Immunology
Abstract
Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), with acute interstitial nephritis (ICI-AIN) being the most common irAE. While the exact mechanism remains unclear, upregulation of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) pathways has been implicated. This study used a humanized chimeric PD-1/PD-L1 mouse model to assess renal effects of ICIs, alone or combined with pro-inflammatory cytokines, and to test if selective TNF-α blockade could prevent ICI-AIN. Mice were randomly divided into four experimental groups: Control, ICI-Only, ICI-Cytokines (ICI-Cyt), and ICI-Block (ICI-TNF-α blockade). Renal function and cytokine profiles were assessed, while kidney tissue was analyzed using microscopy and single-cell RNA sequencing. Histology revealed increased renal infiltration of CD4⁺/CD8⁺ T cells in ICI-treated groups and decreased TNF-α expression following TNF-α blockade. Additionally, kidney tissue ELISA demonstrated reduced IFN-γ levels following TNF-α blockade. Plasma IL-6, MCP-1, and TNF-α were lower in ICI-Block mice. Single-cell RNA sequencing revealed shifts in immune cell populations and genes of interest including: Bcl2a1, Icos, Il18r1, Ccr2, and Jaml. This humanized model replicates ICI-AIN key features, revealing a synergistic role of ICIs and pro-inflammatory cytokines. TNF-α blockade demonstrated protective effects, supporting its potential role in mitigating the risk of ICI-AIN.
Authors
Victor D. Cuenca Narvaez, Coraima Nava Chavez, Omar Al Refai, Johanna E. J. Jacobs, Luis E. Gutierrez, Song Zhang, Xiaoyan Li, Jacob B. Hirdler, Michael F. Romero, Joerg Herrmann, Xiaogang Li, Haidong Dong, Alfonso Eirin, Sandra M. Herrmann
Abstract
This study provides a comprehensive evaluation of the cutaneous adipose tissue (CAT) transcriptome in psoriasis patients and investigates the effects of IL-17 blockade on CAT inflammation through a randomized placebo-controlled trial using secukinumab (ObePso-S study, NCT03055494). RNA sequencing analysis of CAT biopsies from 82 psoriasis patients revealed 2132 differentially expressed transcripts compared to healthy controls. Notably, significant gene dysregulation was observed in both lesional skin (LS)- and non-lesional (NL)-CAT, including activation of IL-17-driven pathways, antimicrobial peptide-related, and neutrophil degranulation signatures. Stratification by obesity demonstrated that obese psoriatic CAT exhibited more than 2-fold higher number of differentially expressed genes than non-obese counterparts, suggesting a synergistic interaction between psoriasis and obesity in driving CAT inflammation. Treatment with secukinumab markedly improved inflammatory signatures in psoriatic CAT, with greater improvements observed in obese patients. These findings reveal a pronounced and partially dependent on IL-17-dependent inflammatory phenotype in psoriatic CAT, challenge the conventional concept of psoriasis as a solely superficial skin disease, and highlight CAT as an important contributor to systemic inflammation in psoriasis.
Authors
Naomi Shishido-Takahashi, Sandra Garcet, Inna Cueto, Hong Beom Hur, Elisa F. Muscianisi, Jennifer Steadman, Andrew Blauvelt, James G. Krueger
Abstract
Patients with COVID-19 who develop platelet-activating antibodies represent a subset at heightened thrombotic risk, yet the immune features associated with this response remains to be defined. We applied single-cell RNA sequencing of B- and T-cells, single B-cell V(D)J sequencing, and plasma cytokine and chemokine analysis to define immune signatures distinguishing patients who did (PEA+) or did not (PEA–) develop these antibodies. PEA⁺ patients showed prominent transcriptional enrichment of inflammatory, antigen-presentation, and B-cell receptor signaling pathways within antigen-experienced B-cell subsets. Expanded B-cell clones in PEA+ patients were disproportionately enriched within atypical memory B-cells and exhibited upregulated IFN-γ–response signatures, increased proliferative mutational patterns, limited class switching, and a significant overrepresentation of RKH/Y5 heavy-chain motifs associated with platelet-activating antibodies, consistent with an extrafollicular-biased response. Parallel T-cell profiling revealed IL-12 pathway enrichment across most T-cell subsets, increased IFN-γ transcription, and elevated plasma levels of Th1-associated cytokines in PEA+ patients. Collectively, these data highlight a coordinated inflammatory environment marked by Th1-skewed T-cell activation and selective expansion of atypical memory B-cell clones carrying RKH/Y5 motifs, defining immunologic features associated with platelet-activating antibody development in COVID-19.
