Systemic lupus erythematosus (SLE) affects 1 in 537 Black women, which is >2-fold more than White women. Black patients develop the disease at a younger age, have more severe symptoms, and have a greater chance of early mortality. We used a multiomics approach to uncover ancestry-associated immune alterations in patients with SLE and healthy controls that may contribute biologically to disease disparities. Cell composition, signaling, epigenetics, and proteomics were evaluated by mass cytometry; droplet-based single-cell transcriptomics and proteomics; and bead-based multiplex soluble mediator levels in plasma. We observed altered whole blood frequencies and enhanced activity in CD8+ T cells, B cells, monocytes, and DCs in Black patients with more active disease. Epigenetic modifications in CD8+ T cells (H3K27ac) could distinguish disease activity level in Black patients and differentiate Black from White patient samples. TLR3/4/7/8/9-related gene expression was elevated in immune cells from Black patients with SLE, and TLR7/8/9 and IFN-α phospho-signaling and cytokine responses were heightened even in immune cells from healthy Black control patients compared with White individuals. TLR stimulation of healthy immune cells recapitulated the ancestry-associated SLE immunophenotypes. This multiomic resource defines ancestry-associated immune phenotypes that differ between Black and White patients with SLE, which may influence the course and severity of SLE and other diseases.
Samantha Slight-Webb, Kevin Thomas, Miles Smith, Catriona A. Wagner, Susan Macwana, Aleksandra Bylinska, Michele Donato, Mai Dvorak, Sarah E. Chang, Alex Kuo, Peggie Cheung, Laurynas Kalesinskas, Ananthakrishnan Ganesan, Denis Dermadi, Carla J. Guthridge, Wade DeJager, Christian Wright, Mariko H. Foecke, Joan T. Merrill, Eliza Chakravarty, Cristina Arriens, Holden T. Maecker, Purvesh Khatri, Paul J. Utz, Judith A. James, Joel M. Guthridge
BACKGROUND While B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODS We evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTS In contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell–depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell–depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSION These results demonstrate that serial vaccination strategies can be effective for a subset of B cell–depleted patients.FUNDING The NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).
Hiromitsu Asashima, Dongjoo Kim, Kaicheng Wang, Nikhil Lele, Nicholas C. Buitrago-Pocasangre, Rachel Lutz, Isabella Cruz, Khadir Raddassi, William E. Ruff, Michael K. Racke, JoDell E. Wilson, Tara S. Givens, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Steven H. Kleinstein, Ruth R. Montgomery, Albert C. Shaw, Fangyong Li, Rong Fan, David A. Hafler, Mary M. Tomayko, Erin E. Longbrake
IgG4-related disease (IgG4-RD) is a systemic autoimmune disease with unclear pathogenesis. We performed single-cell RNA-seq and surface proteome analyses on 61,379 PBMCs from 9 treatment-naïve IgG4-RD patients and 7 age- and sex-matched healthy controls. Integrative analyses were performed for altered gene expression in IgG4-RD, and flow cytometry and immunofluorescence were used for validation. We observed expansion of plasmablasts with enhanced protein processing and activation, which correlated with number of involved organs in IgG4-RD. Increased proportions of CD4+ cytotoxic T lymphocytes (CTLs), CD8+ CTLs-GNLY (granulysin) and γδT cells with enhanced chemotaxis and cytotoxicity but with suppressed inhibitory receptors characterize IgG4-RD. Prominent infiltration of lymphocytes with distinct compositions were found in different organs of IgG4-RD patients. Transcription factors (TFs) including PRDM1/XBP1 and RUNX3 were upregulated in IgG4-RD, promoting the differentiation of plasmablasts and CTLs, respectively. Monocytes in IgG4-RD have stronger expression of genes related to cell adhesion and chemotaxis, which may give rise to profibrotic macrophages in lesions. The gene activation pattern in peripheral immune cells indicated activation of multiple interaction pathways between cell types, in part through chemokines or growth factors and their receptors. Specific upregulation of TFs and expansion of plasmablasts and CTLs may be involved in the pathogenesis of IgG4-RD, and each of these populations are candidate targets for therapeutic interventions in this disease.
