Interleukin-2 Receptor Beta Research Articles

Positive transcriptional response on inflammation and joint remodelling influenced by physical exercise in proteoglycan-induced arthritis: An animal study.

AimsTo assess the effect of physical exercise (PE) on the histological and transcriptional characteristics of proteoglycan-induced arthritis (PGIA) in BALB/c mice.MethodsFollowing PGIA, mice were subjected to treadmill PE for ten weeks. The tarsal joints were used for histological and genetic analysis through microarray technology. The genes differentially expressed by PE in the arthritic mice were obtained from the microarray experiments. Bioinformatic analysis in the DAVID, STRING, and Cytoscape bioinformatic resources allowed the association of these genes in biological processes and signalling pathways.ResultsArthritic mice improved their physical fitness by 42.5% after PE intervention; it induced the differential expression of 2,554 genes. The bioinformatic analysis showed that the downregulated genes (n = 1,371) were significantly associated with cellular processes that mediate the inflammation, including Janus kinase-signal transducer and activator of transcription proteins (JAK-STAT), Notch, and cytokine receptor interaction signalling pathways. Moreover, the protein interaction network showed that the downregulated inflammatory mediators interleukin (IL) 4, IL5, IL2 receptor alpha (IL2rα), IL2 receptor beta (IL2rβ), chemokine ligand (CXCL) 9, and CXCL12 were interacting in several pathways associated with the pathogenesis of arthritis. The upregulated genes (n = 1,183) were associated with processes involved in the remodelling of the extracellular matrix and bone mineralization, as well as with the processes of aerobic metabolism. At the histological level, PE attenuated joint inflammatory infiltrate and cartilage erosion.ConclusionPhysical exercise influences parameters intimately linked to inflammatory arthropathies. Research on the effect of PE on the pathogenesis process of arthritis is still necessary for animal and human models.Cite this article: Bone Joint Res. 2020;9(1):36–48.

Polymorphisms in the 5’-UTR region of IL-10RA gene are associated with chronic kidney disease

Chronic kidney disease (CKD), characterized by the progressive, irreversible loss of kidney function, has been a significant socioeconomic burden. Thus, identifying potential treatment targets and incipient biological risk indicators for CKD prediction is crucial. Recently several studies revealed that IL-10, IL-10RA, and IL-10RB genes were involved in the development of vascular complications in hypertension and stroke. The purpose of this study was to evaluate the association between CKD and IL-10, IL-10RA, and IL-10RB gene polymorphisms in the Korean population. Ninety-two CKD patients and 312 control subjects participated in the study. Blood samples were drawn for biochemical measurements and genetic polymorphism analysis. To analyze the genotypes of each single nucleotide polymorphism (SNP), PCR products were sequenced by a DNA analyzer. The four SNPs of the IL-10RA gene showed significant associations between CKD and the control group in the codominant1 (rs2228054, rs2228055, and rs9610, OR = 0.48, 95% CI = 0.28–0.82, p = 0.007; rs2256111, OR = 0.49, 95% CI = 0.29–0.83, p = 0.008, respectively), dominant (rs2228054, rs2228055, and rs9610, OR = 0.59, 95% CI = 0.36–0.95, p = 0.028; rs2256111, OR = 0.60, 95% CI = 0.38–0.97, p = 0.037, respectively), and over-dominant model (rs2228054 and rs2228055, OR = 0.47, 95% CI = 0.28–0.79, p = 0.0034; rs9610, OR = 0.48, 95% CI = 0.29–0.80, p = 0.0037; rs2256111, OR = 0.49, 95% CI = 0.29–0.80, p = 0.0039). The four SNPs of IL-10 showed significant associations with the estimated glomerular filtration rate (eGFR) and C-reactive protein (CRP), with the minor homozygote genotype of each SNP associated with lower eGFRs and decreased CRP levels ( p < 0.05, p = 0.001, respectively). The two SNPs of IL-10RA showed significant associations with the CRP levels ( p < 0.05). The two SNPs of IL-10RB were significantly associated with the eGFR, with the minor homozygote genotype of each SNP associated with lower eGFRs ( p < 0.01). Our results show that IL-10RA gene variants are associated with CKD development. Additionally, this study suggests that SNPs of IL-10RA were associated with CRP levels in CKD.

Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2.

Loss of IL-10 signaling in macrophages (Mφs) leads to inflammatory bowel disease (IBD). Induced pluripotent stem cells (iPSCs) were generated from an infantile-onset IBD patient lacking a functional IL10RB gene. Mφs differentiated from IL-10RB-/- iPSCs lacked IL-10RB mRNA expression, were unable to phosphorylate STAT3, and failed to reduce LPS induced inflammatory cytokines in the presence of exogenous IL-10. IL-10RB-/- Mφs exhibited a striking defect in their ability to kill Salmonella enterica serovar Typhimurium, which was rescuable after experimentally introducing functional copies of the IL10RB gene. Genes involved in synthesis and receptor pathways for eicosanoid prostaglandin E2 (PGE2) were more highly induced in IL-10RB-/- Mφs, and these Mφs produced higher amounts of PGE2 after LPS stimulation compared with controls. Furthermore, pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade enhanced bacterial killing in Mφs. These results identify a regulatory interaction between IL-10 and PGE2, dysregulation of which may drive aberrant Mφ activation and impaired host defense contributing to IBD pathogenesis.

Association between ADRB2, IL33, and IL2RB gene polymorphisms and lung cancer risk in a Chinese Han population

PurposeThis study aimed to explore the associations between polymorphisms of a very important pharmacogene, ADRB2, two inflammation-related genes, IL33 and IL2RB, and the risk of lung cancer. MethodsSix polymorphisms of ADRB2, IL33, and IL2RB were genotyped in 300 lung cancer patients and 300 healthy controls using MassARRAY. The relationship between genotypes and lung cancer risk was evaluated using chi-square tests. ResultsThe minor allele of rs1042711 was a risk allele for lung cancer, whereas the minor alleles of rs7025417 and rs5756523 had protective effects against lung cancer (p＜0.05). The CT genotype of rs1042711 and the GT genotype of rs1560642 were associated with increased risk of lung cancer, whereas the CC and AA genotypes of rs7025417 and the CT and CC genotypes of rs5756523 were associated with decreased disease risk (p < 0.05). Genetic model analysis shows that rs1042711 and rs1560642 were associated with increased risk of lung cancer; whereas rs7025417, rs5756523, and rs2284033 were associated with decreased disease risk (p < 0.05). Stratification analysis showed that rs1042711 and rs1560642 were associated with increased risk of lung cancer in nonsmokers and smokers, respectively, whereas rs7025417 and rs5756523 were associated with decreased disease risk in both subgroups (p＜0.05). ConclusionOur results shed new light on the association between polymorphisms of ADRB2, IL33, and IL2RB and the risk of lung cancer.

Alloactivation of Naïve CD4+CD8-CD25+T Regulatory Cells: Expression of CD8α Identifies Potent Suppressor Cells That Can Promote Transplant Tolerance Induction.

Therapy with alloantigen-specific CD4+CD25+ T regulatory cells (Treg) for induction of transplant tolerance is desirable, as naïve thymic Treg (tTreg) are not alloantigen-specific and are weak suppressor cells. Naïve tTreg from DA rats cultured with fully allogeneic PVG stimulator cells in the presence of rIL-2 express IFN-gamma receptor (IFNGR) and IL-12 receptor beta2 (IL-12Rβ2) and are more potent alloantigen-specific regulators that we call Ts1 cells. This study examined additional markers that could identify the activated alloantigen-specific Treg as a subpopulation within the CD4+CD25+Foxp3+Treg. After culture of naïve DA CD4+CD8−CD25+T cells with rIL-2 and PVG alloantigen, or rIL-2 without alloantigen, CD8α was expressed on 10–20% and CD8β on <5% of these cells. These cells expressed ifngr and Il12rb2. CD8α+ cells had increased Ifngr that characterizes Ts1 cells as well was Irf4, a transcription factor induced by TCR activation. Proliferation induced by re-culture with rIL-12 and alloantigen was greater with CD4+CD8α+CD25+Treg consistent with the CD8α+ cells expressing IL-12R. In MLC, the CD8α+ fraction suppressed responses against allogeneic stimulators more than the mixed Ts1 population, whereas the CD4+CD8−CD25+T cells were less potent. In an adoptive transfer assay, rIL-2 and alloantigen activated Treg suppress rejection at a ratio of 1:10 with naïve effector cells, whereas alloantigen and rIL-2 activated tTreg depleted of the CD8α+ cells were much less effective. This study demonstrated that expression of CD8α by rIL-2 and alloantigen activation of CD4+CD8−CD25+Foxp3+T cells was a marker of activated and potent Treg that included alloantigen-specific Treg.

