Publications by authors named "Yuta Kochi"

77 Publications

Lupus susceptibility region containing CDKN1B rs34330 mechanistically influences expression and function of multiple target genes, also linked to proliferation and apoptosis.

Arthritis Rheumatol 2021 May 13. Epub 2021 May 13.

Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Objective: A recent genome-wide association study (GWAS) reported a significant genetic association between rs34330 of cyclin-dependent kinase inhibitor 1B (CDKN1B) and risk of systemic lupus erythematosus (SLE) in Han Chinese. This study aims to validate the reported association and elucidate the biochemical mechanisms underlying the variant's effect.

Methods: We performed allelic association with SLE followed by meta-analysis across 11 independent cohorts (n=28,872). We applied in silico bioinformatics and experimental validation in SLE-relevant cell lines to determine the functional consequences of rs34330.

Results: We replicated genetic association between SLE and rs34330 (P =5.29x10 , OR (95% CI)=0.84 (0.81-0.87)). Follow-up bioinformatics and eQTL analysis suggest that rs34330 is located in active chromatin and potentially regulates several target genes. Using luciferase and ChIP-qPCR, we demonstrated substantial allele-specific promoter and enhancer activity, and allele-specific binding of three histone marks (H3K27ac, H3K4me3, H3K4me1), RNA pol II, CTCF, and a critical immune transcription factor (IRF-1). Chromosome conformation capture (3C) detected long-range chromatin interactions between rs34330 and the promoters of neighboring genes APOLD1 and DDX47, and effects on CDKN1B and the other target genes were directly validated by CRISPR-based genome editing. Finally, CRISPR-dCas9-based epigenetic activation/silencing confirmed these results. Gene-edited cell lines also showed higher levels of proliferation and apoptosis.

Conclusion: Collectively, these findings suggest a mechanism whereby the rs34330 risk allele (C) influences the presence of histone marks, RNA pol II, and the IRF-1 transcription factor to regulate expression of several target genes linked to proliferation and apoptosis, which potentially underlie the association of rs34330 with SLE.
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http://dx.doi.org/10.1002/art.41799DOI Listing
May 2021

Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases.

Cell 2021 Apr 21. Epub 2021 Apr 21.

Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.

Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.
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http://dx.doi.org/10.1016/j.cell.2021.03.056DOI Listing
April 2021

HERV-Derived Is Conserved in Simiiformes, Exhibiting Expression in Hematopoietic Cell Lineages Including Macrophages.

Int J Mol Sci 2021 Apr 26;22(9). Epub 2021 Apr 26.

Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.

(1) Background: The gene in humans is derived from an envelope () gene of a human endogenous retrovirus group, HERV-P(b). The gene reportedly has a conserved open reading frame (ORF) in Old World monkeys. Although its forced expression led to cell-fusion in an ex vivo cell culture system, like other -derived genes such as and - its mRNA expression is not placenta-specific, but almost ubiquitous, albeit being quite low in human tissues and organs, implying a distinct role for . (2) Methods: To elucidate the cell lineage(s) in which the ERVPb1 protein is translated in human development, we developed a novel, highly sensitive system for detecting HERV-derived proteins/peptides expressed in the tissue differentiation process of human induced pluripotent stem cells (iPSCs). (3) Results: We first determined that is also conserved in New World monkeys. Then, we showed that the ERVPb1 protein is translated from a uniquely spliced transcript in hematopoietic cell lineages, including a subset of macrophages, and further showed that its mRNA expression is upregulated by lipopolysaccharide (LPS) stimulation in primary human monocytes. (4) Conclusions: is unique to Simiiformes and actually translated in hematopoietic cell lineages, including a subset of macrophages.
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http://dx.doi.org/10.3390/ijms22094504DOI Listing
April 2021

Contribution of a European-Prevalent Variant near CD83 and an East Asian-Prevalent Variant near IL17RB to Herpes Zoster Risk in Tofacitinib Treatment: Results of Genome-Wide Association Study Meta-Analyses.

Arthritis Rheumatol 2021 Jan 17. Epub 2021 Jan 17.

Pfizer Inc, Cambridge, Massachusetts, USA.

Objective: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis, and has been previously investigated for psoriasis (PsO). Genome-wide association studies (GWAS) were performed to identify genetic factors associated with increased risk/faster onset of herpes zoster (HZ) upon tofacitinib treatment, and potential mechanisms of the varying HZ rate across ethnicities.

