IL18 and IL18R1 polymorphisms, lung CT and fibrosis: A longitudinal study in coal miners.

It has been suggested that interleukin (IL)-18 plays a role in the development of inflammatory and fibrosing lung diseases. Associations of polymorphisms in the genes coding for IL-18 (IL18 /G-656T, C-607A, G-137C, T113G, C127T) and its receptor (IL18R1 /C-69T) with coal workers' pneumoconiosis (CWP) were studied in 200 miners who were examined in 1990, 1994 and 1999. Coal-dust exposure was assessed according to job history and ambient measures. The main health outcome was lung computed tomography (CT) score in 1990. Internal coherence was assessed by studying CT score in 1994, 4-yr change in CT score and CWP incidence and prevalence. CT score in 1990 was a good predictor of radiographic grade in 1999 and, therefore, an appropriate subclinical quantitative trait. The IL18 -137C allele was associated with lower CT score in 1990 and 1994 (1.24 versus 1.69 and 1.57 versus 2.46, respectively), slower progression of CT score between 1990 and 1994 and lower pneumoconiosis prevalence in 1999 relative to the G allele (0.33 versus 0.77 and 8.2 versus 19.6%, respectively). Smoking- or dust-adjustment, and stratification on IL18R1 genotype and adjustment for haplotype effects did not change the conclusions. In conclusion, the results of the present study suggest a role for IL18 in reducing the development of this fibrosing lung disease.     

The relationship between ApoE, TNFA, IL1a, IL1b and IL12b genes and HIV-1-associated dementia

Objectives

Host genetic factors implicated in AIDS dementia complex (ADC) were studied.

Methods

DNA from ADC patients (n=56), unselected HIV‐seropositive patients (n=112, 171, 185 and 204) and HIV‐seronegative controls (n=204, 60, 60, 96 and 624) were typed for polymorphic loci in genes encoding tumour necrosis factor (TNF)‐α, interleukin (IL)‐1α, IL‐1β, IL‐12 and Apolipoprotein E (ApoE). Diagnosis of ADC was based on neurological symptoms, signs and neuroimaging findings with other causes of dementia excluded. Patients selected had ADC stage ≥1 and CD4 counts of <500 cells/μL.

Results

Allele 2 of TNFA‐308 was more common in ADC patients compared to HIV‐positive or HIV‐negative controls (P=0.005, 0.024). No other differences between ADC patients and control groups were significant. Meta‐analyses confirmed these results.

Conclusions

This study suggests that TNFA‐308 allele 2 or an allele in linkage disequilibrium with this locus influences ADC.     

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Acute myeloid leukemia (AML) is associated with a poor survival rate, and there is an urgent need for novel and more efficient therapies, ideally targeting AML stem cells that are essential for maintaining the disease. The interleukin 1 receptor accessory protein (IL1RAP; IL1R3) is expressed on candidate leukemic stem cells in the majority of AML patients, but not on normal hematopoietic stem cells. We show here that monoclonal antibodies targeting IL1RAP have strong antileukemic effects in xenograft models of human AML. We demonstrate that effector-cell–mediated killing is essential for the observed therapeutic effects and that natural killer cells constitute a critical human effector cell type. Because IL-1 signaling is important for the growth of AML cells, we generated an IL1RAP-targeting antibody capable of blocking IL-1 signaling and show that this antibody suppresses the proliferation of primary human AML cells. Hence, IL1RAP can be efficiently targeted with an anti-IL1RAP antibody capable of both achieving antibody-dependent cellular cytotoxicity and blocking of IL-1 signaling as modes of action. Collectively, these results provide important evidence in support of IL1RAP as a target for antibody-based treatment of AML.Acute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by clonal expansion of leukemic cells. Despite an increased understanding of the underlying disease biology in AML, the standard treatment with cytotoxic chemotherapy has remained largely unchanged over the last decades and the overall 5-y survival remains poor, being <30% (1, 2). Hence, there is a pressing need for novel therapies with increased efficacy and decreased toxicity, ideally targeting the AML stem cells because these cells are believed to be critical in the pathogenesis of AML, and their inadequate eradication by standard therapy is thought to contribute to the high incidence of relapse (3, 4). Although therapeutic antibodies directed at cell-surface molecules have proven effective for the treatment of malignant disorders such as lymphomas and acute lymphoblastic leukemia, as well as solid tumors (5, 6), no antibody-based therapy is currently approved for AML.The interleukin 1 receptor accessory protein (IL1RAP), also called IL1R3, is a coreceptor of type 1 interleukin 1 receptor (IL1R1) and is indispensable for transmission of IL-1 signaling (7). We have previously reported that IL1RAP is a biomarker for putative chronic myeloid leukemia stem cells (8). In a recent study, we showed that IL1RAP is expressed on the cell surface in ∼80% of AML patients and that candidate CD34⁺CD38⁻ AML stem cells can be selectively killed in vitro by antibody-dependent cellular cytotoxicity (ADCC) (9). Furthermore, IL1RAP is up-regulated on immature cells in high-risk AML with chromosome 7 aberrations, and increased IL1RAP expression correlates with poor prognosis (10). These findings could suggest IL1RAP as a novel and specific target for an antibody-based therapy in AML; however, in vivo evidences for therapeutic effects of IL1RAP targeting are lacking. Here, we demonstrate that antibodies targeting IL1RAP in immunodeficient mice transplanted with human AML cells have strong in vivo antileukemic effects. We further show that effector-cell–mediated killing is a critical mechanism for the observed therapeutic effects and that IL1RAP antibodies capable of inhibiting IL-1 signaling suppress the proliferation of primary human AML cells, suggesting that this dual mode of action of anti-IL1RAP antibodies is an efficient and promising approach in future treatment of AML.     

