Development Of Immune Diseases Research Articles

Inhibition activity of triazoles as a new family for the inhibition of the Indoleamine 2,3-dioxygenase 1 IDO1 protein using 2D-QSAR approach

Protein IDO1 (indoleamine 2,3-dioxygenase) occupies a critical position in the regulation of the immune system and is involved in cancer progression and the development of immune diseases. Being a therapeutic target for such critical diseases, we aimed to investigate the IDO1 inhibition activity of thirty-nine triazole derivatives using a quantitative structure-activity relationship. The dataset was under principal component analysis, multiple linear regression, and multiple non-linear regression from which two models were generated. The best 2D-QSAR model was generated using linear regression, demonstrating a determination coefficient of R2=0.680, a good acceptable internal cross-validated coefficient of R2cv=0.700, an error of MSE=0.074, and a good predictive potential of R2test=0.809. The QSAR model was further investigated using the applicability domain, which showed that all molecules were within the applicability domain, hence the absence of an outlier. Overall, the obtained results provide a reliable and highly predictive model for the design and prediction of new IDO1 inhibitors thereby influencing cancer progression and autoimmune disease development.

TIM-3 regulates the proliferation by BDNF-mediated PI3K/AKT axis in the process of endometriosis

BackgroundT cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) initially discovered on the surface of Th1 cells, negatively regulates immune responses and mediates apoptosis of Th1 cells. An increasing number of studies have since shown that TIM-3 is crucial in the genesis and development of immune diseases, cancers, and chronic infectious illnesses. However, the effect of TIM-3 on endometriosis is still unknown.MethodsQuantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry were used to measure TIM-3 levels in endometriosis. Cell Counting Kit-8, 5-ethynyl-2’-deoxyuridine, colony-forming, Transwell® migration, Matrigel® invasion, and flow cytometry assays were used to explore the function of TIM-3 in vitro, and xenograft experiments in nude mice were used to assess its role in vivo. According to the RNA seq, brain-derived neurotrophic factor (BDNF) was screened. The involvement of specific proliferation-related signaling molecules was determined by transfecting a plasmid and adding an inhibitor in vivo and in vitro.ResultsTIM-3 mRNA and protein expression levels were significantly higher in eutopic and ectopic endometrial tissues than in normal endometrial tissues. By examining the effects of TIM-3 overexpression and knockdown on cell proliferation, migration, and invasion in vitro, and lesions formation in vivo, we found that the expression of TIM-3 was positively correlated with cell proliferation and clone formation in vitro, as well as lesions growth in nude mice. By adding the phosphatidylinositol 3 kinase/protein kinase B(PI3K/AKT) pathway inhibitor LY294002 and knocking down PI3K, we further verified that TIM-3 promotes proliferation in vivo and in vitro via the PI3K pathway. By transfecting the plasmid into ESC cells and gave inhibitors to endometriotic rats models, we tested that TIM-3 regulates the proliferation by BDNF-mediated PI3K/AKT axis.ConclusionTIM-3 can promote the proliferation of endometriosis by BDNF-mediated PI3K/AKT axis in vivo and in vitro, which may provide a new therapeutic target for the treatment of endometriosis.

Mold, Mycotoxins and a Dysregulated Immune System: A Combination of Concern?

Fungi represent one of the most diverse and abundant eukaryotes on earth. The interplay between mold exposure and the host immune system is still not fully elucidated. Literature research focusing on up-to-date publications is providing a heterogenous picture of evidence and opinions regarding the role of mold and mycotoxins in the development of immune diseases. While the induction of allergic immune responses by molds is generally acknowledged, other direct health effects like the toxic mold syndrome are controversially discussed. However, recent observations indicate a particular importance of mold/mycotoxin exposure in individuals with pre-existing dysregulation of the immune system, due to exacerbation of underlying pathophysiology including allergic and non-allergic chronic inflammatory diseases, autoimmune disorders, and even human immunodeficiency virus (HIV) disease progression. In this review, we focus on the impact of mycotoxins regarding their impact on disease progression in pre-existing immune dysregulation. This is complemented by experimental in vivo and in vitro findings to present cellular and molecular modes of action. Furthermore, we discuss hypothetical mechanisms of action, where evidence is missing since much remains to be discovered.

Emerging Roles for NLRC5 in Immune Diseases.

Innate immunity activates the corresponding immune response relying on multiple pattern recognition receptors (PRRs) that includes pattern recognition receptors (PRRs), like NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and C-type lectin receptors (CLRs), which could accurately recognize invasive pathogens. In particular, NLRs belong to a large protein family of pattern recognition receptors in the cytoplasm, where they are highly correlated with activation of inflammatory response system followed by rapid clearance of invasive pathogens. Among the NLRs family, NLRC5, also known as NOD4 or NOD27, accounts for a large proportion and involves in immune responses far and wide. Notably, in the above response case of inflammation, the expression of NLRC5 remarkably increased in immune cells and immune-related tissues. However, the evidence for higher expression of NLRC5 in immune disease still remains controversial. It is noted that the growing evidence further accounts for the participation of NLRC5 in the innate immune response and inflammatory diseases. Moreover, NLRC5 has also been confirmed to exert a critical role in the control of regulatory diverse signaling pathways. Together with its broad participation in the occurrence and development of immune diseases, NLRC5 can be consequently treated as a potential therapeutic target. Nevertheless, the paucity of absolute understanding of intrinsic characteristics and underlying mechanisms of NLRC5 still make it hard to develop targeting drugs. Therefore, current summary about NLRC5 information is indispensable. Herein, current knowledge of NLRC5 is summarized, and research advances in terms of NLRC5 in characteristics, biological function, and regulatory mechanisms are reviewed.