Methods: In an ethnicity-/indication-specific and trans-ethnic trans-indication meta-analysis of GWAS in subjects from RA and PsO phase II, III, and long-term extension tofacitinib studies, 8 million genetic variants on time to HZ and HZ event (case versus control) were evaluated via Cox and logistic regression, respectively.

Results: 5,246 subjects were included (RA: 3,168; PsO: 2,078). Adjusting for age, baseline absolute lymphocyte count, genetically-defined ethnicity, and concomitant methotrexate use (RA only), 4 loci were significantly associated with faster HZ onset in Europeans (P < 5×10 ), including a single-nucleotide polymorphism (SNP) near CD83 (risk allele in Europeans ~2%, East Asian ~0.1%). In the trans-ethnic trans-population meta-analysis, the CD83 SNP remained significant, and 4 additional significant loci were identified, among which a SNP near IL17RB was associated with faster HZ onset (meta-analysis hazard ratio [95% confidence interval] 3.6 [2.40, 5.44], P = 7.6×10 ; risk allele in East Asian subjects ~12%, European subjects <0.2%).

Conclusion: Genetic analysis of tofacitinib-treated RA and PsO subjects identified multiple loci associated with increased HZ risk. European or East Asian population-specific prevalent variants near immune-relevant genes of CD83 and IL17RB, respectively, may contribute to HZ risk in tofacitinib-treated subjects.
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http://dx.doi.org/10.1002/art.41655DOI Listing
January 2021

[TRANSCRIPTOME ANALYSIS OF IMMUNE CELLS AND DISEASE SUSCEPTIBLE GENES].

Authors:
Yuta Kochi

Arerugi 2020;69(10):947-951

Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University.

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http://dx.doi.org/10.15036/arerugi.69.947DOI Listing
February 2021

Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.

Ann Rheum Dis 2020 Dec 3. Epub 2020 Dec 3.

Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.

Objective: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations.

Methods: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations.

Results: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (r=-0.242) and non-albumin protein (r=0.238).

Conclusion: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.
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http://dx.doi.org/10.1136/annrheumdis-2020-219209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053352PMC
December 2020

Cystoscopic Imaging for Bladder Cancer Detection Based on Stepwise Organic Transfer Learning with a Pretrained Convolutional Neural Network.

J Endourol 2020 Dec 4. Epub 2020 Dec 4.

Department of Urology, University of Tsukuba Hospital, Tsukuba, Japan.

Nonmuscle-invasive bladder cancer is diagnosed, treated, and monitored using cystoscopy. Artificial intelligence (AI) is increasingly used to augment tumor detection, but its performance is hindered by the limited availability of cystoscopic images required to form a large training data set. This study aimed to determine whether stepwise transfer learning with general images followed by gastroscopic images can improve the accuracy of bladder tumor detection on cystoscopic imaging. We trained a convolutional neural network with 1.2 million general images, followed by 8728 gastroscopic images. In the final step of the transfer learning process, the model was additionally trained with 2102 cystoscopic images of normal bladder tissue and bladder tumors collected at the University of Tsukuba Hospital. The diagnostic accuracy was evaluated using a receiver operating characteristic curve. The diagnostic performance of the models trained with cystoscopic images with or without stepwise organic transfer learning was compared with that of medical students and urologists with varying levels of experience. The model developed by stepwise organic transfer learning had 95.4% sensitivity and 97.6% specificity. This performance was better than that of the other models and comparable with that of expert urologists. Notably, it showed superior diagnostic accuracy when tumors occupied >10% of the image. Our findings demonstrate the value of stepwise organic transfer learning in applications with limited data sets for training and further confirm the value of AI in medical diagnostics. Here, we applied deep learning to develop a tool to detect bladder tumors with an accuracy comparable with that of a urologist. To address the limitation that few bladder tumor images are available to train the model, we demonstrate that pretraining with general and gastroscopic images yields superior results.
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http://dx.doi.org/10.1089/end.2020.0919DOI Listing
December 2020

Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis.

Ann Rheum Dis 2020 Nov 2. Epub 2020 Nov 2.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Objectives: Synovial fibroblasts (SFs) are one of the major components of the inflamed synovium in rheumatoid arthritis (RA). We aimed to gain insight into the pathogenic mechanisms of SFs through elucidating the genetic contribution to molecular regulatory networks under inflammatory condition.

