Details of a Researcher - Ishigaki, Kazuyoshi

Papers - Ishigaki, Kazuyoshi

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Host Genetic Architecture between Epstein-Barr Virus Activity and Multiple Sclerosis Reveals Shared Pathways.

Yasumizu Y, Kim N, Rivier CA, Moon J, Kojima S, Chen HL, Buitrago-Pocasangre N, Quinn E, Vaughn S, Morgan A, Huo S, Silberfeld A, Sumida TS, Ishigaki K, Longbrake EE, Falcone GJ, Hafler DA

medRxiv : the preprint server for health sciences 2025.12

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The dynamic role of HLA proteins on compositional alterations of T-cell repertoires in inflammatory bowel disease

2025.10

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Nonrandomized Allocation of Steroid Therapy in Patients With Fukuyama Congenital Muscular Dystrophy: Study Protocol for a Phase II Clinical Trial.

Murakami T, Sato T, Ishizuka T, Nakamura H, Tachimori H, Harada H, Oi H, Hatano K, Oba MS, Ishiguro K, Shichiji M, Kihara Y, Takeshima Y, Taniguchi-Ikeda M, Hattori A, Shimizu-Motohashi Y, Awano H, Bo R, Nagata S, Ishigaki K

Neuropsychopharmacology reports 45 ( 3 ) e70043 2025.09

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Tracking clonal dynamics of CD8 T cells and immune dysregulation in progression of systemic lupus erythematosus with nephritis

Paek S.J., Lee H.S., Lee Y.J., Bang S.Y., Kim D., Kang B.K., Park D.J., Joo Y.B., Kim M., Kim H., Park S.Y., Park W.Y., Abe T., Itamiya T., Nagafuchi Y., Ishigaki K., Fujio K., Kim K.T., Bae S.C.

Experimental and Molecular Medicine 57 ( 8 ) 1700 - 1710 2025.08

ISSN 12263613

The fluctuating nature of disease activity in systemic lupus erythematosus (SLE), alternating between flares and remissions, poses substantial challenges for its effective management. The use of current biomarkers for monitoring SLE is limited in clinical settings owing to insufficient comprehension of the complex immune involvement underlying the disease course. Here, therefore, we profiled peripheral blood mononuclear cells at both stable and exacerbation states (total of n = 19) from six patients with SLE and 32 healthy donors using integrated single-cell RNA and T cell receptor (TCR) sequencing. To validate our findings, we analyzed two independent external datasets: bulk RNA sequencing and TCR data from 79 controls and 62 patients with SLE and single-cell RNA sequencing data from 99 healthy controls and 162 patients with SLE. Our analysis revealed cell type-specific activation of interferon-related genes in SLE grouped into four clusters, with elevated activity in disease-associated immune cells. Among these, atypical B cells associated with autoantibody production exhibited distinct differentiation patterns compared with conventional memory B cells, driven by heightened interferon signaling in SLE. Notably, clonal expansion of effector CD8 T cells emerged as a key driver of disease exacerbation, as indicated by reduced TCR diversity. Specific CD8 T cell clonotypes expanded during flare states, transitioning to effector phenotypes that exhibited heightened cytotoxicity and amplified interferon signaling, strongly correlating with tissue damage and flare severity. Our findings establish a critical link between interferon-driven mechanisms and cytotoxic T cell dysfunction in SLE flares, offering potential targets for therapeutic intervention and predictive biomarkers.

