Issue published May 1, 2025 Previous issue
- Volume 135, Issue 9
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On the cover: Improving cryopreservation of umbilical cord blood
Huang, Xie, Liu, Zheng et al. report that cryopreservation induces mitochondrial dysfunction in umbilical cord blood-derived hematopoietic stem and progenitor cells that adversely affects reconstitution. The cover art depicts the impact of cryopreservation on hematopoietic cells derived from umbilical cord blood and the mitigating effect of sulforaphane on their regenerative capacity. Image credit: Wenxi Ye.
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Letter to the Editor
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Abstract
Authors
Abdullah H. Alfalah, Alfadil Haroon, Ahmed Alfares, Syed Osman Ahmed, Sateesh Maddirevula
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Review Series
Ravikumar Aalinkeel, … , Richard J. Quigg, Jessy Alexander Published May 1, 2025
Citation Information: J Clin Invest. 2025;135(9):e188351. https://doi.org/10.1172/JCI188351.
×Abstract
Kidney cancer poses unique clinical challenges because of its resistance to conventional treatments and its tendency to metastasize. The kidney is particularly susceptible to dysfunction of the complement system, an immune network that tumors often exploit. Recent discoveries have highlighted that the complement system not only plays a crucial role in immune surveillance and defense in the circulatory system, but also functions intracellularly and autonomously. This concept has shifted the focus of investigation toward understanding how complement proteins influence cancer progression by regulating the tumor microenvironment (TME), cell signaling, proliferation, metabolism, and the immune response. With the complement system and its inhibitors emerging as a promising new class of immunotherapeutics and potential complement-targeted treatments advancing through development pipelines and clinical trials, this Review provides a timely examination of how harnessing the complement system could lead to effective tumor treatments and how to strategically combine complement inhibitors with other cancer treatments, offering renewed hope in the fight against kidney cancer.
Authors
Ravikumar Aalinkeel, Richard J. Quigg, Jessy Alexander
Sarah A. Thomas, Stephane Lajoie Published May 1, 2025
Citation Information: J Clin Invest. 2025;135(9):e188352. https://doi.org/10.1172/JCI188352.
×Abstract
Type 2 (Th2) allergic diseases are chronic conditions characterized by a Th2-polarized immune response to allergens. These diseases can be categorized by affected barrier sites: skin (atopic dermatitis, allergic contact dermatitis), gut (food allergy), and respiratory tract (e.g., asthma, chronic rhinosinusitis). The global prevalence of Th2 allergic diseases has increased the need for a deeper understanding of their pathophysiology. Several associations have been identified between genetic variants in the genes encoding components of the complement system and allergic disease. Moreover, levels of several complement proteins are elevated in patients with allergy. Experimental evidence demonstrates that the complement system plays a critical role in the development of these diseases across barrier sites. While site-specific differences exist in the complement components involved, key pathways, particularly C3 and C5, are prominent across the skin, gut, and lung.
Authors
Sarah A. Thomas, Stephane Lajoie
×Abstract
Reduced kidney function is associated with increased risk of cardiovascular disease in addition to kidney disease progression. Kidney disease is considered an inflammatory state, based on elevated levels of C-reactive protein and inflammatory cytokines. A key mediator of cardiovascular and kidney disease progression in the setting of reduced kidney function is systemic and vascular inflammation. However, the exact pathways that link chronic kidney disease (CKD) with inflammation remain incompletely understood. For decades it has been known that factor D, the main activator of the alternative complement pathway, is increased in the plasma of patients with reduced kidney function. Recent biomarker evidence suggests alternative pathway activation in this setting. CKD, therefore, seems to alter the balance of alternative pathway proteins, promoting inflammation and potentially exacerbating complement-mediated diseases and CKD-associated complications. In this manuscript, we review the impact of reduced kidney function on biomarkers of the alternative complement pathway and the implications of alternative pathway activation on cardiovascular disease and kidney disease progression. Importantly, we highlight the need for ongoing research efforts that may lead to opportunities to target the alternative pathway of complement withx the goal of improving kidney and cardiovascular outcomes in persons with reduced kidney function.
Authors
Diana I. Jalal, Joshua M. Thurman, Richard J.H. Smith
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Initially identified as a regulator of complement activation on host cells, the known roles of CD46 (membrane cofactor protein [MCP]) have expanded. We now know that this ancient molecule is expressed on almost all nucleated cells as a family of four predominant isoforms. It also is involved in human reproduction, modulation of T cell activation and immunoinflammatory effector functions, autophagy, and the newly identified intracellular complement system (complosome). CD46 is also known as a “pathogen” magnet, being a port of entry for at least seven bacteria and five viruses. Moreover, CD46 has recently emerged as a key player in cancer biology. Numerous studies provide evidence of the association among elevated CD46 expression, malignant transformation, and metastasizing potential. These features, along with its roles as pathogen receptor, have made CD46 a target for cancer therapeutics. Thus, modified viral vectors (such as strains of adenovirus and measles virus) targeting CD46 currently are being exploited against a wide range of cancers. Another oncologic treatment utilizes a CD46-targeting human mAb as an antibody-drug conjugate. Herein, we review CD46 and its “multiverse” of cancer interactions.
Authors
M. Kathryn Liszewski, John P. Atkinson
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Commentaries
David Collister, Adeera Levin Published May 1, 2025
Citation Information: J Clin Invest. 2025;135(9):e191907. https://doi.org/10.1172/JCI191907.
×Abstract
There are known sex (i.e., biological) and gender (i.e., social) differences in the epidemiology and outcomes of chronic kidney disease. In this issue of the JCI, van Eeghen et al. provide a prospective multicenter observational study of transgender individuals initiating masculinizing and feminizing hormone therapy. Testosterone and estrogen with testosterone blockade had differential effects on kidney physiology including renal plasma blood flow, measured glomerular filtration rate, tubular biomarkers, and various proteins involved in inflammatory and repair pathways. The findings suggest that estrogen is renoprotective and that testosterone may be harmful to kidney function, but requires validation in larger, more diverse cohorts. The insights gained also need to be examined in the context of both endogenous and exogenous sex hormones in individuals over the life cycle.