Lack of association of type 1 diabetes with the IL4R gene

Aims/hypothesis The association between IL4R and type 1 diabetes has been tested in many studies in recent years, with contradictory results. The aim of this study was to re-evaluate the genetic association in type 1 diabetic nuclear families of mixed European background.Subjects, materials and methods We genotyped six non-synonymous single-nucleotide polymorphisms (SNPs) of the IL4R gene in 830 nuclear families as specified above, including a French Canadian subset.Results No association between type 1 diabetes and any SNP or haplotype was found by the transmission disequilibrium test.Conclusions/interpretation Previous positive reports may be due to population stratification as, according to HapMap data, allele frequencies in the IL4R region vary considerably by ethnicity.Electronic Supplementary Material Supplementary material is available for this article at http://doi.     

Investigation of association of the IL12B and IL23R genes with psoriatic arthritis

Objective

Recent reports have confirmed association of single‐nucleotide polymorphisms (SNPs) mapping to the interleukin‐23 receptor (IL‐23R) and IL‐12β genes with psoriasis susceptibility. The aim of this study was to determine whether these variants are also associated with susceptibility to psoriatic arthritis (PsA).

Methods

Two IL23R SNPs (rs7530511 and rs11209026) and 2 IL12B SNPs (rs3212227 and rs6887695) were genotyped in DNA samples from 520 white patients with PsA and 2,260 control subjects, all of whom resided in the UK. For SNP rs3212227, data on a larger group of controls (n = 4,681) were publicly available; this information was used in the analysis. Genotype counts were compared between patients with PsA and population controls, using the trend test.

Results

A haplotype comprising carriage of the common variants of both IL23R SNPs was associated with PsA susceptibility (adjusted P = 0.013 [1,000 permutations]). Both IL12B SNPs were independently associated with PsA susceptibility, and this association was strongest under a dominant model, with homozygosity for the common allele being more frequent in patients with PsA than in control subjects: for rs3212227, the odds ratio (OR) for carriage of AA versus other genotypes was 1.43 (95% confidence interval [95% CI] 1.17–1.76); for rs6887695, the OR for carriage of GG versus other genotypes was 1.43 (95% CI 1.18–1.74).

Conclusion

Variation within IL23R and IL12B is associated with susceptibility to both psoriasis and PsA. The effect sizes observed in patients with PsA appear to be smaller than those previously reported in patients with psoriasis, suggesting that both loci are primarily associated with psoriasis susceptibility. However, this does support the idea that the genetic etiology of the psoriasis present in patients with PsA has susceptibility loci in common with those observed in patients with uncomplicated psoriasis.