Association and Interaction Effects of Interleukin-12 Related Genes and Physical Activity on Cognitive Aging in Old Adults in the Taiwanese Population.

Evidence suggests that the neuro-inflammation mechanisms associated with interleukin-12 (IL-12) may be linked to Alzheimer's diseases and cognitive aging. In this study, we speculate that single nucleotide polymorphisms (SNPs) in IL-12-associated genes, such as IL12A, IL12B, IL12RB1, and IL12RB2 genes, could be associated with cognitive aging individually and/or via complicated interactions in the elder Taiwanese population. There were totally 3,730 Taiwanese individuals with age ≥60 years from the Taiwan Biobank. Mini-Mental State Examination (MMSE) was analyzed for all participants. We employed MMSE scores to assess cognitive functions. Our analysis revealed that the IL12A gene (including rs116910715, rs78902931, and rs78569420), the IL12B gene (including rs730691), and the IL12RB2 gene (including rs3790558, rs4655538, rs75699623, and rs1874396) were associated with cognitive aging. Among these SNPs, the association with the IL12RB2 rs3790558 SNP remained significant after performing Bonferroni correction (P = 6.87 × 10−4). Additionally, we found that interactions between the IL12A and IL12RB2 genes influenced cognitive aging (P = 0.022). Finally, we pinpointed the effects of interactions between IL12A, IL12B, and IL12RB2 with physical activity (P < 0.001, = 0.002, and < 0.001, respectively). Our study suggests that the IL-12-associated genes may contribute to susceptibility to cognitive aging independently as well as through gene-gene and gene-physical activity interactions.

Association analysis of immune response loci related to Haemonchus contortus exposure in sheep and goats using a targeted approach

Haemonchus contortus infections are an important source of animal production loss to livestock industry. Genetics of helminth resistance involves a complex set of factors related to the host immune response. The increasing use of genetic markers such as single nucleotide polymorphisms (SNPs) in genome wide association studies (GWAS) offers the potential to identify loci or regions associated with nematode resistance in small ruminants. The aims of this study were: (1) to use a targeted sequencing approach to identify SNPs in 100 genes related to immune response during Haemonchus contortus exposure in growing males of St. Croix, Katahdin and Dorper sheep, and in Kiko, Boer and Spanish goats, and (2) to perform an association analysis for fecal egg count (FEC), packed cell volume (PCV), immunoglobulin levels (IgA, IgG and IgM) and average daily gain (ADG) in the populations under study. After quality control (call rate < 95%, MAF < 0.05), 1356 SNPs (sheep) and 1,029 SNPs (goats) were used for the association analysis. A mixed model was used to analyze the phenotypic information. To control for population structure, the genomic relationship matrix (G) calculated from marker information was included in the model. Fixed effects included year and breed. Bonferroni correction was used to control for multiple testing. For sheep, SNPs located on OAR1 (42487870, 42489606) and OAR2 (192231080, 26321541) were significantly associated with IgM, ADG, and FEC. For goats, SNPs on CHR3 (42898132) and CHR22 (23066762) were associated with ADG and IgM. In both species, no significant associations were found for IgA, IgG and PCV. The results from this study revealed genes involved in the immune response to H. contortus exposure and provide additional SNP marker information that has potential to aid selection of resistance to gastrointestinal parasites in sheep and goats from different breeds. Significant SNPs within IL12RB2, NFIL3 and STAT4 genes could be potential markers for IgM, FEC and ADG in sheep populations. For goats, potential markers for IgM and ADG were identified within IL5RA and IL12RB2 genes. These results could be directly implemented in the populations used in this study, however, they should be validated before using these markers in other sheep and goat populations.