Methods: SFs from RA and osteoarthritis (OA) patients (n=30 each) were stimulated with eight different cytokines (interferon (IFN)-α, IFN-γ, tumour necrosis factor-α, interleukin (IL)-1β, IL-6/sIL-6R, IL-17, transforming growth factor-β1, IL-18) or a combination of all 8 (8-mix). Peripheral blood mononuclear cells were fractioned into five immune cell subsets (CD4 T cells, CD8 T cells, B cells, natural killer (NK) cells, monocytes). Integrative analyses including mRNA expression, histone modifications (H3K27ac, H3K4me1, H3K4me3), three-dimensional (3D) genome architecture and genetic variations of single nucleotide polymorphisms (SNPs) were performed.

Results: Unstimulated RASFs differed markedly from OASFs in the transcriptome and epigenome. Meanwhile, most of the responses to stimulations were shared between the diseases. Activated SFs expressed pathogenic genes, including whose induction by IFN-γ was significantly affected by an RA risk SNP (rs6074022). On chromatin remodelling in activated SFs, RA risk loci were enriched in clusters of enhancers (super-enhancers; SEs) induced by synergistic proinflammatory cytokines. An RA risk SNP (rs28411362), located in an SE under synergistically acting cytokines, formed 3D contact with the promoter of gene, whose binding motif showed significant enrichment in stimulation specific-SEs. Consistently, inhibition of MTF1 suppressed cytokine and chemokine production from SFs and ameliorated mice model of arthritis.

Conclusions: Our findings established the dynamic landscape of activated SFs and yielded potential therapeutic targets associated with genetic risk of RA.
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http://dx.doi.org/10.1136/annrheumdis-2020-218189DOI Listing
November 2020

Is type 2 diabetes mellitus an inverse risk factor for the development of rheumatoid arthritis?

J Hum Genet 2021 Feb 8;66(2):219-223. Epub 2020 Sep 8.

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA) are both chronic diseases. Although the link between metabolic abnormalities and dysregulated inflammation has received much attention, it is not known whether T2DM can be a risk for the development of RA. Also, observational studies have the disadvantage that the possibility of confounding factors, such as environmental factors, cannot be ruled out. Therefore, the current study performed the mendelian randomization (MR) analysis using recent large-scale genome-wide association studies datasets of T2DM and RA separately European and Asian ancestries. As a result, T2DM had an inverse causal effect on the risk of RA. This study proposed a novel hypothesis that a protective effect of T2DM for the risk of RA.
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http://dx.doi.org/10.1038/s10038-020-00837-2DOI Listing
February 2021

Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.

Nat Genet 2020 07 8;52(7):669-679. Epub 2020 Jun 8.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
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http://dx.doi.org/10.1038/s41588-020-0640-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968075PMC
July 2020

Support System of Cystoscopic Diagnosis for Bladder Cancer Based on Artificial Intelligence.

J Endourol 2020 03 14;34(3):352-358. Epub 2020 Jan 14.

Department of Urology, University of Tsukuba Hospital, Tsukuba, Japan.

Nonmuscle-invasive bladder cancer has a relatively high postoperative recurrence rate despite the implementation of conventional treatment methods. Cystoscopy is essential for diagnosing and monitoring bladder cancer, but lesions are overlooked while using white-light imaging. Using cystoscopy, tumors with a small diameter; flat tumors, such as carcinoma ; and the extent of flat lesions associated with the elevated lesions are difficult to identify. In addition, the accuracy of diagnosis and treatment using cystoscopy varies according to the skill and experience of physicians. Therefore, to improve the quality of bladder cancer diagnosis, we aimed to support the cystoscopic diagnosis of bladder cancer using artificial intelligence (AI). A total of 2102 cystoscopic images, consisting of 1671 images of normal tissue and 431 images of tumor lesions, were used to create a dataset with an 8:2 ratio of training and test images. We constructed a tumor classifier based on a convolutional neural network (CNN). The performance of the trained classifier was evaluated using test data. True-positive rate and false-positive rate were plotted when the threshold was changed as the receiver operating characteristic (ROC) curve. In the test data (tumor image: 87, normal image: 335), 78 images were true positive, 315 true negative, 20 false positive, and 9 false negative. The area under the ROC curve was 0.98, with a maximum Youden index of 0.837, sensitivity of 89.7%, and specificity of 94.0%. By objectively evaluating the cystoscopic image with CNN, it was possible to classify the image, including tumor lesions and normality. The objective evaluation of cystoscopic images using AI is expected to contribute to improvement in the accuracy of the diagnosis and treatment of bladder cancer.
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http://dx.doi.org/10.1089/end.2019.0509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099426PMC
March 2020

Identification of rare coding variants in protective for rheumatoid arthritis in the Japanese population and their effects on cytokine signalling.