Authors
David Collister, Adeera Levin
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Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, are widely used in the treatment of metabolic disorders, including type 2 diabetes (T2D) and obesity. These medications primarily function by enhancing insulin secretion; however, emerging evidence suggests that the effects extend beyond metabolic regulation. In this issue of the JCI, Farokhnia et al. evaluated the effects of GLP-1RAs alongside another T2D treatment, dipeptidyl peptidase-4 inhibitors (DPP-4Is), on alcohol consumption in humans and preclinical models. In humans, GLP1-RAs, but not DPP-4Is, were associated with reductions in alcohol consumption. Similarly, DPP-4 inhibition had no effect on alcohol intake in rodents. These findings invite further exploration of the mechanisms by which GLP-1RAs reduce alcohol consumption and redefine our pharmacotherapy approach to alcohol use disorder (AUD) by opening the possibility for application as an early harm-reduction tool.
Authors
Gavin N. Petrie, Leah M. Mayo
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Research Letter
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Abstract
Authors
Tran Xuan Ngoc Huy, Huynh Tan Hop
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Research Articles
Payam Mohassel, … , Daniel B. Rifkin, Carsten G. Bönnemann Published May 1, 2025
Citation Information: J Clin Invest. 2025;135(9):e173354. https://doi.org/10.1172/JCI173354.
×Abstract
Collagen VI–related disorders (COL6-RDs) are a group of rare muscular dystrophies caused by pathogenic variants in collagen VI genes (COL6A1, COL6A2, and COL6A3). Collagen type VI is a heterotrimeric, microfibrillar component of the muscle extracellular matrix (ECM), predominantly secreted by resident fibroadipogenic precursor cells in skeletal muscle. The absence or mislocalization of collagen VI in the ECM underlies the noncell-autonomous dysfunction and dystrophic changes in skeletal muscle with a yet elusive direct mechanistic link between the ECM and myofiber dysfunction. Here, we conducted a comprehensive natural history and outcome study in a mouse model of COL6-RDs (Col6a2–/– mice) using standardized (TREAT-NMD) functional, histological, and physiological parameters. Notably, we identify a conspicuous dysregulation of the TGF-β pathway early in the disease process and propose that the collagen VI–deficient matrix is not capable of regulating the dynamic TGF-β bioavailability both at baseline and in response to muscle injury. Thus, we propose a new mechanism for pathogenesis of the disease that links the ECM regulation of TGF-β with downstream skeletal muscle abnormalities, paving the way for the development and validation of therapeutics that target this pathway.
Authors
Payam Mohassel, Hailey Hearn, Jachinta Rooney, Yaqun Zou, Kory Johnson, Gina Norato, Matthew A. Nalls, Pomi Yun, Tracy Ogata, Sarah Silverstein, David A. Sleboda, Thomas J. Roberts, Daniel B. Rifkin, Carsten G. Bönnemann
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BACKGROUND Lipogenesis contributes substantially to the pathological accumulation of intrahepatic triacylglycerol (IHTG) in metabolic dysfunction–associated steatotic liver disease (MASLD). Since hepatic lipogenesis is highly sensitive to energy intake, we hypothesized that mechanisms of MASLD regression induced by weight loss would be driven by a marked reduction in the lipogenic pathway.METHODS Overweight adults with high liver fat (HighLF; n = 9; IHTG ≥ 5.6% measured by 1H-magnetic resonance spectroscopy) or low (normal) liver fat (LowLF; n = 6; IHTG < 5.6%) received dietary counseling for 6 months and underwent comprehensive metabolic phenotyping during inpatient studies that captured fasting and fed states. Multiple stable isotopes were used to assess the contribution of lipogenesis, free fatty acids (FFAs), and dietary fat to IHTG.RESULTS Body weight loss (–10% ± 2%) reduced IHTG in individuals with MASLD (19.4% ± 3.6% to 4.5% ± 2.1%, P < 0.001). Insulin sensitivity improved significantly (46%, P < 0.01), while fasting FFA flux from adipose tissue was not different. VLDL-triacylglycerol (VLDL-TG) concentrations fell by 38% (P = 0.02) because of a 67% reduction in contribution from lipogenesis (P = 0.02), whereas the absolute contributions from FFAs and dietary fat to VLDL-TG were not different. Reduced lipogenesis was significantly associated with loss of IHTG.CONCLUSION These data underscore the primary role of lipogenesis in MASLD pathology and highlight the importance of controlling this pathway through treatment strategies.TRIAL REGISTRATION ClinicalTrials.gov (NCT01371396).FUNDING National Institutes of Health (NIH) grant RL1DK081187; Task Force for Obesity Research at Southwestern (TORS) NIH UL1DE019584; and Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences UL1-RR024982.
Authors
Jennifer E. Lambert, Maria A. Ramos-Roman, Maressa J. Valdez, Jeffrey D. Browning, Thomas Rogers, Elizabeth J. Parks
Ke Liao, … , Ahmed G.E. Ibrahim, Eduardo Marbán Published March 25, 2025
Citation Information: J Clin Invest. 2025;135(9):e179262. https://doi.org/10.1172/JCI179262.
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Regulatory T cells (Tregs) modulate immune responses and attenuate inflammation. Extracellular vesicles from human cardiosphere-derived cells (CDC-EVs) enhance Treg proliferation and IL-10 production, but the mechanisms remain unclear. Here, we focused on BCYRN1, a long noncoding RNA (lncRNA) highly abundant in CDC-EVs, and its role in Treg function. BCYRN1 acts as a “microRNA sponge,” inhibiting miR-138, miR-150, and miR-98. Suppression of these miRs leads to increased Treg proliferation via ATG7-dependent autophagy, CCR6-dependent Treg migration, and enhanced Treg IL-10 production. In a mouse model of myocardial infarction, CDC-EVs, particularly those overexpressing BCYRN1, were cardioprotective, reducing infarct size and troponin I levels even when administered after reperfusion. Underlying the cardioprotection, we verified that CDC-EVs overexpressing BCYRN1 increased cardiac Treg infiltration, proliferation, and IL-10 production in vivo. These salutary effects were negated when BCYRN1 levels were reduced in CDC-EVs or when Tregs were depleted systemically. Thus, we have identified BCYRN1 as a booster of Treg number and bioactivity, rationalizing its cardioprotective efficacy. While we studied BCYRN1 overexpression in the context of ischemic injury here, the same approach merits testing in other disease processes (e.g., autoimmunity or transplant rejection) where increased Treg activity is a recognized therapeutic goal.