Effect of IL2RA and IL2RB gene polymorphisms on lung cancer risk

BackgroundInflammation is crucial for lung cancer development. Variants of multiple genes in inflammation pathways may lead to susceptibility to lung cancer. In the present study, we aimed to assess the influence of polymorphisms in inflammation-related genes (IL2RA and IL2RB) on lung cancer risk. MethodsA total of 507 patients with lung cancer and 503 healthy controls were genotyped for seven polymorphisms of IL2RA and IL2RB using the Agena MassARRAY platform. We evaluated the relationship of the genotypes with lung cancer susceptibility using odds ratio (OR), 95% confidence interval (95% CI) and chi square test. ResultsWe found that IL2RA rs12722498 was significantly associated with a decreased risk of lung cancer in dominant (p = 0.040, OR = 0.71, 95% CI = 0.51–0.98), additive (p = 0.016, OR = 0.68, 95% CI = 0.50–0.93) and allele (p = 0.019, OR = 0.69, 95% CI = 0.51–0.94) models. After stratification analysis, the results showed that IL2RA rs12569923 (non-smokers), IL2RA rs791588 (≤60 years old, non-drinkers, BMI < 24 kg/m2), IL2RA rs12722498 (≤60 years old, non-drinkers, BMI < 24 kg/m2, female) and IL2RB rs2281089 (female, stage) significantly decreased the risk of lung cancer. Additionally, the haplotypes of rs12569923 and rs791588 in IL2RA had strong relationships with lung cancer in the subgroups of BMI < 24 kg/m2, age ≤ 60 years old, non-smokers and non-drinkers. ConclusionOur results showed that the IL2RA and IL2RB polymorphisms were associated with lung cancer risk in the Chinese Han population, which suggests roles for IL2RA and IL2RB polymorphisms in lung cancer.

Abstract 2787: Artificial intelligence approach identifies IL2RB as a common prognostic and potential predictive biomarker associated with immune checkpoints in colorectal cancer

Abstract Identifying robust predictive biomarkers to enable stratification of colorectal cancer (CRC) patients, based on their response to immune checkpoint therapy, is an area of unmet clinical need. Genetic algorithms represent an exciting branch of artificial intelligence which can be used to extract meaningful associations from ‘big data’ now emerging more frequently in oncological research. We have employed Atlas Correlation Explorer (ACE), a user-friendly workbench that utilises a genetic algorithm to mine data deposited in The Cancer Genome Atlas (TCGA). Our aim was to establish common intersections between gene expression analyses in ACE using nine well established immune checkpoint markers (CD274, PDCD1, CTLA4, LAG3, TIM3, TIGIT, ICOS, IDO1 and BTLA). We observed IL2RB to be the common gene associated with immune checkpoints in both microarray and RNA sequencing data from the TCGA (7/9 gene lists). Assessment of IL2RB indicates that it is highly expressed on CD56+ natural killer cells and is associated with an increased infiltration of cytotoxic lymphocytes and a decreased infiltration of fibroblasts. It is also significantly enriched in the immune consensus molecular subtype group CMS1. We next demonstrated that patients with high IL2RB gene expression have better relapse free survival in the TCGA CRC cohort (n = 322, log-rank p = 0.011) and an all stage CRC validation cohort GSE39582 (n = 519, log-rank p = 0.006). It is also an independent prognostic factor by multivariate analysis (p = 0.01). We next observed strong correlations between IL2RB gene expression in CRC and previously published predictive gene signatures for anti-PD1 therapies in other solid tumours (Pearson correlation, R = 0.88). Finally, we optimised assessment of IL2RB immunohistochemistry in a large CRC cohort (n=661) using a digital pathology approach with the open-source QuPath software. To conclude, we have validated IL2RB as prognostic biomarker and have provided evidence to demonstrate that IL2RB expression could be used for CRC patient stratification in future immunotherapy based clinical trials. Citation Format: Matthew Alderdice, Stephanie Craig, Matt Humphries, Alan Gilmore, Victoria Bingham, Nicole Johnston, Stephen McQuaid, Manuel Salto-Tellez, Mark Lawler, Darragh G. McArt. Artificial intelligence approach identifies IL2RB as a common prognostic and potential predictive biomarker associated with immune checkpoints in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2787.

