.34±3.99) (P<0.001). However, no correlations were found between IL-23 and DAS 28 score, and other patients characteristics. CONCLUSION: Our results imply that IL-23 may potentially play a role in the pathogenesis of RA and may be a useful biomarker for the diagnosis of this disease. Targeting the IL-23 cytokine may provide a new therapeutic approach in the treatment of RA.

Interleukins 17 and 10 in a sample of Egyptian relapsing remitting multiple sclerosis patients.

BACKGROUND: Cytokines are major contributors in the immune disruption in multiple sclerosis (MS). OBJECTIVE: Evaluating the proinflammatory (IL-17A) and anti-inflammatory (IL-10) cytokines in relapsing-remitting (RR) MS patients at time of relapse and during remission. SUBJECTS AND METHOD: A case-control study including 30 RRMS patients and 15 controls. Patients were recruited from the Kasr Al-Ainy MS research unit (KAMSU), Cairo University, Egypt. Levels of IL-17A and IL-10 were assessed in patients' sera, during relapse and 30days after IV methylprednisolone, and in control subjects using enzyme linked immunosorbent assays (ELISA). RESULTS: IL-17 was higher in patients during relapse and remission phases when compared with controls (P=0.001), whereas, IL-10 was higher in patients during remission but normal during relapse (P=0.01; 0.86 respectively). IL-17 increased during relapses (P=0.001) while IL-10 increased during remissions (P=0.028). No significant correlations were found between both interleukins and age at onset; disease duration, number of relapses; or EDSS. CONCLUSION: RRMS patients can have a regulatory imbalance between both pro-and antiinflammatory cytokines, which could be a target for treatment strategies rather than focusing on a single cytokine.