Authors
Ke Liao, Jiayi Yu, Akbarshakh Akhmerov, Zahra Mohammadigoldar, Liang Li, Weixin Liu, Natasha Anders, Ahmed G.E. Ibrahim, Eduardo Marbán
Manuel A. Torres Acosta, … , Samuel E. Weinberg, Benjamin D. Singer Published March 18, 2025
Citation Information: J Clin Invest. 2025;135(9):e179572. https://doi.org/10.1172/JCI179572.
×Abstract
CD4+FOXP3+ Treg cells maintain self tolerance, suppress the immune response to cancer, and protect against tissue injury during acute inflammation. Treg cells require mitochondrial metabolism to function, but how Treg cells adapt their metabolic programs to optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis–maintaining enzyme AMPK to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. During viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking AMPK function to mitochondrial metabolism via DNA methylation. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.
Authors
Manuel A. Torres Acosta, Jonathan K. Gurkan, Qianli Liu, Nurbek Mambetsariev, Carla Reyes Flores, Kathryn A. Helmin, Anthony M. Joudi, Luisa Morales-Nebreda, Kathleen Cheng, Hiam Abdala-Valencia, Samuel E. Weinberg, Benjamin D. Singer
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Fibroblastic reticular cells (FRCs) are the master regulators of the lymph node (LN) microenvironment. However, the role of specific FRC subsets in controlling alloimmune responses remains to be studied. Single-cell RNA sequencing (scRNA-Seq) of naive and draining LNs (DLNs) of heart-transplanted mice and human LNs revealed a specific subset of CXCL12hi FRCs that expressed high levels of lymphotoxin-β receptor (LTβR) and are enriched in the expression of immunoregulatory genes. CXCL12hi FRCs had high expression of CCL19, CCL21, indoleamine 2,3-dioxygenase (IDO), IL-10, and TGF-β1. Adoptive transfer of ex vivo–expanded FRCs resulted in their homing to LNs and induced immunosuppressive environments in DLNs to promote heart allograft acceptance. Genetic deletion of LTβR and Cxcl12 in FRCs increased alloreactivity, abrogating the effect of costimulatory blockade in prolonging heart allograft survival. As compared with WT recipients, CXCL12+ FRC–deficient recipients exhibited increased differentiation of CD4+ T cells into Th1 cells. Nano delivery of CXCL12 to DLNs improved allograft survival in heart-transplanted mice. Our study highlights the importance of DLN CXCL12hi FRCs in promoting transplant tolerance.
Authors
Yuta Yamamura, Gianmarco Sabiu, Jing Zhao, Sungwook Jung, Andy J. Seelam, Xiaofei Li, Yang Song, Marina W. Shirkey, Lushen Li, Wenji Piao, Long Wu, Tianshu Zhang, Soyeon Ahn, Pilhan Kim, Vivek Kasinath, Jamil R. Azzi, Jonathan S. Bromberg, Reza Abdi
Sandy Peltier, … , Angelo D’Alessandro, Pascal Amireault Published March 11, 2025
Citation Information: J Clin Invest. 2025;135(9):e183099. https://doi.org/10.1172/JCI183099.
×Abstract
Although refrigerated storage slows the metabolism of volunteer donor RBCs, which is essential in transfusion medicine, cellular aging still occurs throughout this in vitro process. Storage-induced microerythrocytes (SMEs) are morphologically altered senescent RBCs that accumulate during storage and are cleared from circulation following transfusion. However, the molecular and cellular alterations that trigger clearance of this RBC subset remain to be identified. Using a staining protocol that sorts long-stored SMEs (i.e., CFSEhi) and morphologically normal RBCs (CFSElo), these in vitro aged cells were characterized. Metabolomics analysis identified depletion of energy, lipid-repair, and antioxidant metabolites in CFSEhi RBCs. By redox proteomics, irreversible protein oxidation primarily affected CFSEhi RBCs. By proteomics, 96 proteins, mostly in the proteostasis family, had relocated to CFSEhi RBC membranes. CFSEhi RBCs exhibited decreased proteasome activity and deformability; increased phosphatidylserine exposure, osmotic fragility, and endothelial cell adherence; and were cleared from the circulation during human spleen perfusion ex vivo. Conversely, molecular, cellular, and circulatory properties of long-stored CFSElo RBCs resembled those of short-stored RBCs. CFSEhi RBCs are morphologically and metabolically altered, have irreversibly oxidized and membrane-relocated proteins, and exhibit decreased proteasome activity. In vitro aging during storage selectively alters metabolism and proteostasis in these storage-induced senescent RBCs targeted for clearance.
Authors
Sandy Peltier, Mickaël Marin, Monika Dzieciatkowska, Michaël Dussiot, Micaela Kalani Roy, Johanna Bruce, Louise Leblanc, Youcef Hadjou, Sonia Georgeault, Aurélie Fricot, Camille Roussel, Daniel Stephenson, Madeleine Casimir, Abdoulaye Sissoko, François Paye, Safi Dokmak, Papa Alioune Ndour, Philippe Roingeard, Emilie-Fleur Gautier, Steven L. Spitalnik, Olivier Hermine, Pierre A. Buffet, Angelo D’Alessandro, Pascal Amireault
Yaojin Huang, … , Yingchi Zhang, Tao Cheng Published March 4, 2025
Citation Information: J Clin Invest. 2025;135(9):e183607. https://doi.org/10.1172/JCI183607.
×Abstract
Umbilical cord blood (UCB) plays substantial roles in hematopoietic stem cell (HSC) transplantation and regenerative medicine. UCB is usually cryopreserved for years before use. It remains unclear whether and how cryopreservation affects UCB function. We constructed a single-cell transcriptomics profile of CD34+ hematopoietic stem and progenitor cells (HSPCs) and mononuclear cells (MNCs) from fresh and cryopreserved UCB stored for 1, 5, 10, and 19 years. Compared with fresh UCB, cryopreserved HSCs and multipotent progenitors (MPPs) exhibited more active cell-cycle and lower expression levels of HSC and multipotent progenitor signature genes. Hematopoietic reconstitution of cryopreserved HSPCs gradually decreased during the first 5 years but stabilized thereafter, aligning with the negative correlation between clinical neutrophil engraftment and cryopreservation duration of UCB. Cryopreserved HSPCs also showed reduced megakaryocyte generation. In contrast, cryopreserved NK cells and T cells maintained a capacity for cytokine production and cytotoxicity comparable to that of fresh cells. Mechanistically, cryopreserved HSPCs exhibited elevated ROS, reduced ATP synthesis, and abnormal mitochondrial distribution, which collectively led to attenuated hematopoietic reconstitution. These effects could be ameliorated by sulforaphane (SF). Together, we elucidate the negative effect of cryopreservation on UCB HSPCs and identify SF as a mitigation strategy, broadening the temporal window and scope for clinical applications of cryopreserved UCB.