Ann Rheum Dis 2019 08 22;78(8):1062-1069. Epub 2019 May 22.

Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

Objective: Although genome-wide association studies (GWAS) have identified approximately 100 loci for rheumatoid arthritis (RA), the disease mechanisms are not completely understood. We evaluated the pathogenesis of RA by focusing on rare coding variants.

Methods: The coding regions of 98 candidate genes identified by GWAS were sequenced in 2294 patients with RA and 4461 controls in Japan. An association analysis was performed using cases and controls for variants, genes and domains of TYK2. Cytokine responses for two associated variants (R231W, rs201917359; and R703W, rs55882956) in as well as a previously reported risk variant (P1004A, rs34536443) for multiple autoimmune diseases were evaluated by reporter assays.

Results: A variant in (R703W) showed a suggestive association (p=5.47×10, OR=0.48). We observed more accumulation of rare coding variants in controls in (p=3.94×10, OR=0.56). The four-point-one, ezrin, radixin, moesin (FERM; 2.14×10, OR=0.66) and pseudokinase domains (1.63×10, OR=0.52) of TYK2 also showed enrichment of variants in controls. R231W in FERM domain especially reduced interleukin (IL)-6 and interferon (IFN)-γ signalling, whereas P1104A in kinase domain reduced IL-12, IL-23 and IFN-α signalling. R703W in pseudokinase domain reduced cytokine signals similarly to P1104A, but the effects were weaker than those of P1104A.

Conclusions: The FERM and pseudokinase domains in TYK2 were associated with the risk of RA in the Japanese population. Variants in had different effects on cytokine signalling, suggesting that the regulation of selective cytokine signalling is a target for RA treatment.
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http://dx.doi.org/10.1136/annrheumdis-2019-215062DOI Listing
August 2019

Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians.

PLoS Genet 2019 04 25;15(4):e1008092. Epub 2019 Apr 25.

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology.
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http://dx.doi.org/10.1371/journal.pgen.1008092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504188PMC
April 2019

PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes.

Ann Rheum Dis 2019 04 24;78(4):509-518. Epub 2019 Jan 24.

Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by autoantibody production and widespread inflammation damaging many organs. Previous genome-wide association studies (GWASs) have revealed over 80 genetic determinants of SLE, but they collectively explain a fraction of the heritability, and only a few were proven in vivo for the involvement in SLE. We conducted a meta-analysis of SLE GWAS in the Japanese population, followed by functional analyses of a susceptibility gene with use of mutant mice.

Methods: We conducted a meta-analysis of two GWASs comprising a total of 1363 cases and 5536 controls using the 1000 Genome Project data as an imputation reference. Enrichment analyses for functional annotations were conducted. We examined Phospholipase D4 (Pld4) mutant mice to assess functional involvement of a genetic determinant.

Results: We found a total of 14 significant loci, which included rs2582511 in / recently reported in a Chinese study and a novel locus of rs143181706 in (p=7.9×10 and 3.7×10, respectively). PLD4 risk allele was associated with anti-dsDNA antibody production. Enrichment analysis of genetic signals revealed involvement of a wide range of immune-related cells and pathways. Pld4 mutant mice revealed remarkably low body weight. The mice demonstrated autoimmune phenotypes compatible with SLE, including splenomegaly and lymphadenopathy, expansion of B cells and hypersecretion of BAFF and production of autoantibodies especially anti-nuclear antibody and anti-dsDNA antibody.

Conclusions: We found a novel susceptibility gene to SLE. Pld4 mutant mice revealed autoimmune phenotypes suggesting functional involvement of PLD4 with the basics of SLE.
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http://dx.doi.org/10.1136/annrheumdis-2018-214116DOI Listing
April 2019

Genetics of rheumatoid arthritis: 2018 status.