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Accurate, sensitive, and efficient chromatin accessibility quantification at target loci using UNIChro-seq

2025.07

<jats:title>Abstract</jats:title>
<jats:p>Recent progress in statistical and experimental fine mapping of disease risk variants prompts us to focus on specific target loci for functional investigation. However, current genetics is hindered by a limited toolbox for target-loci analysis. To address this, we developed UNIChro-seq, a method that digitally counts accessible chromatin molecules at target loci. UNIChro-seq allows for accurate, sensitive, and efficient quantification of allelic effects compared to conventional methods. Using UNIChro-seq, we investigated the effects of 57 autoimmunity risk alleles on chromatin accessibility and estimated the causal effects of 20 artificial variants generated through genome editing. As a caveat, non-negligible fraction of the edited allele exhibited a falsely positive effect on chromatin accessibility, which can be effectively distinguished from the true causal effect through bi-directional genome editing. Finally, functional dissection of a fine-mapped risk variant at the <jats:italic>LEF1</jats:italic> locus illuminated its impact on T cell pathology in rheumatoid arthritis. Together, these findings underscore the utility of combining UNIChro-seq with genome editing technology to enable precise and scalable functional analysis of disease-associated loci.</jats:p>

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Granzyme K activates the entire complement cascade

Donado C.A., Theisen E., Zhang F., Nathan A., Fairfield M.L., Rupani K.V., Jones D., Johannes K.P., Wyse A., Cordle A., Li Z.J., Zhu Z., Xiao Q., Weisman M.H., Weisenfeld D., Weinand K., Utz P.J., Tabechian D., Smith M., Slowikowski K., Singaraju A., Scheel-Toellner D., Seifert J.A., Sakaue S., Sahbudin I., Rumker L., Robinson W.H., Rivellese F., Ritchlin C., Reshef Y., Raza K., Rangel-Moreno J., Pitzalis C., Perlman H., Orange D.E., Nerviani A., Nayar S., Moreland L., Millard N., Meednu N., Mears J.R., McGeachy M.J., McDavid A., Maybury M., Marks K.E., Mantel I., Mandelin A.M., Liao K., Li Y., Lewis M.J., Lederer J.A., Lakhanpal A., Keras G., Kang J.B., James J.A., Ishigaki K., Ivashkiv L.B., Hughes L.B., Horowitz D., Holers V.M., Gutierrez-Arcelus M., Guthridge J.M., Gregersen P.K., Rao D., Gravallese E.M., Goodman S.M., Geraldino-Pardilla L., Forbess L., Firestein G.S., Carr H., Filer A., Dunn P., Donlin L.T., DiCarlo E., Deane K.D., Curtis M., Chicoine A., Ceponis A., Campbell D., Bykerk V.P., Bridges S.L., Boyle D.L., Boyce B.F., Ben-Artzi A., Bathon J.M., Barnas J.L., Apruzzese W., Anolik J.H., Albrecht J., Raychaudhuri S., Dwyer D.F., Jonsson A.H., Brenner M.B.

Nature 641 ( 8061 ) 211 - 221 2025.05

ISSN 00280836

Granzymes are a family of serine proteases that are mainly expressed by CD8+ T cells, natural killer cells and innate-like lymphocytes1. Although their primary function is thought to be the induction of cell death in virally infected cells and tumours, accumulating evidence indicates that some granzymes can elicit inflammation by acting on extracellular substrates1. We previously found that most tissue CD8+ T cells in rheumatoid arthritis synovium, and in inflamed organs for some other diseases, express granzyme K (GZMK)2, a tryptase-like protease with poorly defined function. Here, we show that GZMK can activate the complement cascade by cleaving the C2 and C4 proteins. The nascent C4b and C2b fragments form a C3 convertase that cleaves C3, enabling the assembly of a C5 convertase that cleaves C5. The resulting convertases generate all the effector molecules of the complement cascade: the anaphylatoxins C3a and C5a, the opsonins C4b and C3b, and the membrane attack complex. In rheumatoid arthritis synovium, GZMK is enriched in regions with abundant complement activation, and fibroblasts are the main producers of complement proteins that serve as substrates for GZMK-mediated complement activation. Furthermore, Gzmk-deficient mice are significantly protected from inflammatory disease, exhibiting reduced arthritis and dermatitis, with concomitant decreases in complement activation. Our findings describe the discovery of a previously unidentified mechanism of complement activation that is driven entirely by lymphocyte-derived GZMK. Given the widespread abundance of GZMK-expressing T cells in tissues in chronic inflammatory diseases, GZMK-mediated complement activation is likely to be an important contributor to tissue inflammation in multiple disease contexts.