Authors
Yaojin Huang, Xiaowei Xie, Mengyao Liu, Yawen Zhang, Junye Yang, Wenling Yang, Yu Hu, Saibing Qi, Yahui Feng, Guojun Liu, Shihong Lu, Xuemei Peng, Jinhui Ye, Shihui Ma, Jiali Sun, Lu Wang, Linping Hu, Lin Wang, Xiaofan Zhu, Hui Cheng, Zimin Sun, Junren Chen, Fang Dong, Yingchi Zhang, Tao Cheng
×Abstract
BACKGROUND T cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disorder of cytotoxic T lymphocytes (CTLs), often with gain-of-function STAT3 mutations. T-LGLL represents a unique model for the study of persistent CTL expansions. Albeit autoimmunity is implied, various paradoxical observations led us to investigate whether immunodeficiency traits underpin T-LGLL.METHODS This is a comprehensive immunogenomic study of 92 consecutive patients from a large T-LGLL cohort with full laboratory-clinical characterization (n = 271). Whole-exome profiling of variants associated with inborn errors of immunity (IEI) and somatic mutations in T cell lymphoid drivers was analyzed. Single-cell RNA-Seq and TCR-Seq in T-LGLL samples and RNA-Seq in T cell cancer cell lines were utilized to establish biological correlations.RESULTS Lymphocytopenia and/or hypogammaglobulinemia were identified in 186 of 241 (77%) T-LGLL patients. Genetic screening for IEI revealed 43 rare heterozygous variants in 38 different immune genes in 34 of 92 (36%) patients (vs. 167/63,026 [0.26%] in controls). High-confidence deleterious variants associated with dominant, adult-onset IEIs were detected in 15 of 92 (16%) patients. Carriers showed atypical features otherwise tied to the cryptic IEI, such as earlier onset, lower lymphocyte counts, lower STAT3 mutational rate, and higher proportions of hypogammaglobulinemia and immune cytopenia/bone marrow failure than noncarriers. Somatic mutational landscape, RNA-Seq, and TCR-Seq analyses supported immune imbalance caused by the IEI variants and interactions with somatic mutations in T cell lymphoid drivers.CONCLUSIONS Our findings in T-LGLL reveal that maladaptive CTL expansions may stem from cryptic immunodeficiency traits and open the horizon of IEIs to clonal hematopoiesis and bone marrow failure.FUNDING NIH; Aplastic Anemia and MDS International Foundation; VeloSano; Edward P. Evans Foundation; Instituto de Salud Carlos III; European Research Council; European Research Area Network on Personalised Medicine; Academy Finland; Cancer Foundation Finland.
Authors
Carlos Bravo-Perez, Carmelo Gurnari, Jani Huuhtanen, Naomi Kawashima, Luca Guarnera, Aashray Mandala, Nakisha D. Williams, Christopher Haddad, Michaela Witt, Serhan Unlu, Zachary Brady, Olisaemeka Ogbue, Mark Orland, Arooj Ahmed, Yasuo Kubota, Simona Pagliuca, Arda Durmaz, Satu Mustjoki, Valeria Visconte, Jaroslaw P. Maciejewski
Farha Naz, … , Gregory R. Madden, William A. Petri Jr. Published March 6, 2025
Citation Information: J Clin Invest. 2025;135(9):e184659. https://doi.org/10.1172/JCI184659.
×Abstract
Clostridioides difficile infection (CDI) recurs in 1 of 5 patients. Monoclonal antibodies targeting the virulence factor TcdB reduce disease recurrence, suggesting that an inadequate anti-TcdB response to CDI leads to recurrence. In patients with CDI, we discovered that IL-33 measured at diagnosis predicts future recurrence, leading us to test the role of IL-33 signaling in the induction of humoral immunity during CDI. Using a mouse recurrence model, IL-33 was demonstrated to be integral for anti-TcdB antibody production. IL-33 acted via ST2+ ILC2 cells, facilitating germinal center T follicular helper (GC-Tfh) cell generation of antibodies. IL-33 protection from reinfection was antibody-dependent, as μMT KO mice and mice treated with anti-CD20 mAb were not protected. These findings demonstrate the critical role of IL-33 in generating humoral immunity to prevent recurrent CDI.
Authors
Farha Naz, Md Jashim Uddin, Nicholas Hagspiel, Mary K. Young, David Tyus, Rachel Boone, Audrey C. Brown, Girija Ramakrishnan, Isaura Rigo, Claire Fleming, Gregory R. Madden, William A. Petri Jr.
Hyesun Hyun, … , Jonathan S. Serody, Andrew Z. Wang Published March 11, 2025
Citation Information: J Clin Invest. 2025;135(9):e184964. https://doi.org/10.1172/JCI184964.
×Abstract
Biological targeting is crucial for effective cancer treatment with reduced toxicity but is limited by the availability of tumor surface markers. To overcome this, we developed a nanoparticle-based (NP-based), tumor-specific surface marker–independent (TRACER) targeting approach. Utilizing the unique biodistribution properties of NPs, we encapsulated Ac4ManNAz (Maz) to selectively label tumors with azide-reactive groups. Surprisingly, while NP-delivered Maz was cleared by the liver, it did not label macrophages, potentially reducing off-target effects. To exploit this tumor-specific labeling, we functionalized anti–4-1BB Abs with dibenzocyclooctyne to target azide-labeled tumor cells and activate the immune response. In syngeneic B16F10 melanoma and orthotopic 4T1 breast cancer models, TRACER enhanced the therapeutic efficacy of anti–4-1BB, increasing the median survival time. Immunofluorescence analyses revealed increased tumor infiltration of CD8+ T and NK cells with TRACER. Importantly, TRACER reduced the hepatotoxicity associated with anti–4-1BB, resulting in normal serum ALT and AST levels and decreased CD8+ T cell infiltration into the liver. Quantitative analysis confirmed a 4.5-fold higher tumor-to-liver ratio of anti–4-1BB accumulation with TRACER compared with conventional anti–4-1BB Abs. Our work provides a promising approach for developing targeted cancer therapies that circumvent limitations imposed by the paucity of tumor-specific markers, potentially improving efficacy and reducing off-target effects to overcome the liver toxicity associated with anti–4-1BB.