Chenyang Lu, Shasha Li, Pingying Qing, Qiuping Zhang, Xing Ji, Zhigang Tang, Chunyan Chen, Tong Wu, Yidan Hu, Yi Zhao, Xiaohui Zhang, Qi He, David A. Fox, Chunyu Tan, Yubin Luo, Yi Liu
Cutaneous lupus erythematosus (CLE) is a disfiguring autoimmune skin disease characterized by an inflammatory infiltrate rich in T cells, which are strongly implicated in tissue damage. How these cells adapt to the skin environment and promote tissue inflammation and damage is not known. In lupus nephritis, we have previously identified an inflammatory gene program in kidney-infiltrating T cells that is dependent on hypoxia-inducible factor-1 (HIF-1), a transcription factor critical for the cellular and developmental response to hypoxia as well as inflammation-associated signals. In our current studies using a mouse model of lupus skin disease, we find that skin-infiltrating CD4+ and CD8+ T cells also express high levels of HIF-1. Skin-infiltrating T cells demonstrate a strong cytotoxic signature at the transcript and protein level, and HIF-1 inhibition abrogates skin and systemic disease in association with decreased T cell cytotoxic activity. We also demonstrate in human CLE tissue that the T cell rich inflammatory infiltrate exhibits increased amounts of HIF-1 and a cytotoxic signature. Granzyme B-expressing T cells are concentrated at sites of skin tissue damage in CLE, suggesting relevance of this pathway to human disease.
Alicia J. Little, Ping-Min Chen, Matthew D. Vesely, Rahanna N. Khan, Jacob Fiedler, James Garritano, Fahrisa M. Islam, Jennifer M. McNiff, Joseph E. Craft
The proportions and phenotypes of immune cell subsets in peripheral blood undergo continual and dramatic remodeling throughout the human lifespan, which complicates efforts to identify disease-associated immune signatures in type 1 diabetes (T1D). We conducted cross-sectional flow cytometric immune profiling on peripheral blood from 826 individuals [stage 3 T1D (n=240), their first-degree relatives (n=310), those with >2 islet autoantibodies (n=24), and autoantibody negative healthy controls (n=252)]. We constructed an immune-age predictive model in healthy participants and observed accelerated immune aging in the T1D cohort (p<0.001). We used generalized additive models for location, shape, and scale (GAMLSS) to obtain age-corrected data for 192 flow cytometry and complete blood count readouts, which can be visualized in our interactive portal (ImmScape; https://ufdiabetes.shinyapps.io/ImmScape/); 46 parameters were significantly associated with age only, 25 with T1D only, and 23 with both age and T1D. Phenotypes associated with accelerated immunological aging in T1D included increased CXCR3+ and PD-1+ frequencies in naïve and memory T cell subsets, despite reduced PD-1 expression levels (MFI) on memory T cells. Phenotypes associated with T1D after age-correction were predictive of T1D status (AUROC=82.3%). Our findings demonstrate advanced immune aging in T1D and highlight disease-associated phenotypes for biomarker monitoring and therapeutic interventions.
Melanie R. Shapiro, Xiaoru Dong, Daniel J. Perry, James M. McNichols, Puchong Thirawatananond, Amanda L. Posgai, Leeana D. Peters, Keshav Motwani, Richard S. Musca, Andrew Muir, Patrick Concannon, Laura M. Jacobsen, Clayton E. Mathews, Clive H. Wasserfall, Michael J. Haller, Desmond A. Schatz, Mark A. Atkinson, Maigan A. Brusko, Rhonda Bacher, Todd M. Brusko
U1RNP complex, Ro/SSA and La/SSB are major RNA-containing autoantigens. Immune complexes (ICs) composed of RNA-containing autoantigens and autoantibodies are suspected to be involved in the pathogenesis of some systemic autoimmune diseases. Therefore, RNase treatment, which degrades RNA in ICs, has been tested in clinical trials as a potential therapeutic agent. However, no studies have specifically evaluated the effect of RNase treatment on the Fcγ receptor-stimulatory activity of RNA-containing ICs. In this study, using a reporter system that specifically detects Fcγ receptor-stimulatory capacity, we investigated the effect of RNase treatment on the Fcγ receptor-stimulatory activity of RNA-containing ICs composed of autoantigens and autoantibodies from patients with systemic autoimmune diseases such as systemic lupus erythematosus. We found that RNase enhanced the Fcγ receptor-stimulatory activity of Ro/SSA- and La/SSB-containing ICs, but attenuated that of the U1RNP complex-containing ICs. RNase decreased autoantibody binding to the U1RNP complex, but increased autoantibody binding to Ro/SSA and La/SSB. Our results suggest that RNase enhances Fcγ receptor activation by promoting the formation of ICs containing Ro/SSA or La/SSB. Our study provides new insights into the pathophysiology of autoimmune diseases involving anti-Ro/SSA and anti-La/SSB autoantibodies, and into the therapeutic application of RNase treatment for systemic autoimmune diseases.