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Asian diversity in human immune cells

Kock K.H., Tan L.M., Han K.Y., Ando Y., Jevapatarakul D., Chatterjee A., Lin Q.X.X., Buyamin E.V., Sonthalia R., Rajagopalan D., Tomofuji Y., Sankaran S., Park M.S., Abe M., Chantaraamporn J., Furukawa S., Ghosh S., Inoue G., Kojima M., Kouno T., Lim J., Myouzen K., Nguantad S., Oh J.M., Rayan N.A., Sarkar S., Suzuki A., Thungsatianpun N., Venkatesh P.N., Moody J., Nakano M., Chen Z., Tian C., Zhang Y., Tong Y., Tan C.T.Y., Tizazu A.M., Loh M., Hwang Y.Y., Ho R.C., Larbi A., Ng T.P., Won H.H., Wright F.A., Villani A.C., Park J.E., Choi M., Liu B., Maitra A., Pithukpakorn M., Suktitipat B., Ishigaki K., Okada Y., Yamamoto K., Carninci P., Chambers J.C., Hon C.C., Matangkasombut P., Charoensawan V., Majumder P.P., Shin J.W., Park W.Y., Prabhakar S.

Cell 188 ( 8 ) 2288 - 2306.e24 2025.04

ISSN 00928674

The relationships of human diversity with biomedical phenotypes are pervasive yet remain understudied, particularly in a single-cell genomics context. Here, we present the Asian Immune Diversity Atlas (AIDA), a multi-national single-cell RNA sequencing (scRNA-seq) healthy reference atlas of human immune cells. AIDA comprises 1,265,624 circulating immune cells from 619 donors, spanning 7 population groups across 5 Asian countries, and 6 controls. Though population groups are frequently compared at the continental level, we found that sub-continental diversity, age, and sex pervasively impacted cellular and molecular properties of immune cells. These included differential abundance of cell neighborhoods as well as cell populations and genes relevant to disease risk, pathogenesis, and diagnostics. We discovered functional genetic variants influencing cell-type-specific gene expression, which were under-represented in non-Asian populations, and helped contextualize disease-associated variants. AIDA enables analyses of multi-ancestry disease datasets and facilitates the development of precision medicine efforts in Asia and beyond.

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Unveiling the dynamics of B lymphocytes in systemic lupus erythematosus patients treated with belimumab through longitudinal single-cell RNA sequencing

Bang S.Y., Joh C.S.Y., Itamiya T., Jeong S., Lee J.H., Kwon H., Jin H., Jung J., Chung H., Lee B.H., Gong J.R., Ishigaki K., Fujio K., Bae S.C., Kim H.J., Lee H.S.

Rheumatology 64 ( 4 ) 2220 - 2226 2025.04

ISSN 14620324

Objectives: Unravelling the mechanisms underlying treatment response for targeted therapeutics in systemic lupus erythematosus (SLE) patients is challenging due to the limited understanding of diverse responses of circulating immune cells, particularly B cells. We investigated B lymphocyte dynamics during anti-BAFF treatment, utilizing longitudinal single-cell transcriptome data. Methods: We conducted single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) in four Korean SLE patients before and after belimumab treatment at the following time points: 2 weeks, 1, 3, 6 and 12 months. Results: Analysing over 73 000 PBMCs, we identified eight distinct subsets of B cells and plasmablasts and analysed dynamic changes within these cell subsets: initial declines in naïve and transitional B cells followed by an increase at 3 months, contrasted by an initial increase and subsequent decrease in memory B cells by the third month. Meanwhile, plasmablasts exhibited a consistent decline throughout the treatment. B cell activation pathways, specifically in naïve and memory B cells, were downregulated during the third and sixth months. These findings were validated at the protein level throughout the first 4 weeks of treatment using flow cytometry. Comparative analysis with bulk transcriptome data from 22 Japanese SLE patients showed increased NR4A1 expression 6 months post-belimumab treatment, indicating its role in restricting self-reactive B cells, thereby contributing to the biological responses of anti-BAFF treatment. Conclusion: The observed B cell dynamics provided insights into the immunological mechanisms underlying the therapeutic effects of anti-BAFF in SLE patients. Furthermore, it underscores the need for research in predicting drug responses based on immune profiling.