Authors
Hyesun Hyun, Bo Sun, Mostafa Yazdimamaghani, Albert Wielgus, Yue Wang, Stephanie Ann Montgomery, Tian Zhang, Jianjun Cheng, Jonathan S. Serody, Andrew Z. Wang
×Abstract
Osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) has been recognized as the principal mechanism underlying vascular calcification (VC). Runt-related transcription factor 2 (RUNX2) in VSMCs plays a pivotal role because it constitutes an osteogenic transcription factor essential for bone formation. As a key DNA demethylation enzyme, ten-eleven translocation 2 (TET2) is crucial in maintaining the VSMC phenotype. However, whether TET2 involves in VC progression remains elusive. Here we identified a substantial downregulation of TET2 in calcified human and mouse arteries, as well as human primary VSMCs. In vitro gain- and loss-of-function experiments demonstrated that TET2 regulated VC. Subsequently, in vivo knockdown of TET2 significantly exacerbated VC in both vitamin D3– and adenine diet–induced chronic kidney disease (CKD) mouse models. Mechanistically, TET2 bound to and suppressed activity of the P2 promoter within the RUNX2 gene; however, an enzymatic loss-of-function mutation of TET2 did not change its binding and suppressive effects. Furthermore, TET2 formed a complex with histone deacetylases 1/2 (HDAC1/2) to deacetylate H3K27ac on the P2 promoter, thereby inhibiting its transcription. Moreover, SNIP1 was indispensable for TET2 to interact with HDAC1/2 to exert an inhibitory effect on VC, and knockdown of SNIP1 accelerated VC in mice. Collectively, our findings imply that TET2 might serve as a potential therapeutic target for VC.
Authors
Dayu He, Jianshuai Ma, Ziting Zhou, Yanli Qi, Yaxin Lian, Feng Wang, Huiyong Yin, Huanji Zhang, Tingting Zhang, Hui Huang
Thierry Gauthier, … , Gloria H. Su, WanJun Chen Published March 11, 2025
Citation Information: J Clin Invest. 2025;135(9):e187063. https://doi.org/10.1172/JCI187063.
×Abstract
Phosphorylation of Smad3 is a critical mediator of TGF-β signaling, which plays an important role in regulating innate immune responses. However, whether Smad3 activation can be regulated in innate immune cells in TGF-β–independent contexts remains poorly understood. Here, we show that Smad3 is activated through the phosphorylation of its C-terminal residues (pSmad3C) in murine and human macrophages in response to bacterial and viral ligands, and this activation is mediated by activin A in a TGF-β–independent manner. Specifically, infectious ligands, such as LPS, induced secretion of activin A through the transcription factor STAT5 in macrophages, and activin A signaling in turn activated pSmad3C. This activin A/Smad3 axis controlled mitochondrial ATP production and ATP conversion into adenosine by CD73 in macrophages, enforcing an antiinflammatory mechanism. Consequently, mice with a deletion of activin A receptor 1b specifically in macrophages (Acvr1bfl/fl-Lyz2cre) succumbed more to sepsis as a result of uncontrolled inflammation and exhibited exacerbated skin disease in a mouse model of imiquimod-induced psoriasis. Thus, we have revealed a previously unrecognized natural brake to inflammation in macrophages that occurs through the activation of Smad3 in an activin A–dependent manner.
Authors
Thierry Gauthier, Yun-Ji Lim, Wenwen Jin, Na Liu, Liliana C. Patiño, Weiwei Chen, James Warren, Daniel Martin, Robert J. Morell, Gabriela Dveksler, Gloria H. Su, WanJun Chen
×Abstract
Postoperative atrial fibrillation (poAF) is AF occurring days after surgery, with a prevalence of 33% among patients undergoing open-heart surgery. The degree of postoperative inflammation correlates with poAF risk, but less is known about the cellular and molecular mechanisms driving postoperative atrial arrhythmogenesis. We performed single-cell RNA-seq comparing atrial nonmyocytes from mice with and without poAF, which revealed infiltrating CCR2+ macrophages to be the most altered cell type. Pseudotime trajectory analyses identified Il-6 as a gene of interest driving in macrophages, which we confirmed in pericardial fluid collected from human patients after cardiac surgery. Indeed, macrophage depletion and macrophage-specific Il6ra conditional knockout (cKO) prevented poAF in mice. Downstream STAT3 inhibition with TTI-101 and cardiomyocyte-specific Stat3 cKO rescued poAF, indicating a proarrhythmogenic role of STAT3 in poAF development. Confocal imaging in isolated atrial cardiomyocytes (ACMs) uncovered what we believe to be a novel link between STAT3 and CaMKII-mediated ryanodine receptor–2 (RyR2)-Ser(S)2814 phosphorylation. Indeed, nonphosphorylatable RyR2S2814A mice were protected from poAF, and CaMKII inhibition prevented arrhythmogenic Ca2+ mishandling in ACMs from mice with poAF. Altogether, we provide multiomic, biochemical, and functional evidence from mice and humans that IL-6-STAT3-CaMKII signaling driven by infiltrating atrial macrophages is a pivotal driver of poAF, which portends therapeutic utility for poAF prevention.
Authors
Joshua A. Keefe, Yuriana Aguilar-Sanchez, J. Alberto Navarro-Garcia, Isabelle Ong, Luge Li, Amelie Paasche, Issam Abu-Taha, Marcel A. Tekook, Florian Bruns, Shuai Zhao, Markus Kamler, Ying H. Shen, Mihail G. Chelu, Na Li, Dobromir Dobrev, Xander H.T. Wehrens
Mehdi Farokhnia, … , Christopher T. Rentsch, Lorenzo Leggio Published March 6, 2025
Citation Information: J Clin Invest. 2025;135(9):e188314. https://doi.org/10.1172/JCI188314.