     

NOD2,IL23R and ATG16L1 polymorphisms in Lithuanian patients with inflammatory bowel disease

AIM:To investigate the frequency of NOD2, IL23R and ATG16L1 genetic variants in a case-control panel for inflammatory bowel disease (IBD) from Lithuania.METHODS: One hundred and eighty unrelated IBD pa- tients [57 Crohn‘s disease (CD) and 123 ulcerative colitis (UC)] and 186 healthy controls were genotyped for the following known genetic susceptibility variants:NOD2-Arg702Trp (rs2066844), Gly908Arg (rs2066845) and Leu1007insC (rs2066847), as well as IL23R-Arg381Gln (rs11209026) and ATG16L1-Thr300Ala (rs2241...     

NOD2/CARD15 , ATG16L1 and IL23R gene polymorphisms and childhood-onset of Crohn’s disease

AIM: To assess whether the polymorphisms of NOD2/ CARD15 , autophagy-related 16-like 1 (ATG16L1 ), and interleukin-23 receptor (IL23R ) genes play a more critical role in the susceptibility of childhood-onset than in adult-onset Crohn’s disease (CD). METHODS: Polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 ; rs2241880 A/G of ATG16L1 , and rs11209026 (R381Q) of IL23R gene were assessed in 110 childhood-onset CD, 364 adult-onset CD, and 539 healthy individuals. Analysis of polymorphisms R702W, G908R, ...     

NOD2/CARD15 and TNFA, but not IL1B and IL1RN, are associated with Crohn's disease

BACKGROUND: NOD2/CARD15 was described as the first susceptibility gene to Crohn's disease (CD). Polymorphisms in the TNFA gene and in the IL1 gene cluster, which are associated with an enhanced chronic inflammatory response, may also play a role in the development of CD. The aim of this study was to determine the association of polymorphisms in the CARD15, TNFA, IL1B, and IL1RN genes with risk of development of CD and with the clinicopathological profile of CD patients. METHODS: In a case-control study including 235 CD patients and 312 controls (929 controls for TNFA genotyping), the CARD15 (R702W, G908R, and 1007fs), TNFA (-308G/A and -857C/T), IL1B (-511C/T), and IL1RN (intron 2 variable number of tandem repeats) polymorphisms were genotyped. RESULTS: We observed a significant association between CD and the CARD15 polymorphisms, with an odds ratio (OR) of 2.9 [95% confidence interval (CI), 1.9 to 4.6] for carriers of 1 variant allele and an OR of 11.8 (95% CI, 3.5 to 40.4) for carriers of 2 variant alleles. Patients with CARD15 polymorphisms had more frequently ileal or ileocolonic disease location, stricturing phenotype, abdominal surgery, and no extraintestinal manifestations. The TNFA-308A/A genotype was associated with susceptibility to CD with an OR of 3.0 (95% CI, 1.2 to 7.2). TNFA-308A/A homozygotes showed a higher frequency of erythema nodosum and arthritis, colonic disease location, and absence of abdominal surgery. No associations were found with the TNFA-857, IL1B-511, and the IL1RN VNTR polymorphisms. CONCLUSIONS: These findings suggest that CARD15 and TNFA-308 genetic polymorphisms are associated with increased risk of CD displaying distinct clinicopathological profiles.     

IL7R and RAG1/2 genes mutations/polymorphisms in patients with SCID

SCID disorder is major failure of the immune system, usually genetic. The aim of this study was on mutations detection of RAG1, RAG2, and IL7RG genes in SCID cases. Mutation detection was performed by PCR sequencing. Our results indicated that 13 mutations were found through cases which include 4 mutations in IL7R gene (T661I, I138V, T56A, C57W), 7 mutations in RAG1 (W896X, W204R, M324V, T731I, M1006V, K820R, and R249H), and 2 mutations in RAG2 gene (R229W, ΔT251).     