Authors
Nathan Witman, Mei Yu, Yuqi Zhang, Kexin Gai, Yuhong Chen, Lu Zhou, Christine Nguyen, Wen Zhu, Yongwei Zheng, Shawn M. Jobe, Mary Beth Graham, Weiguo Cui, Demin Wang, Renren Wen
Abstract
While the pathogenic role of autoantibodies targeting the podocyte protein THSD7A in membranous nephropathy (MN) is well described, the consequences of autoantibody binding for podocyte homeostasis and the function of THSD7A remain unclear. Here, we induced an MN model in control and podocyte-specific Thsd7a knockout (Thsd7a–/–) mice using rabbit anti-THSD7A antibodies, followed by transcriptome and proteome analyses. Anti-THSD7A antibodies in WT mice caused significant loss of key slit diaphragm (SD) proteins such as nephrin and NEPH1, without transcriptional downregulation. Glomeruli showed substantial transcriptomic and proteomic reconfiguration indicative of extensive podocyte injury, including disruptions in podocyte adhesion, cytoskeletal dynamics, and marked upregulation of ubiquitin-proteasome system components, cathepsins and ADAM proteases. Notably, experiments in C3-deficient mice revealed that proteolytic activation and SD protein loss are driven by complement-independent pathways. While Thsd7a–/– mice only displayed a mild phenotype under basal conditions, they were completely protected from MN development upon anti-THSD7A antibody transfer. Finally, interactomic analysis identified a protein complex including THSD7A and integrin α3, linking THSD7A complexes to pathogenic regulation of cytoskeleton, adhesion, and membrane signaling in MN. Thus, anti-THSD7A antibodies induce profound molecular reconfiguration, including dysregulated proteolytic systems via a complement-independent pathway, revealing potential therapeutic targets in MN.
Authors
Ming Huang, Moritz Lassé, Silke Dehde, Felicitas E. Hengel, Fatih Demir, Anja M. Billing, Ning Song, Larissa Seifert, Oliver Kretz, Florian Grahammer, Ulf Panzer, Sebastian Brähler, Tobias B. Huber, Gunther Zahner, Markus M. Rinschen, Nicola M. Tomas
Abstract
Authors
Johanna Tennigkeit, Maurice Wiegelmann, Chiara Massa, Jonas Lübcke, Werner Dammermann, Karina Börner, Filip Schröter, Barbara Seliger, Maximilian Kleinert, Oliver Ritter, Gregor Sachse
Abstract
Coinfection with both HIV and M. tuberculosis (Mtb) results in disseminated tuberculosis (TB) and accelerated HIV progression. Despite greater access to antiretroviral treatment (ART), it remains unclear whether suppression of HIV replication protects against severe Mtb infection. Here, using a macaque model of SIV/Mtb coinfection, we investigated whether treatment of SIV infection with ART influenced control of a subsequent Mtb challenge compared with SIV-infected macaques that were not treated with ART. Macaques were first infected with SIVB670, SIVB670 with ART, or saline followed by a low-dose Mtb inoculation with serial clinical and PET-CT imaging assessments. At necropsy, gross pathology, viremia, bacterial burden, and immunologic parameters were compared. SIV-TB animals had greater gross pathology and total bacterial burden than TB-only and SIV/ART/TB groups. However, despite normal blood CD4 counts and undetectable SIV RNA, SIV/ART/TB macaques showed similar clinical parameters and extrapulmonary involvement as SIV/TB animals. Analysis of barcoded-Mtb suggests that ART control of SIV replication did not prevent Mtb extrapulmonary dissemination. These data indicate that people living with HIV on ART remain at high risk of bacterial dissemination and extrapulmonary TB disease. Understanding the mechanisms of extrapulmonary spread and disease severity during HIV/TB coinfection remains an important issue.