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Peripheral blood immunophenotypic diversity in patients with rheumatoid arthritis and its impact on therapeutic responsiveness

Kubo S., Miyazaki Y., Nishino T., Fujita Y., Kono M., Kawashima T., Ishigaki K., Kusaka K., Tanaka H., Ueno M., Satoh-Kanda Y., Inoue Y., Todoroki Y., Miyagawa I., Hanami K., Nakayamada S., Tanaka Y.

Annals of the Rheumatic Diseases 84 ( 2 ) 210 - 220 2025.02

ISSN 00034967

Objective: Considering the diverse aetiologies and immunodysregulatory statuses observed in each patient with rheumatoid arthritis (RA), stratification based on peripheral blood immunophenotyping holds the potential to enhance therapeutic responses to molecular targeted therapies, biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Methods: Immunophenotype analysis was conducted on a cohort of over 500 b/tsDMARDs-naïve patients using flow cytometry. Patients with RA were stratified based on their immunophenotypes, and the treatment response to each targeted therapy was evaluated. Validation was performed using an additional cohort of 183 b/tsDMARDs-naïve patients with RA. Results: Patients with RA were stratified into five clusters, two of which exhibited distinct RA phenotypes compared with controls, characterised by significant increases in CD4+ effector memory T cells re-expressing CD45RA. Notably, the effectiveness of different b/tsDMARDs varied across clusters. The group using promising b/tsDMARDs was labelled as ‘expected’ whereas the ‘non-expected’ group comprised those using others. The expected group outperformed the non-expected group with higher 26-week remission rates (39.9% vs 24.6%, p=0.0004) and low disease activity achievement (80.8% vs 60.2%, p<0.0001). Trajectory analysis showed the non-expected group's 26-week disease activity was influenced by Clinical Disease Activity Index at baseline unlike the expected group. Additionally, different molecular targeted therapies influenced the proportions of each immune cell subset variably. To validate, immunophenotyping was performed on a validation cohort. When 183 cases were grouped based on their b/tsDMARDs usage into expected/non-expected groups, the expected group had a higher remission rate (p=0.0021), further confirming the observed trend. Conclusion: Our findings offer valuable insights into the diversity of RA and potential therapeutic strategies grounded in the molecular underpinnings.

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Proximity-dependent biotinylation reveals an interaction between ubiquitin-specific peptidase 46 and centrosome-related proteins.

Yoshioka K, Nakagawa R, Nguyen CLK, Suzuki H, Ishigaki K, Mizuno S, Okiyoneda T, Ebihara S, Murata K

FEBS open bio 15 ( 1 ) 151 - 164 2025.01

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Naturally arising memory-phenotype CD4+ T lymphocytes contain an undifferentiated population that can generate TH1, TH17, and Treg cells

Kawajiri A., Li J., Koinuma K., Yang Z., Yoon H.J., Yi J., Nagashima H., Ishii M., Gao F., Sato K., Tayama S., Harigae H., Iwakura Y., Ishii N., Sher A., Ishigaki K., Zhu J., Kim K.S., Kawabe T.