×Abstract
BACKGROUND Despite growing preclinical evidence that glucagon-like peptide1 receptor agonists (GLP-1RAs) could be repurposed to treat alcohol use disorder (AUD), clinical evidence is scarce. Additionally, the potential impact of dipeptidyl peptidase-4 inhibitors (DPP-4Is) on alcohol intake is largely unknown.METHODS We conducted a large cohort study using 2008–2023 electronic health records data from the U.S. Department of Veterans Affairs. Changes in Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores were compared between propensity-score–matched GLP-1RA recipients, DPP-4I recipients, and unexposed comparators. We further tested the effects of 2 DPP-4Is, linagliptin and omarigliptin, on binge-like alcohol drinking in mice and operant oral alcohol self administration in alcohol-dependent rats, models previously used to show a significant effect of the GLP-1RA semaglutide in reducing alcohol intake.RESULTS GLP-1RA recipients reported a greater reduction in AUDIT-C scores than unexposed individuals (difference-in-difference [DiD]: 0.09 [95% CI: 0.03, 0.14], P = 0.0025) and DPP-4I recipients (DiD: 0.11 [95% CI: 0.05,0.17], P = 0.0002). Reductions in drinking were more pronounced among individuals with baseline AUD (GLP-1RA versus unexposed: 0.51 [95% CI: 0.29,0.72], P < 0.0001; GLP-1RA versus DPP-4I: 0.65 [95% CI: 0.43,0.88], P < 0.0001) and baseline hazardous drinking (GLP-1RA versus unexposed: 1.38 [95% CI: 1.07,1.69], P < 0.0001; GLP-1RA versus DPP-4I: 1.00 [95% CI: 0.68,1.33], P < 0.0001). There were no differences between DPP-4I recipients and unexposed individuals. The latter results were confirmed via a reverse translational approach. Specifically, neither linagliptin nor omarigliptin reduced alcohol drinking in mice or rats. The rodent experiments also confirmed target engagemhent, as both DPP-4Is reduced blood glucose levels.CONCLUSION Convergent findings across humans, mice, and rats indicated that GLP-1RAs, but not DPP-4Is, reduce alcohol consumption and may be efficacious in treating AUD.FUNDING This work was supported by the National Institutes of Health Intramural Research Program (ZIA DA000635, ZIA DA000644, ZIA DA000602), National Institute on Alcohol Abuse and Alcoholism extramural funding (R01 AA030041, P01 AA029545, U01 AA026224, U24 AA020794, U01 AA020790, U10 AA013566), the U.S. Department of Veterans Affairs (I01BX004820), and an Alkermes Pathways Research Award.
Authors
Mehdi Farokhnia, John Tazare, Claire L. Pince, Nicolaus Bruns VI, Joshua C. Gray, Vincent Lo Re III, David A. Fiellin, Henry R. Kranzler, George F. Koob, Amy C. Justice, Leandro F. Vendruscolo, Christopher T. Rentsch, Lorenzo Leggio
Mary Grace Katusiime, … , Maud Mavigner, Mary F. Kearney Published March 6, 2025
Citation Information: J Clin Invest. 2025;135(9):e188533. https://doi.org/10.1172/JCI188533.
×Abstract
BACKGROUND Naive cells comprise 90% of the CD4+ T cell population in neonates and exhibit distinct age-specific capacities for proliferation and activation. We hypothesized that HIV-infected naive CD4+ T cell populations in children on long-term antiretroviral therapy (ART) would thus be distinct from infected memory cells.METHODS Peripheral blood naive and memory CD4+ T cells from 8 children with perinatal HIV on ART initiated at age 1.7–17 months were isolated by FACS. DNA was extracted from sorted cells, and HIV proviruses were counted, evaluated for intactness, and subjected to integration site analysis (ISA).RESULTS Naive CD4+ T cells containing HIV proviruses were detected in children with 95% statistical confidence. A median 4.7% of long terminal repeat–containing naive CD4+ T cells also contained HIV genetic elements consistent with intactness. Full-length proviral sequencing confirmed intactness of 1 provirus. In the participant with the greatest degree of naive cell infection, ISA revealed infected expanded cell clones in both naive and memory T cells, with no common HIV integration sites detected between subsets. Divergent integration site profiles reflected differential gene expression patterns of naive and memory T cells.CONCLUSION These results demonstrate that HIV persisted in both naive and memory CD4+ T cells that underwent clonal expansion and harbored intact proviruses, and suggest that infected memory T cell clones do not frequently arise from naive cell differentiation in children with perinatal HIV on long-term ART.FUNDING Center for Cancer Research, NCI; Office of AIDS Research; NCI FLEX; Children’s and Emory Junior Faculty Focused Award.
Authors
Mary Grace Katusiime, Victoria Neer, Shuang Guo, Sean C. Patro, Wenjie Wang, Brian Luke, Adam A. Capoferri, Xiaolin Wu, Anna M. Horner, Jason W. Rausch, Ann Chahroudi, Maud Mavigner, Mary F. Kearney
Apabrita Ayan Das, … , Taylor A. Covington, Thomas Michel Published March 18, 2025
Citation Information: J Clin Invest. 2025;135(9):e188743. https://doi.org/10.1172/JCI188743.
×Abstract
Aortic aneurysms are potentially fatal focal enlargements of the aortic lumen; the disease burden is increasing as the human population ages. Pathological oxidative stress is implicated in the development of aortic aneurysms. We pursued a chemogenetic approach to create an animal model of aortic aneurysm formation using a transgenic mouse line, DAAO-TGTie2, that expresses yeast d-amino acid oxidase (DAAO) under control of the endothelial Tie2 promoter. In DAAO-TGTie2 mice, DAAO generated the ROS hydrogen peroxide (H2O2) in endothelial cells only when provided with d-amino acids. When DAAO-TGTie2 mice were chronically fed d-alanine, the animals became hypertensive and developed abdominal, but not thoracic, aortic aneurysms. Generation of H2O2 in the endothelium led to oxidative stress throughout the vascular wall. Proteomics analyses indicated that the oxidant-modulated protein kinase JNK1 was dephosphorylated by the phosphoprotein phosphatase DUSP3 (dual specificity phosphatase 3) in abdominal, but not thoracic, aorta, causing activation of Kruppel-like Factor 4 (KLF4)-dependent transcriptional pathways that triggered phenotypic switching and aneurysm formation. Pharmacological DUSP3 inhibition completely blocked the aneurysm formation caused by chemogenetic oxidative stress. These studies establish that regional differences in oxidant-modulated signaling pathways lead to differential disease progression in discrete vascular beds and identify DUSP3 as a potential pharmacological target for the treatment of aortic aneurysms.