Recently alloactivated CD4+CD8−CD25+T regulatory cells express CD8alpha and are potent suppressor cells

Abstract Therapy with antigen-specific CD4+CD25+ T regulatory cells (Treg) for induction of transplant tolerance is desirable, as naïve thymic Treg (tTreg) are non-antigen specific and weak suppressor cells. Naïve tTreg from DA rats cultured with fully allogeneic PVG stimulator cells and IL-2 express IFN-gamma receptor (IFNGR) and IL-12 receptor beta2 (IL-12Rb2) and are more potent alloantigen-specific regulators that we call Ts1 cells. This study examined other markers that could identify the activated alloantigen-specific Treg as a subpopulation within the CD4+CD25+Foxp3+Treg. After culture of naïve DA CD4+CD8−CD25+T cells with rIL-2 and PVG alloantigen, CD8a was expressed on 10–20% and CD8b on &amp;lt;5% of these cells. RT-PCR showed the CD8+ cells had increased Ifngr that characterizes Ts1 cells as well was Irf4, a transcription factor induced by TCR activation. Proliferation induced by re-culture with rIL-12 and alloantigen was greater with CD4+CD8+CD25+Treg consistent with the CD8a+ cells expressing IL-12R. In MLC, the CD8+ fraction had greater suppression than the mixed Ts1 population, whereas the CD4+CD8−CD25+T cells had less suppression. In an adoptive transfer assay, rIL-2 and alloantigen activated Treg suppress rejection at a ratio of 1:10 with naïve effector cells, whereas alloantigen and rIL-2 activated tTreg depleted of the CD8a cells did not prevent rejection. This study showed the expression of CD8alpha by rIL-2 and alloantigen activation of CD4+CD8−CD25+Foxp3+T cells was a marker of alloantigen-specific Treg and may be of use to enrich alloantigen-specific Treg.

Human interleukin-2 receptor beta mutations associated with defects in immunity and peripheral tolerance

Abstract Interleukin-2, which conveys essential signals for effective immunity and immunological tolerance, operates through a heterotrimeric receptor. Genetic deficiency of the alpha or gamma chain causes debilitating disease. Here we identify human interleukin-2 receptor (IL-2R) beta chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the human IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rbeta and were unable to respond normally to high-dose IL-2 stimulation. By contrast, patient natural killer (NK) cells retained partial IL-2Rbeta expression and cytotoxic function. IL-2Rbeta loss of function was recapitulated in a recombinant system, in which endoplasmic reticulum sequestration was revealed as the mechanism by which certain missense mutations cause disease. Hematopoietic stem cell transplant resulted in resolution of clinical symptoms in one patient. The hypomorphic nature of this disease highlights the significance of variable IL-2Rbeta expression between different lymphocyte subsets and during their maturation as a means of modulating immune function. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance.

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

Three novel compound heterozygous IL12RB1 mutations in Chinese patients with Mendelian susceptibility to mycobacterial disease

Mendelian Susceptibility to Mycobacterial Diseases (MSMD) is a primary immunodeficiency disease (PID) characterized by variable susceptibility to weakly virulent mycobacteria (Bacille Calmette-Guerin, BCG) and various intramacrophagic bacteria, fungi, parasites. Mycobacterial disease generally begins in childhood, more rarely during adolescence and adulthood. The pathogenesis of MSMD is the inherited impaired production of interferon gamma (IFN-γ) or inadequate response to it. Autosomal recessive IL12RB1 deficiency is the most common genetic etiology of MSMD. Here we identified three novel compound heterozygous mutations in IL12RB1 gene (c.635G>A, c.765delG; c.632G>C, c.847C>T; c.64G>A, c.1673insGAGCTTCCTGAG) in three Chinese families with MSMD.