Authors
Collin R. Diedrich, Tara Rutledge, Janelle L. Gleim, Christopher Kline, Pauline Maiello, Jessica M. Medrano, H. Jacob Borish, Harris B. Chishti, Justin L. Gaines, Edwin Klein, Forrest Hopkins, Jacob E. Klein, Daniel Fillmore, Kara Kracinovsky, Jaime Tomko, Jennifer Schober, Sarah M. Fortune, Michael C. Chao, JoAnne L. Flynn, Zandrea Ambrose, Philana Ling Lin
Abstract
Sepsis, a systemic inflammatory response to infection, remains a leading cause of mortality in intensive care units, with sepsis-induced immunosuppression being a critical pathophysiological process. In this study, we investigated the role of histone deacetylase 1 (HDAC1) in sepsis-induced CD8+ T cell exhaustion, a key driver of immunosuppression. Clinical analyses of patients with sepsis revealed that reduced peripheral blood lymphocyte levels, particularly CD8+ T cell depletion, strongly correlated with worsened outcomes. In a murine sepsis model, single-cell RNA-Seq revealed a significant decrease in the proportion of CD8+ T cells and an increase in the proportion of exhausted CD8+ T cells in mouse lungs. Adoptive transfer of CD8+ T cells effectively reduced sepsis mortality by preserving organ function. We further demonstrated that HDAC1 expression was significantly upregulated in CD8+ T cells from patients with sepsis. In vitro studies showed that HDAC1 inhibition preserved CD8+ T cell function by maintaining T cell activity and reducing the expression of inhibitory molecules such as PD-1. Pharmacological inhibition of HDAC1 reduced mortality and reversed CD8+ T cell exhaustion by restoring the balance between activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT). Additionally, we found that HDAC1 directly interacted with NFAT1, promoting its nuclear translocation and further enhancing the expression of inhibitory molecules. Our findings highlight HDAC1 as a potential therapeutic target for sepsis-induced immunosuppression. By elucidating the molecular mechanisms underlying HDAC1-mediated immunosuppression, we have provided potential strategies for developing immunomodulatory therapies for the treatment of sepsis.
Authors
Liu Di, Jiang-bo Fan, Rui Wang, You Li, Wan-da Bi, Si-yuan Huang, Heng-hai Nie, Xi-feng Feng, Hua-cai Zhang, Juan Du, Xiao-fei Huang, An-yong Yu, Zhe Xu, Fei Xia, Jian-xin Jiang, Shuang-shuang Dai, Xiang Xu, Zhen Wang, Ling Zeng
Abstract
Antibody-dependent enhancement (ADE) of infection is a well-described phenomenon for several viruses, including dengue, Ebola, respiratory syncytial virus, and HIV. ADE occurs when virus-antibody complexes engage Fc receptors (FcRs) and virus-specific receptors, enhancing infection under conditions of incomplete neutralization. The Coronavirus Immunotherapeutic Consortium (CoVIC) assembled a comprehensive dataset of functional properties for over 400 mAbs, enabling direct comparison of neutralization, Fc-mediated functions, receptor binding, and infection of immune cells. Infection rates in most primary human immune cell types were low, with modest increases observed for some mAbs. In contrast, macrophages were more susceptible to SARS-CoV-2 and exhibited substantial ADE with select mAbs. ADE was completely inhibited by FcR blockade and significantly reduced by antibody- or ceftazidime-mediated blocking of angiotensin-converting enzyme 2 (ACE2). Neutralization potency did not correlate with ADE, as both strongly and weakly neutralizing antibodies induced enhancement. Instead, ADE magnitude depended on an antibody’s ability to block spike protein binding to ACE2. Importantly, ADE resulted in productive infection with release of infectious virus. Evaluation of antibodies against the BA.1 (Omicron) variant revealed reduced or lost ADE for most mAbs, with increased ADE observed for several mAbs relative to the USA-WA1/2020 strain.