Ann Rheum Dis 2019 04 8;78(4):446-453. Epub 2018 Dec 8.

Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

Study of the genetics of rheumatoid arthritis (RA) began about four decades ago with the discovery of Since the beginning of this century, a number of non-HLA risk loci have been identified through genome-wide association studies (GWAS). We now know that over 100 loci are associated with RA risk. Because genetic information implies a clear causal relationship to the disease, research into the pathogenesis of RA should be promoted. However, only 20% of GWAS loci contain coding variants, with the remaining variants occurring in non-coding regions, and therefore, the majority of causal genes and causal variants remain to be identified. The use of epigenetic studies, high-resolution mapping of open chromatin, chromosomal conformation technologies and other approaches could identify many of the missing links between genetic risk variants and causal genetic components, thus expanding our understanding of RA genetics.
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http://dx.doi.org/10.1136/annrheumdis-2018-213678DOI Listing
April 2019

Genetic determinants and an epistasis of and HLA-B*52 in Takayasu arteritis.

Proc Natl Acad Sci U S A 2018 12 29;115(51):13045-13050. Epub 2018 Nov 29.

Department of Rheumatology, Sapporo Medical University School of Medicine, Sapporo Medical University, Sapporo 060-8556, Japan.

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in , /, , and , respectively. Two additional significant loci unreported in non-European GWAS were identified, namely / and chr21q.22. We found that a single variant associated with the expression of , a ligand for natural killer (NK) cell receptor, could explain the entire association with the region. Rs2322599 is strongly associated with the expression of Rs103294 risk allele in / is known to be a tagging SNP for the deletion of , a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 ( = 1.2 × 10). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells ( = 8.8 × 10, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.
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http://dx.doi.org/10.1073/pnas.1808850115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304955PMC
December 2018

Transcriptome analysis of peripheral blood from patients with rheumatoid arthritis: a systematic review.

Inflamm Regen 2018 5;38:21. Epub 2018 Nov 5.

4Center for Integrative Medical Sciences, the Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045 Japan.

In the era of precision medicine, transcriptome analysis of whole gene expression is an essential technology. While DNA microarray has a limited dynamic range and a problem of background hybridization, RNA sequencing (RNA-seq) has a broader dynamic range and a lower background signal that increase the sensitivity and reproducibility. While transcriptome analyses in rheumatoid arthritis (RA) have generally focused on whole peripheral blood mononuclear cells (PBMC), analyses of detailed cell subsets have an increased need for understanding the pathophysiology of disease because the involvement of CD4 T cells in the pathogenesis of RA has been established. Transcriptome analysis of detailed CD4 T cell subsets or neutrophils shed new light on the pathophysiology of RA. There are several analyses about the effect of biological treatment. Many studies report the association between type I interferon signature gene expression and response to therapy.
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http://dx.doi.org/10.1186/s41232-018-0078-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217768PMC
November 2018

Exploring predictive biomarkers from clinical genome-wide association studies via multidimensional hierarchical mixture models.

Eur J Hum Genet 2019 01 10;27(1):140-149. Epub 2018 Sep 10.

Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.

Although the detection of predictive biomarkers is of particular importance for the development of accurate molecular diagnostics, conventional statistical analyses based on gene-by-treatment interaction tests lack sufficient statistical power for this purpose, especially in large-scale clinical genome-wide studies that require an adjustment for multiplicity of a huge number of tests. Here we demonstrate an alternative efficient multi-subgroup screening method using multidimensional hierarchical mixture models developed to overcome this issue, with application to stroke and breast cancer randomized clinical trials with genomic data. We show that estimated effect size distributions of single nucleotide polymorphisms (SNPs) associated with outcomes, which could provide clues for exploring predictive biomarkers, optimizing individualized treatments, and understanding biological mechanisms of diseases. Furthermore, using this method we detected three new SNPs that are associated with blood homocysteine levels, which are strongly associated with the risk of stroke. We also detected six new SNPs that are associated with progression-free survival in breast cancer patients.
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http://dx.doi.org/10.1038/s41431-018-0251-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303260PMC
January 2019

Sample Size for Successful Genome-Wide Association Study of Major Depressive Disorder.

Front Genet 2018 28;9:227. Epub 2018 Jun 28.

CREST, JST, Tokyo, Japan.