Molecular, Immunological, and Clinical Features of 16 Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, triggered by non-tuberculous mycobacteria or Bacillus Calmette-Guérin (BCG) vaccines and characterized by severe diseases. All known genetic etiologies are inborn errors of IFN-γ-mediated immunity. Here, we report the molecular, cellular, and clinical features of patients from 15 Iranian families with disseminated disease without vaccination (2 patients) or following live BCG vaccination (14 patients). We used whole blood samples from 16 patients and 12 age-matched healthy controls. To measure IL-12 and IFN-γ, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for the patients. Eight patients affected as a result of parental first-cousin marriages. Seven patients originated from multiplex kindred with positive history of death because of tuberculosis or finding the MSMD-related gene mutations. Two patients died due to mycobacterial disease at the ages of 8months and 3.7years. The remaining patients were alive at the last follow-up and were aged between 2 and 13years. Patients suffered from infections including chronic mucocutaneous candidiasis (n = 10), salmonellosis (n = 2), and Leishmania (responsible for visceral form) (n = 2). Thirteen patients presented with autosomal recessive (AR) IL-12Rβ1 deficiency, meaning their cells produced low levels of IFN-γ. Bi-allelic IL12RB1 mutations were detected in nine of patients. Three patients with AR IL-12p40 deficiency (bi-allelic IL12B mutations) produced low levels of both IL-12 and IFN-γ. Overall, we found five mutations in the IL12RB1 gene and three mutations in the IL12B gene. Except one mutation in exon 5 (c.510C>A) of IL12B, all others were previously reported to be loss-of-function mutations. We found low levels of IFN-γ production and failure to respond to IL12 in 13 Iranian MSMD patients. Due to complicated clinical manifestations in affected children, early cellular and molecular diagnostics is crucial in susceptible patients.

An Analysis and Survey on Interleukin-10 Receptor Mutation in Inflammatory Bowel Disease in Iranian IBD Cohort

Background: Early-onset inflammatory bowel disease (IBD) is classified to Crohn’s disease, ulcerative colitis and unclassified disorders which have chronic, relapsing course and can result in substantial long-term morbidity. IBD is a multifactorial disorder with genetic susceptibility, immunological predisposition and environmental triggers. Objective: To generally determine prevalence of IL10R mutation in IBD patients in Iran-Isfahan, we performed sequencing of all exons in IL10RA and IL10RB in cohort of IBD patients and healthy control. Material and Method: Total DNA content of 76 patients and 50 healthy controls were extracted from whole blood and PCR amplification and sequencing was done. Result: Overall identified IL-10RA mutations were P.(I224V), P.(A153V), P.(A153A), P.(S159G), P.(R263Q), P.(R284C), P.(R351Q), P.(Q376Q), P.(T416I), P.(A493V), P.(A511A) and P.(S563S). In IL10RB gene the only detected mutation was P. (K47E). Of them, P.(A153V), P.(A153A), P.(R284C), P.(T416I), P.(A493V), P.(A511A), P.(S563S) were Not reported variant in IBD variants. Conclusion: Our results also confirmed that early-onset IBD could be attributed to a synergistic effect of several variant alleles of the genes encoding IL10 receptors. These variants, alone, could only give rise to a sub-clinical manifestation of the IBD.

Clinical findings and genetic analysis of the patients with IL-12Rβ1 deficiency from southeast Turkey.

Doğruel D, Gündeşlioğlu ÖÖ, Yılmaz M, Alabaz D, Altıntaş DU, Kocabaş E. Clinical findings and genetic analysis of the patients with IL- 12Rβ1 deficiency from southeast Turkey. Turk J Pediatr 2019; 61: 174-179. IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to poorly pathogenic mycobacteria, salmonella and candida species. We aimed to analyze the clinical manifestations, immunological and genetic features of IL-12Rβ1 deficiency in 10 Turkish patients from a single center. We retrospectively studied the clinical manifestations and genetic analysis of the IL-12Rβ1 deficiency patients from 2008 to 2016. Ten patients were diagnosed and followed for eight years. The mean age at onset and diagnosis were 24.1±42.5 (med:10.5) and 52.3±6.83 (med:20) months, respectively. Parental consanguinity rate was 81.8%. All patients were BCG vaccinated. Abscess and axillary lymphadenopathy in the vaccinated area was the most common initial presentation following the BCG vaccination, six patients had recurring oral candidiasis. Active infections were treated appropriately, in addition to prophylactic therapy with IFNɣ. We identified 6 different mutations in the IL12RB1 gene in 10 patients including 5 splice-site mutations, 3 missense, 1 frameshift, 1 premature stop codon. One of these mutations was novel. The most common mutation was IVS8+1G > A(c.783+1G > A) followed by p.R175W(c.523C > T). This study emphasizes that patients presented with abscess and axillary lymphadenopathy associated with BCG vaccination should be evaluated for IL-12Rβ1 deficiency.