Science Advances 10 ( 49 ) eadq6618 2024.12

Memory-phenotype (MP) CD4+ T lymphocytes develop from naïve cells via self-recognition at homeostasis. While previous studies defined MP cells as a heterogeneous population that comprises T helper 1 (T<inf>H</inf>1)/17–like subsets, functional significance of the T-bet− Rorγt− subpopulation remains unknown. Here we show that MP lymphocytes as a whole population can differentiate into T<inf>H</inf>1/17/regulatory T (T<inf>reg</inf>) cells to mediate mild and persistent inflammation in lymphopenic environments, whereas naïve cells exhibit strong, T<inf>H</inf>1-dominated responses. Moreover, we demonstrate that MP lymphocytes comprise not only T<inf>H</inf>1/17-differentiated subsets but a polyclonal, transcriptomically immature “undifferentiated” subpopulation at homeostasis. Furthermore, our data argue that while the T-bet+ Rorγt− MP subset is terminally T<inf>H</inf>1-differentiated, its undifferentiated counterpart retains the capacity to rapidly proliferate to differentiate into T<inf>H</inf>1/17/T<inf>reg</inf> cells, with the latter response tonically constrained by preexisting T<inf>reg</inf> cells. Together, our results identify undifferentiated MP CD4+ T lymphocytes as a unique precursor that has a diverse differentiation potential to generate T<inf>H</inf>1/17/T<inf>reg</inf> cells to contribute to pathogenesis of inflammation.

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The genetic basis of autoimmunity seen through the lens of T cell functional traits

Lagattuta K.A., Park H.L., Rumker L., Ishigaki K., Nathan A., Raychaudhuri S.

Nature Communications 15 ( 1 ) 1204 2024.12

Autoimmune disease heritability is enriched in T cell-specific regulatory regions of the genome. Modern-day T cell datasets now enable association studies between single nucleotide polymorphisms (SNPs) and a myriad of molecular phenotypes, including chromatin accessibility, gene expression, transcriptional programs, T cell antigen receptor (TCR) amino acid usage, and cell state abundances. Such studies have identified hundreds of quantitative trait loci (QTLs) in T cells that colocalize with genetic risk for autoimmune disease. The key challenge facing immunologists today lies in synthesizing these results toward a unified understanding of the autoimmune T cell: which genes, cell states, and antigens drive tissue destruction?

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Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases

Tian C., Zhang Y., Tong Y., Kock K.H., Sim D.Y., Liu F., Dong J., Jing Z., Wang W., Gao J., Tan L.M., Han K.Y., Tomofuji Y., Nakano M., Buyamin E.V., Sonthalia R., Ando Y., Hatano H., Sonehara K., Moody J., Lin Q.X.X., Venkatesh P.N., Maitra A., Lim J., Kouno T., Kojima M., Suzuki A., Oh J.M., Myouzen K., Inoue G., Furukawa S., Abe M., Thungsatianpun N., Sarkar S., Nguantad S., Jevapatarakul D., Ghosh S., Chatterjee A., Chantaraamporn J., Sankaran S., Rayan N.A., Rajagopalan D., Yamamoto K., Suktitipat B., Pithukpakorn M., Chambers J.C., Carninci P., Matangkasombut P., Majumder P.P., Charoensawan V., Jin X., Loh M., Hon C.C., Choi M., Park J.E., Ishigaki K., Okamura T., Fujio K., Okada Y., Park W.Y., Shin J.W., Roca X., Prabhakar S., Liu B.

Nature Genetics 56 ( 12 ) 2739 - 2752 2024.12

ISSN 10614036

Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific. We identify 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes and 107 dynamic sQTLs. Colocalization between cis-eQTLs and trans-sQTLs revealed a cell-type-specific regulatory relationship between HNRNPLL and PTPRC. We observed an enrichment of cis-sQTL effects in autoimmune and inflammatory disease heritability. Specifically, we functionally validated an Asian-specific sQTL disrupting the 5′ splice site of TCHP exon 4 that putatively modulates the risk of Graves’ disease in East Asian populations. Our work highlights the impact of ancestral diversity on splicing and provides a roadmap to dissect its role in complex diseases at single-cell resolution.