Authors
Apabrita Ayan Das, Markus Waldeck-Weiermair, Shambhu Yadav, Fotios Spyropoulos, Arvind Pandey, Tanoy Dutta, Taylor A. Covington, Thomas Michel
×Abstract
BACKGROUND Men with chronic kidney disease (CKD) experience faster kidney function decline than women. Studies in individuals undergoing sex hormone therapy suggest a role for sex hormones, as estimated glomerular filtration rate (eGFR) increases with feminizing therapy and decreases with masculinizing therapy. However, effects on measured GFR (mGFR), glomerular and tubular function, and involved molecular mechanisms remain unexplored.METHODS This prospective, observational study included individuals initiating feminizing (estradiol and antiandrogens; n = 23) or masculinizing (testosterone; n = 21) therapy. Baseline and 3-month assessments included mGFR (iohexol clearance), kidney perfusion (para-aminohippuric acid clearance), tubular injury biomarkers, and plasma proteomics.RESULTS During feminizing therapy, mGFR and kidney perfusion increased (+3.6% and +9.1%, respectively; P < 0.05) without increased glomerular pressure. Tubular injury biomarkers, including urine neutrophil gelatinase-associated lipocalin, epidermal growth factor (EGF), monocyte chemoattractant protein-1, and chitinase 3-like protein 1 (YKL-40), decreased significantly (–53%, –42%, –45%, and –58%, respectively). During masculinizing therapy, mGFR and kidney perfusion remained unchanged, but urine YKL-40 and plasma tumor necrosis factor receptor 1 (TNFR-1) increased (+134% and +8%, respectively; P < 0.05). Proteomic analysis revealed differential expression of 49 proteins during feminizing and 356 proteins during masculinizing therapy. Many kidney-protective proteins were positively associated with estradiol and negatively associated with testosterone, including proteins involved in endothelial function (SFRP4, SOD3), inflammation reduction (TSG-6), and maintaining kidney tissue structure (agrin).CONCLUSION Sex hormones influence kidney physiology, with estradiol showing protective effects on glomerular and tubular function, while testosterone predominantly exerts opposing effects. These findings emphasize the role of sex hormones in sexual dimorphism observed in kidney function and physiology and suggest new approaches for sex-specific precision medicine.TRIAL REGISTRATION Dutch Trial Register (ID: NL9517); ClinicalTrials.gov (ID: NCT04482920).
Authors
Sarah A. van Eeghen, Laura Pyle, Phoom Narongkiatikhun, Ye Ji Choi, Wassim Obeid, Chirag R. Parikh, Taryn G. Vosters, Irene G.M. van Valkengoed, Merle M. Krebber, Daan J. Touw, Martin den Heijer, Petter Bjornstad, Daniël H. van Raalte, Natalie J. Nokoff
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Abstract
Background: Tebentafusp is the first T-cell receptor-based bispecific protein approved for clinical use in HLA-A*02:01+ adult patients with unresectable/metastatic uveal melanoma. It redirects T-cells toward gp100-expressing target cells, frequently inducing skin-related early adverse events. Methods: This study investigated immunological and cellular responses using single-cell and spatial analysis of skin biopsies from patients with metastatic uveal melanoma treated with tebentafusp. Results: 81.8% of patients developed acute cutaneous adverse events, which correlated with improved survival. Multimodal analysis revealed a brisk infiltration of CD4+ and CD8+ T-cells, while melanocyte numbers declined. Single-cell RNA-sequencing revealed T-cell activation, proliferation, and IFN-γ/cytotoxic gene upregulation. CD8+ T-cells co-localized with melanocytes and upregulated LAG3, suggesting potential for combination therapies with tebentafusp. Melanocytes upregulated antigen presentation and apoptotic pathways, while pigmentation gene expression decreased. However, gp100 remained stably expressed. Conclusion: Sequential skin biopsies enable in vivo pharmacodynamic modeling of tebentafusp, offering insights into immune activation, toxicity, and treatment response. Examining the on-target effects of bispecifics in tissues amenable to longitudinal sampling enhances our understanding of toxicity and therapeutic escape mechanisms, guiding strategies for treatment optimization.
Authors
Ramon Staeger, Aizhan Tastanova, Adhideb Ghosh, Nicola Winkelbeiner, Prachi Shukla, Isabel Kolm, Patrick Turko, Adel Benlahrech, Jane Harper, Anna Broomfield, Antonio Camera, Marianna Ambrosio, Veronika Haunerdinger, Phil F. Cheng, Egle Ramelyte, James P. Pham, Stefanie Kreutmair, Burkhard Becher, Mitchell P. Levesque, Reinhard Dummer, Barbara Meier-Schiesser
Abstract
The rapid viral rebound observed following treatment interruption, despite prolonged time on antiretroviral therapy with plasma HIV-RNA levels <40 copies/mL, suggests persistent HIV-1 reservoir(s) outside of the blood. Studies of HIV-1 proviruses in autopsy tissue samples have hinted at their persistence. However, their distribution across different anatomical compartments and their transcriptional activity within tissues remains unclear. The present study has examined molecular DNA and RNA reservoirs of HIV-1 in autopsy samples from 13 individuals with HIV-1 infection. Of the 13, 5 had detectable levels of HIV-1 RNA in plasma while 8 did not. Cell associated HIV-RNA was detected in 12 out of 13 donors and in 27 of the 30 different tissues examined. HIV-specific DNA and RNA were widely distributed and predominantly associated with clonal expansions. No significant differences were noted between the groups and no tissues were preferentially affected. These data imply that a substantial seeding of tissues with cells harboring transcriptionally active proviral DNA can be seen in the setting of HIV-1 infection despite ART and highlight one of the challenges in achieving an HIV-1 cure.