PROGRESSIVE DECREASE IN T CELL QUANTITY AND FUNCTION IN A PATIENT WITH IL-12 PATHWAY DEFECT

Introduction T helper 1 (TH1) and IFN-g are key players in the cell-mediated immune response. Furthermore, IL-12 is an important cytokine that promotes TH1 cell differentiation and mediates its affects through signal transducer and activator of transcription 4 (STAT4). Mutations in the gene encoding the IL-12 receptor beta1 subunit have been identified in patients with disseminated Salmonella and nontuberculous mycobacterial (NTM) infections or disseminated Bacillus Calmette-Guerin (BCG) infection following vaccine administration. Case Description 5-month old female with history of recurrent salmonella enteritis and meningitis at 3 weeks and 3 months of age who presented to our Immunology clinic for an immune evaluation. Initial T cell lymphocyte subsets showed elevated CD3, CD4, CD8 and CD16/CD56 absolute values. Her mitogen culture proliferation assay was reported as low lymphocyte proliferation to ConA and PHA, however based on our assessment she had greater than tenfold response to stimulus and therefore normal function. The patient's lymphocyte subsets have been reassessed on a yearly basis and have showed progressive decline. This year, her CD4 and CD8 were 754 and 338 respectively. Mitogen proliferation culture re-assessment this year also showed significant decline in her T cell function and she was therefore started on Bactrim prophylaxis. Discussion Our patient showed progressive decline in her T cell subset values and decrease in overall function. Although classically MSMD (mendelian susceptibility to mycobacterial disease) patients showed increase susceptibility to disseminated BCG and Salmonella disease and is managed with interferon gamma and azithromycin prophylaxis, our patient now requires additional Bactrim prophylaxis. IL-12 Signaling Pathway

Isoproterenol-induced beta-2 adrenergic receptor activation negatively regulates interleukin-2 signaling.

Regulation of intracellular signaling pathways in lymphocytes is critical for cell homeostasis and immune response. Interleukin-2 (IL-2), a key regulator of lymphocytes, signals following receptor-ligand engagement and subsequent recruitment and activation of effector proteins including JAKs and STATs. Lymphocytes can also be regulated by the central nervous system through the β2 adrenergic receptor (β2AR) pathway which can affect cell trafficking, proliferation, differentiation, and cytokine production. The cross-talk between these two signaling pathways represents an important mechanism that has yet to be fully elucidated. The present study provides evidence for communication between the IL-2 receptor (IL-2R) and β2AR. Treatment of human lymphoid cell lines with the β2AR agonist isoproterenol (ISO) alone increased cAMP levels and mediated a stimulatory response by activating AKT and ERK to promote cell viability. Interestingly, ISO activation of β2AR also induced threonine phosphorylation of the IL-2Rβ. In contrast, ISO treatment prior to IL-2 stimulation produced an inhibitory signal that disrupted IL-2 induced activation of the JAK/STAT, MEK/ERK, and PI3K pathways by inhibiting the formation of the IL-2R beta-gamma chain complex, and subsequently cell proliferation. Moreover, γc-family cytokines-mediated STAT5 activation was also inhibited by ISO. These results suggest a molecular mechanism by which β2AR signaling can both stimulate and suppress lymphocyte responses and thus explain how certain therapeutic agents, such as vasodilators, may impact immune responsiveness.

Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells

Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar Typhimurium SL1344 infection. A combination of transcriptomics, bacterial invasion assays, and imaging suggests that IL-22-induced antimicrobial activity is driven by increased phagolysosomal fusion in IL-22-pretreated cells. The antimicrobial phenotype was absent in hIPSCs derived from a patient harboring a homozygous mutation in the IL10RB gene that inactivates the IL-22 receptor but was restored by genetically complementing the IL10RB deficiency. This study highlights a mechanism through which the IL-22 pathway facilitates the human intestinal epithelium to control microbial infection.

Upregulation of integrin-associated protein on tumor T cells in CTCL inhibits IL-12 and Th1 immunity

Th2-skewed immunity in cutaneous T cell lymphoma (CTCL) poses a major clinical challenge and implements a tendency for significant local (skin) and systemic infections with subsequent sepsis. In addition to a global Th2 bias, recent research shows suppressed IL-12-mediated signal transduction in T cells from patients with Sèzary syndrome, associated with the absence of IL-12 receptor beta, but also with decreased IL-12 levels in advanced stage of the disease.