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The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis

Weinand K., Sakaue S., Nathan A., Jonsson A.H., Zhang F., Watts G.F.M., Al Suqri M., Zhu Z., Rao D.A., Anolik J.H., Brenner M.B., Donlin L.T., Wei K., Raychaudhuri S., Albrecht J., Apruzzese W., Banda N., Barnas J.L., Bathon J.M., Ben-Artzi A., Boyce B.F., Boyle D.L., Bridges S.L., Bykerk V.P., Campbell D., Carr H.L., Ceponis A., Chicoine A., Cordle A., Curtis M., Deane K.D., DiCarlo E., Dunn P., Filer A., Firestein G.S., Forbess L., Geraldino-Pardilla L., Goodman S.M., Gravallese E.M., Gregersen P.K., Guthridge J.M., Gutierrez-Arcelus M., Gurajala S., Holers V.M., Horowitz D., Hughes L.B., Ishigaki K., Ivashkiv L.B., James J.A., Kang J.B., Keras G., Korsunsky I., Lakhanpal A., Lederer J.A., Li Z.J., Li Y., Liao K.P., Mandelin A.M., Mantel I., Maybury M., McDavid A., Mears J., Meednu N., Millard N., Moreland L.W., Nerviani A., Orange D.E., Perlman H., Pitzalis C., Rangel-Moreno J., Raza K., Reshef Y., Ritchlin C., Rivellese F., Robinson W.H., Rumker L., Sahbudin I., Scheel-Toellner D., Seifert J.A., Slowikowski K., Smith M.H., Tabechian D., Utz P.J., Weisenfeld D., Weisman M.H., Xiao Q.

Nature Communications 15 ( 1 ) 2024.12

Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has yet to be defined. Here, we examine genome-wide open chromatin at single-cell resolution in 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identify 24 chromatin classes and predict their associated transcription factors, including a CD8 + GZMK+ class associated with EOMES and a lining fibroblast class associated with AP-1. By integrating with an RA tissue transcriptional atlas, we propose that these chromatin classes represent ‘superstates’ corresponding to multiple transcriptional cell states. Finally, we demonstrate the utility of this RA tissue chromatin atlas through the associations between disease phenotypes and chromatin class abundance, as well as the nomination of classes mediating the effects of putatively causal RA genetic variants.

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Population-specific reference panel improves imputation quality for genome-wide association studies conducted on the Japanese population

Flanagan J., Liu X., Ortega-Reyes D., Tomizuka K., Matoba N., Akiyama M., Koido M., Ishigaki K., Ashikawa K., Takata S., Shi M.Y., Aoi T., Momozawa Y., Ito K., Murakami Y., Matsuda K., Koretsune Y., Masumoto A., Higashiyama M., Obata D., Nagayama S., Yoshimori K., Murayama S., Minami S., Yamaguchi H., Sinozaki N., Suzuki T., Takahashi Y., Asai S., Takahashi K., Yamaji K., Obara W., Nagai A., Muto K., Kamatani Y., Morisaki T., Furukawa Y., Yamanashi Y., Morris A.P., Horikoshi M., Terao C.

Communications Biology 7 ( 1 ) 1665 2024.12

To improve imputation quality for genome-wide association studies (GWAS) conducted on the Japanese population, we developed and evaluated four Japanese population-specific reference panels. These panels were constructed through the augmentation of the 1000 Genomes Project (1KG) panel using Japanese whole genome sequencing (WGS) data, with sample sizes ranging from 1 K to 7 K individuals enrolled through the Biobank Japan (BBJ) project, and sequencing depths ranging from 3× to 30×. Among these panels, an augmented reference panel comprising 7472 WGS samples of mixed depth (1KG+7K) exhibit the greatest improvement in imputation quality relative to the Trans-Omics for Precision Medicine (TOPMed) reference panel. Notably, we observe these improvements primarily for rare variants with a minor allele frequency (MAF) <5%. To demonstrate the benefits of improved imputation quality in association analyses of complex traits, we conducted GWAS for serum uric acid and total cholesterol levels following imputation up to the 1KG+7K panel. The analysis reveals several loci reaching genome-wide significance (P < 5 × 10–8) in the 1KG+7K imputation output yet remaining undetected when the same sample set is imputed up to the TOPMed reference panel. In summary, the 1KG+7K panel demonstrates significant advantages in the discovery of trait-associated loci, particularly those influenced by low-frequency association signals.