Major depressive disorder (MDD) is a complex, heritable psychiatric disorder. Advanced statistical genetics for genome-wide association studies (GWASs) have suggested that the heritability of MDD is largely explained by common single nucleotide polymorphisms (SNPs). However, until recently, there has been little success in identifying MDD-associated SNPs. Here, based on an empirical Bayes estimation of a semi-parametric hierarchical mixture model using summary statistics from GWASs, we show that MDD has a distinctive polygenic architecture consisting of a relatively small number of risk variants (~17%), e.g., compared to schizophrenia (~42%). In addition, these risk variants were estimated to have very small effects (genotypic odds ratio ≤ 1.04 under the additive model). Based on the estimated architecture, the required sample size for detecting significant SNPs in a future GWAS was predicted to be exceptionally large. It is noteworthy that the number of genome-wide significant MDD-associated SNPs would rapidly increase when collecting 50,000 or more MDD-cases (and the same number of controls); it can reach as much as 100 SNPs out of nearly independent (linkage disequilibrium pruned) 100,000 SNPs for ~120,000 MDD-cases.
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http://dx.doi.org/10.3389/fgene.2018.00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032046PMC
June 2018

Empirical Bayes Estimation of Semi-parametric Hierarchical Mixture Models for Unbiased Characterization of Polygenic Disease Architectures.

Front Genet 2018 24;9:115. Epub 2018 Apr 24.

Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.

Genome-wide association studies (GWAS) suggest that the genetic architecture of complex diseases consists of unexpectedly numerous variants with small effect sizes. However, the polygenic architectures of many diseases have not been well characterized due to lack of simple and fast methods for unbiased estimation of the underlying proportion of disease-associated variants and their effect-size distribution. Applying empirical Bayes estimation of semi-parametric hierarchical mixture models to GWAS summary statistics, we confirmed that schizophrenia was extremely polygenic [~40% of independent genome-wide SNPs are risk variants, most within odds ratio (OR = 1.03)], whereas rheumatoid arthritis was less polygenic (~4 to 8% risk variants, significant portion reaching OR = 1.05 to 1.1). For rheumatoid arthritis, stratified estimations revealed that expression quantitative loci in blood explained large genetic variance, and low- and high-frequency derived alleles were prone to be risk and protective, respectively, suggesting a predominance of deleterious-risk and advantageous-protective mutations. Despite genetic correlation, effect-size distributions for schizophrenia and bipolar disorder differed across allele frequency. These analyses distinguished disease polygenic architectures and provided clues for etiological differences in complex diseases.
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http://dx.doi.org/10.3389/fgene.2018.00115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928254PMC
April 2018

HLA-DRB1 Shared Epitope Alleles and Disease Activity Are Correlated with Reduced T Cell Receptor Repertoire Diversity in CD4+ T Cells in Rheumatoid Arthritis.

J Rheumatol 2018 07 15;45(7):905-914. Epub 2018 Apr 15.

From the Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.

Objective: Shared epitope (SE) alleles are the most significant genetic susceptibility locus in rheumatoid arthritis (RA); however, their target populations in CD4+ T cells are not well elucidated. We analyzed the association between SE alleles and the T cell receptor (TCR) repertoire diversity of naive and memory CD4+ T cells using next-generation sequencing (NGS).

Methods: The TCR beta chains in naive and memory CD4+ T cells from the peripheral blood of 22 patients with RA and 18 age- and sex-matched healthy donors (HD) were analyzed by NGS. The Renyi entropy was used to evaluate TCR repertoire diversity and its correlations with SE alleles and other variables were examined. Serum cytokine levels were measured by multiplex ELISA.

Results: The TCR repertoire diversity in memory CD4+ T cells was reduced in SE allele-positive patients with RA compared with HD, and showed a significant negative correlation with the SE allele dosage in RA. The TCR repertoire diversity of naive and memory T cells was also negatively correlated with disease activity, and the SE allele dosage and disease activity were independently associated with reduced TCR repertoire diversity. TCR repertoire diversity showed a significant positive correlation with the serum interleukin 2 levels.

Conclusion: SE alleles and disease activity were negatively correlated with the TCR repertoire diversity of CD4+ T cells in RA. Considering the pivotal role of CD4+ T cells in RA, restoring the altered TCR repertoire diversity will provide a potential RA therapeutic target.
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http://dx.doi.org/10.3899/jrheum.170909DOI Listing
July 2018

Splicing variant of augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis.