Ryota Naito, Koichiro Ohmura, Shuhei Higuchi, Wataru Nakai, Masako Kohyama, Tsuneyo Mimori, Akio Morinobu, Hisashi Arase
B cells contribute to multiple aspects of autoimmune disorders, and B cell–targeting therapies, including B cell depletion, have been proven to be efficacious in treatment of multiple autoimmune diseases. However, the development of novel therapies targeting B cells with higher efficacy and a nondepleting mechanism of action is highly desirable. Here we describe a nondepleting, high-affinity anti–human CD19 antibody LY3541860 that exhibits potent B cell inhibitory activities. LY3541860 inhibits B cell activation, proliferation, and differentiation of primary human B cells with high potency. LY3541860 also inhibits human B cell activities in vivo in humanized mice. Similarly, our potent anti-mCD19 antibody also demonstrates improved efficacy over CD20 B cell depletion therapy in multiple B cell–dependent autoimmune disease models. Our data indicate that anti-CD19 antibody is a highly potent B cell inhibitor that may have potential to demonstrate improved efficacy over currently available B cell–targeting therapies in treatment of autoimmune conditions without causing B cell depletion.
Jeffrey S. Boyles, Dorota Sadowski, Scott Potter, Aleksandra Vukojicic, James Parker, William Y. Chang, Yanfei L. Ma, Mark G. Chambers, James Nelson, Barbra Barmettler, Eric M. Smith, Kara Kersjes, Evan R. Himes, Chaohua Lin, Jonathan Lucchesi, Jaladhi Brahmbhatt, Ramtin Sina, Jennifer A. Martin, Evan Maestri, Christopher M. Wiethoff, Gregory L. Dyas, Matthew D. Linnik, Songqing Na, Derrick R. Witcher, Alison Budelsky, Kira Rubtsova
Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated “don’t eat me” signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed pro-inflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase (MPO)-ANCA titers with a reduction in NETs formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.
Satoka Shiratori-Aso, Daigo Nakazawa, Takashi Kudo, Masatoshi Kanda, Yusho Ueda, Kanako Watanabe-Kusunoki, Saori Nishio, Sari Iwasaki, Takahiro Tsuji, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu, Tatsuya Atsumi
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that causes debilitating swelling and destruction of the joints. People with RA are treated with drugs that actively suppress one or more parts of their immune system, and these may alter their response to vaccination against SARS-CoV-2. In this study, we analyzed blood samples from a cohort of RA subjects after receiving a 2-dose mRNA COVID-19 vaccine regimen. Our data show that individuals on the CTLA4-Ig therapy abatacept have reduced levels of SARS-CoV-2-neutralizing antibodies after vaccination. At a cellular level, these subjects show reduced activation and class-switching of SARS-CoV-2-specific B cells, as well as reduced numbers and impaired helper cytokine production by SARS-CoV-2-specific CD4+ T cells. Individuals on methotrexate showed similar but less severe defects in vaccine response, whereas individuals on the B cell-depleting therapy rituximab had a near-total loss of antibody production after vaccination. These data define a specific cellular phenotype associated with impaired response to SARS-CoV-2 vaccination in RA subjects on different immune-modifying therapies, and help inform efforts to improve vaccination strategies in this vulnerable population.
Samuel D Klebanoff, Lauren B. Rodda, Chihiro Morishima, Mark H. Wener, Yevgeniy Yuzefpolskiy, Estelle Bettelli, Jane H. Buckner, Cate Speake, Marion Pepper, Daniel J. Campbell
Multi-organ fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of transforming growth factor-β (TGF-β) and toll-like receptor (TLR) signaling, TGF-β-activated kinase 1 (TAK1) might have a pathogenic role in SSc. We therefore sought to evaluate the TAK1 signaling axis in patients with SSc, and investigate pharmacological TAK1 blockade using a novel drug-like selective TAK1 inhibitor, HS-276. Inhibiting TAK1 abrogated TGF-β1 stimulation of collagen synthesis and myofibroblasts differentiation in healthy skin fibroblasts, and ameliorated constitutive activation of SSc skin fibroblasts. Moreover, treatment with HS-276 prevented dermal and pulmonary fibrosis and reduced the expression of profibrotic mediators in bleomycin-treated mice. Importantly, initiating HS-276 treatment even after fibrosis was already established prevented its progression in affected organs. Together, these findings implicate TAK1 in the pathogenesis of SSc, and identify targeted TAK1 inhibition using a small molecule as a potential strategy for the treatment of SSc and other fibrotic diseases.
Swarna Bale, Priyanka Verma, Bharath Yalavarthi, Scott A. Scarneo, Philip F. Hughes, M. Asif Amin, Pei-Suen Tsou, Dinesh Khanna, Timothy A.J. Haystead, Swati Bhattacharyya, John Varga
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