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Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms

Inamo J., Suzuki A., Ueda M.T., Yamaguchi K., Nishida H., Suzuki K., Kaneko Y., Takeuchi T., Hatano H., Ishigaki K., Ishihama Y., Yamamoto K., Kochi Y.

Nature Communications 15 ( 1 ) 4285 2024.12

Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generate a full-length isoform annotation of human immune cells from an individual by long-read sequencing for 29 cell subsets. This contains a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE in the Alzheimer’s disease locus. We profile characteristics of isoforms and show that repetitive elements significantly explain the diversity of unannotated isoforms, providing insight into the human genome evolution. In addition, some of the isoforms are expressed in a cell-type specific manner, whose alternative 3’-UTRs usage contributes to their specificity. Further, we identify disease-associated isoforms by isoform switch analysis and by integration of several quantitative trait loci analyses with genome-wide association study data. Our findings will promote the elucidation of the mechanism of complex diseases via alternative splicing.

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Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

Dunlap G., Wagner A., Meednu N., Wang R., Zhang F., Ekabe J.C., Jonsson A.H., Wei K., Sakaue S., Nathan A., Bykerk V.P., Donlin L.T., Goodman S.M., Firestein G.S., Boyle D.L., Holers V.M., Moreland L.W., Tabechian D., Pitzalis C., Filer A., Raychaudhuri S., Brenner M.B., Thakar J., McDavid A., Rao D.A., Anolik J.H., Albrecht J., Apruzzese W., Barnas J.L., Bathon J.M., Ben-Artzi A., Boyce B.F., Bridges S.L., Campbell D., Carr H.L., Ceponis A., Chicoine A., Cordle A., Curtis M., Deane K.D., DiCarlo E., Dunn P., Forbess L., Geraldino-Pardilla L., Gravallese E.M., Gregersen P.K., Guthridge J.M., Horowitz D., Hughes L.B., Ishigaki K., Ivashkiv L.B., James J.A., Kang J.B., Keras G., Korsunsky I., Lakhanpal A., Lederer J.A., Li Y., Li Z.J., Liao K.P., Maecker H., Mandelin A.M., Mantel I., Maybury M., McGeachy M.J., Mears J., Nerviani A., Orange D.E., Perlman H., Rangel-Moreno J., Raza K., Reshef Y., Ritchlin C., Rivellese F., Robinson W.H., Rumker L., Sahbudin I., Salomon-Escoto K., Scheel-Toellner D., Seifert J.A., Singaraju A., Smith M.H., Utz P.J., Weinand K., Weisenfeld D., Weisman M.H., Xiao Q., Zhu Z.

Nature Communications 15 ( 1 ) 2024.12

Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.

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Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis

Faust H.J., Cheng T.Y., Korsunsky I., Watts G.F.M., Gal-Oz S.T., Trim W.V., Kongthong S., Jonsson A.H., Simmons D.P., Zhang F., Padera R., Chubinskaya S., Wyse A., Cordle A., Li Z.J., Zhu Z., Xiao Q., Weisman M.H., Weisenfeld D., Weinand K., Utz P.J., Tabechian D., Smith M., Slowikowski K., Singaraju A., Scheel-Toellner D., Seifert J.A., Sakaue S., Sahbudin I., Rumker L., Robinson W.H., Rivellese F., Ritchlin C., Reshef Y., Raza K., Rangel-Moreno J., Pitzalis C., Perlman H., Orange D.E., Nerviani A., Nayar S., Moreland L., Millard N., Meednu N., Mears J.R., McGeachy M.J., McDavid A., Maybury M., Marks K.E., Mantel I., Mandelin A.M., Liao K., Li Y., Lewis M.J., Lederer J.A., Lakhanpal A., Keras G., Kang J.B., James J.A., Ishigaki K., Ivashkiv L.B., Hughes L.B., Horowitz D., Holers V.M., Gutierrez-Arcelus M., Guthridge J.M., Gregersen P.K., Rao D., Gravallese E.M., Goodman S.M., Geraldino-Pardilla L., Forbess L., Firestein G.S., Carr H., Filer A., Dunn P., Donlin L.T., DiCarlo E., Deane K.D., Curtis M., Chicoine A., Ceponis A., Campbell D., Bykerk V.P., Bridges S.L., Boyle D.L., Boyce B.F., Ben-Artzi A., Bathon J.M., Barnas J.L., Apruzzese W., Anolik J.H., Albrecht J., Wei K., Raychaudhuri S., Lynch L., Moody D.B., Brenner M.B.