Ann Rheum Dis 2018 04 13;77(4):602-611. Epub 2018 Jan 13.

Division of Rheumatology Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.

Objectives: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population.

Methods: We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays.

Results: We identified a variant in that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated isoform (tr-), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells.

Conclusions: As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.
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http://dx.doi.org/10.1136/annrheumdis-2017-212149DOI Listing
April 2018

A gene module associated with dysregulated TCR signaling pathways in CD4 T cell subsets in rheumatoid arthritis.

J Autoimmun 2018 05 13;89:21-29. Epub 2017 Nov 13.

Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.

We analyzed the transcriptome of detailed CD4 T cell subsets including them after abatacept treatment, and examined the difference among CD4 T cell subsets and identified gene sets that are closely associated disease activity and abatacept treatment. Seven CD4 T cell subsets (naive, Th1, Th17, Th1/17, nonTh1/17, Tfh and Treg) were sorted from PBMCs taken from 10 RA patients and 10 healthy controls, and three RA patients donated samples before and 6 months after abatacept treatment. Paired-end RNA sequencing was performed using HiSeq 2500. A total of 149 samples except for 12 outliers were analyzed. Overview of expression pattern of RA revealed that administration of abatacept exerts a large shift toward the expression pattern of HC. Most of differentially expressed gene (DEG) upregulated in RA (n = 1776) were downregulated with abatacept treatment (n = 1349). Inversely, most of DEG downregulated in RA (n = 1860) were upregulated with abatacept treatment (n = 1294). This DEG-based analysis revealed shared pathway changes in RA CD4 T cell subsets. Knowledge-based pathway analysis revealed the upregulation of activation-related pathways in RA that was substantially ameliorated by abatacept. Weighted gene co-expression network analysis (WGCNA) evaluated CD4 T cells collectively and identified a gene module that consisted of 227 genes and was correlated with DAS28-CRP (Spearman's rho = 0.46, p = 4 × 10) and abatacept administration (Spearman's rho = -0.91, p = 5 × 10). The most highly connected 30 genes of this module included ZAP70 and JAK3, and pathway analysis of this module revealed dysregulation of the TCR signaling pathway network, which was ameliorated by abatacept.
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http://dx.doi.org/10.1016/j.jaut.2017.11.001DOI Listing
May 2018

Genetic landscape of interactive effects of alleles on susceptibility to ACPA(+) rheumatoid arthritis and ACPA levels in Japanese population.

J Med Genet 2017 12 12;54(12):853-858. Epub 2017 Oct 12.

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: is the strongest susceptibility gene to rheumatoid arthritis (RA). alleles showed significant non-additive and interactive effects on susceptibility to RA in the European population, but these effects on RA susceptibility should vary between populations due to the difference in allelic distribution. Furthermore, non-additive or interactive effects on the phenotypes of RA are not fully known. We evaluated the non-additive and interactive effects of alleles on RA susceptibility and anticitrullinated protein/peptide antibody (ACPA) levels in Japanese patients.

Methods: A total of 5581 ACPA(+) RA and 19 170 controls were genotyped or imputed for alleles. Logistic regression analysis was performed for both allelic non-additive effects and interactive effects of allelic combinations. The significant levels were set by Bonferroni's correction. A total of 4371 ACPA(+) RA were analysed for ACPA levels.

Results: We obtained evidence of non-additive and interactive effects of on ACPA(+) RA susceptibility (p=2.5×10 and 1.5×10, respectively). Multiple alleles including *04:05, the most common susceptibility allele in the Japanese, showed significant non-additive effects (p≤0.0043). We identified multiple allelic combinations with significant interactive effects including a common combination with the European population as well as novel combinations. Additional variance of ACPA(+) RA susceptibility could be explained substantially by heterozygote dominance or interactive effects. We did not find evidence of non-additive and interactive effects on levels of ACPA.

Conclusion: HLA allelic non-additive and interactive effects on ACPA(+) RA susceptibility were observed in the Japanese population. The allelic non-additive and interactive effects depend on allelic distribution in populations.
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http://dx.doi.org/10.1136/jmedgenet-2017-104779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724214PMC
December 2017

Genetics of human autoimmunity: From genetic information to functional insights.

Clin Immunol 2018 01 1;186:9-13. Epub 2017 Sep 1.

Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Genome-wide association studies have identified hundreds of risk variants associated with human autoimmune diseases. Recent evidence suggests that a substantial portion of them affect gene expression in specific cell types. To obtain the functional insights of GWAS findings, comprehensive characterization of genetic variants in human genome is a key task. In parallel with GWAS, many researches in functional genomics have been conducted in the past decade, and our understandings of cell type-specific gene regulatory system have been substantially improved. In this review, we will introduce the main research topics in functional genomics, and explain their utility to understand biological mechanisms of autoimmune diseases.
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http://dx.doi.org/10.1016/j.clim.2017.08.017DOI Listing
January 2018

Human thymoproteasome variations influence CD8 T cell selection.

Sci Immunol 2017 Jun 2;2(12). Epub 2017 Jun 2.

Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan.

The proteasome is a multi-subunit protease complex essential for housekeeping protein degradation and the production of the major histocompatibility complex (MHC) class I-bound antigen peptides that are essential for recognition by CD8 T cells. MHC variations dramatically contribute to T cell selection and autoimmunity, but genetic variations of peptide processing machinery including proteasome genes have been poorly explored in this context. In the computational analysis of human proteasome gene variation, we documented that was highly enriched for nucleotide changes that interfere with protein function. This gene encodes β5t, a thymus-specific catalytic subunit that regulates positive selection of CD8 T cells by producing a distinct set of MHC class I-bound peptides. The introduction of variations into the mouse genome by genome-editing revealed that these variations impaired the development of CD8 T cells in vivo. One of the polymorphisms altered the CD8 T cell repertoire in mice and was associated with a higher risk of an autoimmune disease in humans. Our findings suggest that, in addition to the MHC haplotype, proteasome variations influence T cell repertoire selection and may contribute to the difference in individual susceptibility to autoimmunity.
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http://dx.doi.org/10.1126/sciimmunol.aan5165DOI Listing
June 2017

Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis.

Nat Genet 2017 Jul 29;49(7):1120-1125. Epub 2017 May 29.

Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4 T cells, CD8 T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4 T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases.
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http://dx.doi.org/10.1038/ng.3885DOI Listing
July 2017

Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci.

Hum Mol Genet 2017 03;26(6):1205-1216

Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta = 1.92 × 10-13, OR = 1.14), ATG16L2 (rs11235604, Pmeta = 8.87 × 10 -12, OR = 0.78), CCL22 (rs223881, Pmeta = 5.87 × 10-16, OR = 0.87), ANKS1A (rs2762340, Pmeta = 4.93 × 10-15, OR = 0.87) and RNASEH2C (rs1308020, Pmeta = 2.96 × 10-19, OR = 0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2 > 0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81 × 10-198 < P < 5 × 10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P < 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.
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http://dx.doi.org/10.1093/hmg/ddx026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731438PMC
March 2017

TGF-β3 Inhibits Antibody Production by Human B Cells.

PLoS One 2017 4;12(1):e0169646. Epub 2017 Jan 4.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

TGF-β is a pleotropic cytokine involved in various biological processes. Of the three isoforms of TGF-β, TGF-β1 has long been recognized as an important inhibitory cytokine in the immune system and has been reported to inhibit B cell function in both mice and humans. Recently, it has been suggested that TGF-β3 may play an important role in the regulation of immune system in mice. Murine CD4+CD25-LAG3+ regulatory T cells suppress B cell function through the production of TGF-β3, and it has been reported that TGF-β3 is therapeutic in a mouse model of systemic lupus erythematosus. The effect of TGF-β3 on human B cells has not been reported, and we herein examined the effect of TGF-β3 on human B cells. TGF-β3 suppressed B cell survival, proliferation, differentiation into plasmablasts, and antibody secretion. Although the suppression of human B cells by TGF-β1 has long been recognized, the precise mechanism for the suppression of B cell function by TGF-β1 remains elusive; therefore, we examined the effect of TGF-β1 and β3 on pathways important in B cell activation and differentiation. TGF-β1 and TGF-β3 inhibited some of the key molecules of the cell cycle, as well as transcription factors important in B cell differentiation into antibody secreting cells such as IRF4, Blimp-1, and XBP1. TGF-β1 and β3 also inhibited B cell receptor signaling. Our results suggest that TGF-β3 modifying therapy might be therapeutic in autoimmune diseases with B cell dysregulation in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169646PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215424PMC
August 2017