Authors
Natalia A. Kuzmina, Sivakumar Periasamy, Kritika Kedarinath, Keziah Hernandez, Caroline Atyeo, S. Moses Dennison, Kan Li, Daniel Bedinger, Sharon L. Schendel, Georgia D. Tomaras, Hanif Ali, Galit Alter, Erica Ollmann Saphire, Alexander Bukreyev
Abstract
BACKGROUND The SARS-CoV-2 pandemic provided a rare opportunity to study how human immune responses develop to a novel viral antigen delivered through different vaccine platforms. However, to date, no study has directly compared immune responses to all 3 FDA-approved COVID-19 vaccines at single-cell multiomic resolution.METHODS We longitudinally profiled SARS-CoV-2–naive adults (n = 31) vaccinated with BNT162b2, mRNA-1273, or Ad26.COV2.S, integrating plasma cytokines, antibody titers, and single-cell multiomic data (DOGMA-Seq).RESULTS We discovered a distinct, transient IFN program termed ISG-dim, which emerged specifically 1–2 days after the first mRNA dose in approximately 10% of myeloid cells. This state was characterized by ISGF3 complex activation and its target genes (e.g., MX1, MX2, DDX58), with transcriptional and epigenetic profiles distinct from the robust IFN program observed after mRNA boosting or a single Ad26.COV2.S dose (ISG-high). In vitro stimulation of human monocytes showed that IFN-α alone recapitulates ISG-dim, whereas both IFN-α and IFN-γ are required for ISG-high.CONCLUSION These findings define dose-dependent IFN programming in human myeloid cells and highlight mechanistic differences between priming and boosting, with implications for optimizing vaccine platform choice, dose scheduling, and formulation.FUNDING NIH grants AI142086, U19 AI135972, U01 AI165452, U01 AI165452, R01 AI160706, and P30 AG067988.
Authors
Giray Eryilmaz, Yilmaz Yucehan Yazici, Radu Marches, Eleni P. Mimitou, Lisa Kenyon-Pesce, Kim Handrejk, Sonia Jangra, Michael Schotsaert, Adolfo García-Sastre, George A. Kuchel, Jacques Banchereau, Duygu Ucar
Abstract
We previously demonstrated that blocking TGF-β with galunisertib, a safe, orally available small drug, reactivated latent SIV in vivo by shifting T cells toward a transitional effector phenotype. Here, we investigated the mechanisms underlying this effect using single-cell RNA sequencing, metabolic profiling, and high-dimensional spectral flow cytometry of samples from SIV-infected, antiretroviral therapy–treated (ART-treated) macaques before and after galunisertib. To characterize virus-transcribing, infected cells during ART, we developed a novel, sensitive SIV Transcripts Capture Assay (SCAP) that detected 127 SIV-expressing cells within lymph node single-cell transcriptome libraries. Galunisertib drove broad metabolic reprogramming in CD4+ T cells, with transcriptional upregulation of inflammatory and mitochondrial biosynthesis pathways, confirmed by Seahorse profiling. Metabolomics revealed increased energy metabolites and amino acids and enhanced metabolic flux without proliferation. SIV transcript–positive cells before galunisertib were metabolically quiescent compared with cells without detectable viral transcripts. After galunisertib, virus-expressing cells showed a dramatic metabolic activation, with upregulation of glycolysis, fatty acid metabolism, and TNF-α signaling. High-dimensional flow cytometry demonstrated effects beyond CD4+ T cells, including fewer tissue-resident memory T cells, but more inflammatory macrophages. In conclusion, SCAP represents a specific tool for characterizing rare SIV-infected cells transcribing virus during ART, and it reveals TGF-β as a key mediator of viral latency in vivo through metabolic suppression.
Authors
Romaila Abd-El-Raouf, Jakob Harrison-Gleason, Jinhee Kim, Ching Man Wai, Kayla L. Yerlioglu, Catarina Ananias-Saez, Alec Ksiazek, Jeffrey T. Poomkudy, Mariluz Araínga, Deepanwita Bose, Claudia Cicala, James Arthos, Francois J. Villinger, Ramon Lorenzo-Redondo, Elena Martinelli
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