Nature Communications 15 ( 1 ) 2024.12

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Little is known about what regulates the homeostatic functions of fibroblasts. Here, we perform RNA sequencing and identify a gene expression program in healthy synovial fibroblasts characterized by enhanced fatty acid metabolism and lipid transport. We identify cortisol as the key driver of the healthy fibroblast phenotype and that depletion of adipocytes, which express high levels of Hsd11b1, results in loss of the healthy fibroblast phenotype in mouse synovium. Additionally, fibroblast-specific glucocorticoid receptor Nr3c1 deletion in vivo leads to worsened arthritis. Cortisol signaling in fibroblasts mitigates matrix remodeling induced by TNF and TGF-β1 in vitro, while stimulation with these cytokines represses cortisol signaling and adipogenesis. Together, these findings demonstrate the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease.

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Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis

Luo Y., Huang C.C., Howard N.C., Wang X., Liu Q., Li X., Zhu J., Amariuta T., Asgari S., Ishigaki K., Calderon R., Raman S., Ramnarine A.K., Mayfield J.A., Moody D.B., Lecca L., Fortune S.M., Murray M.B., Raychaudhuri S.

Nature Communications 15 ( 1 ) 10393 2024.12

Infectious disease is the result of interactions between host and pathogen and can depend on genetic variations in both. We conduct a genome-to-genome study of paired human and Mycobacterium tuberculosis genomes from a cohort of 1556 tuberculosis patients in Lima, Peru. We identify an association between a human intronic variant (rs3130660, OR = 10.06, 95%CI: 4.87 − 20.77, P = 7.92 × 10−8) in the FLOT1 gene and a subclavaluee of Mtb Lineage 2. In a human macrophage infection model, we observe hosts with the rs3130660-A allele exhibited stronger interferon gene signatures. The interacting strains have altered redox states due to a thioredoxin reductase mutation. We investigate this association in a 2020 cohort of 699 patients recruited during the COVID-19 pandemic. While the prevalence of the interacting strain almost doubled between 2010 and 2020, its infection is not associated with rs3130660 in this recent cohort. These findings suggest a complex interplay among host, pathogen, and environmental factors in tuberculosis dynamics.

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A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis

Hitomi Y., Ueno K., Aiba Y., Nishida N., Kono M., Sugihara M., Kawai Y., Kawashima M., Khor S.S., Sugi K., Kouno H., Kohno H., Naganuma A., Iwamoto S., Katsushima S., Furuta K., Nikami T., Mannami T., Yamashita T., Ario K., Komatsu T., Makita F., Shimada M., Hirashima N., Yokohama S., Nishimura H., Sugimoto R., Komura T., Ota H., Kojima M., Nakamuta M., Fujimori N., Yoshizawa K., Mano Y., Takahashi H., Hirooka K., Tsuruta S., Sato T., Yamasaki K., Kugiyama Y., Motoyoshi Y., Suehiro T., Saeki A., Matsumoto K., Nagaoka S., Abiru S., Yatsuhashi H., Ito M., Kawata K., Takaki A., Arai K., Arinaga-Hino T., Abe M., Harada M., Taniai M., Zeniya M., Ohira H., Shimoda S., Komori A., Tanaka A., Ishigaki K., Nagasaki M., Tokunaga K., Nakamura M.

Hepatology 80 ( 4 ) 776 - 790 2024.10

ISSN 02709139

Background and Aims: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-Analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. Approach and Results: Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-Analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10-8). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. Conclusions: PTPN2, a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

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