Polymorphisms of micro RNA target genes IL12B,INSR, CCND1 and IL10 in gastric cancer

AIM To evaluate associations between mi RNA target genes IL12B,INSR,CCND1 and IL10 polymorphisms and gastric cancer(GC)in European population.METHODS Gene polymorphisms were analyzed in 508 controls and474 GC patients from 3 tertiary centers in Germany,Lithuania and Latvia.Controls were patients from the out-patient departments,who were referred for upper endoscopy because of dyspeptic symptoms and had no history of previous malignancy.Gastric cancer(GC)patients had histopathological verification of gastric adenocarcinoma.Genomic DNA was extracted using salting out method from peripheral blood mononuclear cells.IL12B TG(rs1368439),INSR TC(rs1051690),CCND1 AC(rs7177)and IL10 TC(rs3024498)SNPs were genotyped by the real-time polymerase chain reaction.Associations between gene polymorphism and GC were evaluated using multiple logistic regression analysis with adjustment for sex,age and country of birth.RESULTS We observed similar distribution of genotypes and allelic frequencies of all polymorphisms between GC patients and controls except of INSR rs1051690.The frequency of the T allele of INSR gene was significantly higher in GC patients than in controls(23.26%and 19.19%respectively,P=0.028).CT genotype was also more prevalent in patients compared to control group(38.48%and 30.12%respectively,P0.021).Logistic regression analysis revealed that only one polymorphism(rs1051690 in INSR gene)was associated with increased risk of GC.Carriers of CT genotype had higher odds of GC when compared to CC genotype(OR=1.45,95%PI:1.08-1.95,P=0.01).Similar association was observed in a dominant model for INSR gene,where comparison of TT+CT vs CC genotypes showed an increased risk of GC(OR=1.44,95%PI:1.08-1.90,P=0.01).Other analyzed SNPs were not associated with the presence of GC.CONCLUSION INSR rs1051690 SNP is associated with increased risk of GC,while polymorphisms in IL12B,CCND1 and IL10genes are not linked with the presence of GC.     

抗IL-14R单抗在SLE患者中对IL-14R的表达及其Ig分泌的影响

目的探索ＩＬ１４Ｒ与ＳＬＥ病程的相关性。方法应用抗ＩＬ１４Ｒ单抗（ＢＡ５）分析了３０例正常人和４３例ＳＬＥ患者外周血淋巴细胞表面ＩＬ１４Ｒ的分布与表达。结果发现ＳＬＥ患者外周血ＩＬ１４Ｒ阳性细胞百分比（２２５６％）明显高于正常人（７８４％）。在活动期和缓解期ＳＬＥ患者中,ＩＬ１４Ｒ表达百分比也具有显著的差异（３２０２％和１３０９％）。结论提示ＢＡ５单抗能拮抗Ｂ细胞激活后ＩＬ１４Ｒ的高表达和ＩｇＧ的分泌。并可能以ＢＡ５单抗阻断和调节ＩＬ１４Ｒ的表达等方面调节Ｂ细胞功能的异常,从而为临床提供新的免疫治疗和检测手段。     

Interleukin 1 (IL 1)

Interleukin 1 is an essential factor of macrophage dependent T cell activation and has a large quantity of other biological activities. This paper gives a review of present knowledge of Interleukin 1. In addition to biochemical properties, the IL 1 production and IL 1 activities, methods for determining of IL 1 and inhibitory factors of IL 1 induced T cell proliferation are described.     

Role of ATG16L, NOD2 and IL23R in Crohn's disease pathogenesis

Inflammatory bowel disease is a group of diseases that includes Crohn's disease (CD) and ulcerative colitis. CD is characterized as a chronic inflammatory disease of the gastrointestinal tract, ranging from the mouth to the anus. Although there are gross pathological and histological similarities between CD and Johne's disease of cattle, the cause of CD remains controversial. It is vital to understand fully the cause of this disease because it affects approximately 500,000 people in North America and Europe. It ranges from 27 to 48 cases per 100,000 people. There are many theories on the cause of CD ranging from possible association with environmental factors including microorganisms to imbalance in the intestinal normal flora of the patients. Regardless of the environmental trigger, there is strong evidence that a genetic disposition is a major key in acquiring CD. Many studies have proven the link between mutations in the ATG16L, NOD2/CARD15, IBD5, CTLA4, TNFSF15 and IL23R genes, and CD. The purpose of this review is to examine all genetic aspects and theories of CD, including up to date multiple population studies performed worldwide.