Nutritional components regulate the gut immune system and its association with intestinal immune disease development

The gut is equipped with a unique immune system for maintaining immunological homeostasis, and its functional immune disruption can result in the development of immune diseases such as food allergy and intestinal inflammation. Accumulating evidence has demonstrated that nutritional components play an important role in the regulation of gut immune responses and also in the development of intestinal immune diseases. In this review, we focus on the immunological functions of lipids, vitamins, and nucleotides in the regulation of the intestinal immune system and as potential targets for the control of intestinal immune diseases.

P2-07-01: Copy Number Variants in Early-Onset-Breast Cancer.

Abstract Background: Copy number variants (CNVs) are known to contribute to the risk for development of immune diseases, neurological disorders and to a lesser extent cancer. Many CNVs do not directly involve gene sequences. CHL1, a cell adhesion molecule with homology to L1CAM, is down-regulated in a large proportion of breast cancer. A deletion CNV immediately 5’ of the CHL1 transcriptional start site has been described. The CHL1 CNV's role in breast cancer risk has not previously been explored. Material and Methods: 50 research subjects recruited to the Washington University/Siteman Cancer Center Young Women's Breast Cancer Program (YWBCP) were selected for a CNV discovery study. These women were diagnosed breast cancer < age 40, tested negative for BRCA1/2 mutations and have a negative family history for breast cancer. The selection criteria enriched for de novo mutations. Comparative genomic hybridization (CGH) analyses were undertaken using the NimbleGen 2.1 million oligonucleotide array. DNA copy number was compared between proband and each of her parents to identify potential deletions or amplifications in the daughter relative to both parents (de novo changes). PCR was used to confirm a subset of the CGH-predicted differences in copy number. Chi-square test was used to determine statistical significances of CNV occurrences near the CHL1 gene between women with breast cancer and control cases. Results: aCGH data analysis has been completed for 25 YWBC trios (patients and parents). 247 differences in copy number in the breast cancer cases relative to their parents were identified (1-18 putative de novo CNVs per case). 91% of the observed changes were deletions and 9% were amplifications. One proband showed an 11,560 bp deletion 5’ of the CHL1 gene that was not seen in her parents. Conventional PCR confirmed a homozygous deletion of a ∼3 kb region in the patient, in the region of a known CNV with a reported frequency of ∼3%. Testing an additional 368 early-onset breast cancer cases for the CHL1 deletion revealed 25 additional homozygous deletions (6.8%). The deletion was present in 9 of 197 controls (4.5%). qPCR studies revealed the parents of the patient with the CHL1 deletion each carried a single copy of the CNV, making de novo copy number change in the proband very unlikely. Deletion specific assays for the CHL1 CNV are being used to test CNV genotypes in an extended case-control study. Discussion: CHL1 expression has previously been shown to be down-regulated in primary breast tumors. Our preliminary analysis of YWBC cases and controls indicates the CHL1 regulatory region CNV is unlikely to be associated with risk for early-onset breast cancer. Additional candidate de novo copy number changes seen in the genomes of patients with early-onset breast cancer are being evaluated to determine their roles as genetic risk factors. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-07-01.

Basic research Environmental toxin 4-nonylphenol and autoimmune diseases: using DNA microarray to examine genetic markers of cytokine expression

IntroductionAdverse progression of autoimmune diseases is linked to the dysregulation of cytokines. In this regard we investigated the role of 4-nonylphenol (4-NP), as a potential contributing factor in the development of immune diseases and compared it to estrogens actions since 4-NP may work via estrogen processes.Material and methodsThe study made cytokine level expression changes in U937 cells by microarray technology coupled to RT PCR as a validating technique.ResultsIt was determined that 4-NP significantly up-regulated proinflammatory cytokine expression (toll-like-receptor [TLR]-6, TLR-10, interleukin [IL]-1, IL-5, IL-6, IL-17C, IL-23A, IL-8RB, IL-receptor-associated-kinase [IRAK-2], tumor-necrosis-factor-receptor [TNFR]-5, and TNFR-10). Estrogen caused insignificant increases but the changes parralelled that of 4-NP. Simultaneously, 4-NP down-regulated the expression of anti-inflammatory cytokines (IL-4 and IL-10), while estrogen up-regulated them.Conclusions4-Nonylphenol may initiate its toxic effects and pose a risk to autoimmunity-prone individuals by eliciting effects up to 4 times more potent than estrogen. Overall, exposure to 4-NP may contribute to autoimmune susceptibility and/or exacerbate existing autoimmune conditions by dys-regulating normal expression of cytokines.