Authors
Hiromi Imamichi, Ven Natarajan, Francesca Scrimieri, Mindy Smith, Yunden Badralmaa, Marjorie Bosche, Jack M. Hensien, Thomas Buerkert, Weizhong Chang, Brad T. Sherman, Kanal Singh, H. Clifford Lane
Abstract
Stem-like T cells selectively contribute to autoimmunity, but the activities that promote their pathogenicity are incompletely understood. Here, we identify the transcription coregulator OCA-B as a driver of the pathogenic maturation of stem-like CD4+ T cell to promote autoimmune demyelination. Using two human multiple sclerosis (MS) datasets, we show that POU2AF1, the gene encoding OCA-B, is elevated in CD4+ T cells from MS patients. We show that T cell-intrinsic OCA-B loss protects mice from experimental autoimmune encephalomyelitis (EAE) while preserving responses to viral CNS infection. In EAE models driven by antigen reencounter, OCA-B deletion nearly eliminates CNS infiltration, proinflammatory cytokine production and clinical disease. OCA-B-expressing CD4+ T cells of mice primed with autoantigen express an encephalitogenic gene program and preferentially confer disease. In a relapsing-remitting EAE model, OCA-B loss protects mice specifically at relapse. During remission, OCA-B promotes the expression of Tcf7, Slamf6, and Sell in proliferating CNS T cell populations. At relapse timepoints, OCA-B loss results in both the accumulation of an immunomodulatory CD4+ T cell population expressing Ccr9 and Bach2, and loss of pro-inflammatory gene expression from Th17 cells. These results identify OCA-B as a driver of pathogenic CD4+ T cells.
Authors
Erik P. Hughes, Amber R. Syage, Elnaz Mirzaei Mehrabad, Thomas E. Lane, Benjamin T. Spike, Dean Tantin
Abstract
Synovial sarcoma is an aggressive soft tissue cancer driven by the chimeric SS18::SSX fusion oncoprotein, which disrupts chromatin remodeling by combining two antagonistic transcriptional regulators. SS18 participates in BAF complexes that open chromatin, while the SSX genes are cancer-testis antigens that interface with chromatin decorated with monoubiquitinated histone H2A placed by Polycomb repressive complexes (PRCs) activity. Because KDM2B brings PRC to unmethylated CpG islands, it is plausible that methylation directly determines the distribution of SS18::SSX to target loci. Given that synovial sarcoma is also characterized by a peculiarly low DNA hypomethylation profile, we hypothesized that further disturbance of DNA methylation would have a negative impact on synovial sarcoma growth. DNMT1 disruption by CRISPR/Cas9 targeting or pharmacologic inhibition with cytidine analogs 5-aza-2ʹ-deoxycytidine (decitabine) and 5-azacytidine led to decreased genome-wide methylation, redistribution of SS18::SSX, and altered gene expression profiles, most prominently including upregulation of tumor suppressor genes, immune-related genes, and mesenchymal differentiation-related genes. These drugs suppressed growth of synovial sarcoma cell lines and drove cytoreduction in mouse genetic models. DNMT1 inhibitors, already approved for treating myelodysplastic syndromes, warrant further clinical investigation for synovial sarcoma as repurposed, targeted treatments exploiting a vulnerability in the intrinsic biology of this cancer.
Authors
Nobuhiko Hasegawa, Nezha S. Benabdallah, Kyllie Smith-Fry, Li Li, Sarah McCollum, Jinxiu Li, Caelen A. Jones, Lena Wagner, Vineet Dalal, Viola Golde, Anastasija Pejkovska, Lara Carroll, Malay Haldar, Seth M. Pollack, Scott W. Lowe, Torsten O. Nielsen, Ana Banito, Kevin B. Jones
Abstract
The ATP6V0A4 gene encodes the a4 subunit of Vacuolar H+-ATPase (V-ATPase), which mediates hydrogen ion transport across the membrane. Previous studies have suggested that mutations in ATP6V0A4 consistently result in a loss of function (LOF), impairing the hydrogen ion transport efficacy of V-ATPase and leading to distal renal tubular acidosis (dRTA) and sensorineural hearing loss. Here, we identified a 32-year-old male patient and his father, both of whom harbored a heterozygous ATP6V0A4 p.V512L mutation, and both exhibited with hypochloremic metabolic alkalosis, acidic urine and hypokalemia. Through a series of protein structural analyses and functional experiments, the V512L mutation was confirmed as a gain-of-function (GOF) mutation in the ATP6V0A4 gene. V512-a4 increased a4 subunit expression abundance by enhancing V512L-a4 stability and reducing its degradation, which in turn potentiated V-ATPase's capacity to acidify the tubular lumen, leading to acidic urine and metabolic alkalosis. Through mutant V512L-a4 subunit structure-based virtual and experimental screening, we discovered F351 (C25H26FN3O2S), a small-molecule inhibitor specifically targeting the V512L-a4 mutant. In conclusion, we identify a GOF mutation in the ATP6V0A4 gene, broadening its phenotypic and mutational spectrum, and provide valuable insights into potential therapeutic approaches for diseases associated with ATP6V0A4 mutations.
Authors
Si-qi Peng, Qian-qian Wu, Wan-yi Wang, Yi-Lin Zhang, Rui-ning Zhou, Jun Liao, Jin-xuan Wei, Yan Yang, Wen Shi, Jun-lan Yang, Xiao-xu Wang, Zhi-yuan Wei, Jia-xuan Sun, Lu Huang, Hong Fan, Hui Cai, Cheng-kun Wang, Xin-hua Li, Ting-song Li, Bi-Cheng Liu, Xiao-liang Zhang, Bin Wang
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Series edited by Claudia Kemper
Complement Biology and Therapeutics
Series edited by Claudia Kemper
The complement system executes an evolutionarily ancient innate immune response with important roles in many human diseases, including a variety of conditions involving the kidney, autoimmune disorders, age-related macular degeneration, and more. This series of reviews, curated by Dr. Claudia Kemper, highlights the latest discoveries in complement biology and examines ongoing efforts to target complement therapeutically. From the relatively newly uncovered functions of intracellular complement (complosome) to the complexities involved in using animal models of complementopathies, these reviews convey the challenges of studying complement and developing complement-targeted therapeutics as well as call attention to recent findings that supply momentum to the field.
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ISSN: 0021-9738 (print), 1558-8238 (online)