Article
Hematology
Gloria F. Gerber, Robert A. Brodsky
Summary: This article discusses the theoretical basis and clinical studies of using C3 inhibitors in the treatment of PNH, as well as provides suggestions for treatment sequencing.
Review
Immunology
Tom E. Mollnes, Benjamin S. Storm, Ole L. Brekke, Per H. Nilsson, John D. Lambris
Summary: The complement system, initially thought to protect the host from infection, has been shown to have numerous other functions and plays a major role in various diseases. Traditional reductionistic models of complement research are limited, and there is a need for holistic models that retain complement activity and allow for the study of interactions with other inflammatory systems. Two such models using anticoagulated whole blood are described here, which will be useful in further understanding complement-driven diseases.
SEMINARS IN IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Robin Schmitz, Zachary W. Fitch, Paul M. Schroder, Ashley Y. Choi, Miriam Manook, Janghoon Yoon, Mingqing Song, John S. Yi, Sanjay Khandelwal, Gowthami M. Arepally, Alton B. Farris, Edimara S. Reis, John D. Lambris, Jean Kwun, Stuart J. Knechtle
Summary: Inhibition of complement component C3 prolongs graft survival by reducing tissue injury and inhibiting T and B cell proliferation/activation. Despite high levels of donor-specific antibodies, Cp40 treatment in primates leads to normal kidney function in half of the treated animals beyond the treatment period.
NATURE COMMUNICATIONS
(2021)
Article
Biotechnology & Applied Microbiology
Cara West, Joel D. Federspiel, Kara Rogers, Arpana Khatri, Sheila Rao-Dayton, Mireia Fernandez Ocana, Sean Lim, Aaron Michael D'Antona, Sandra Casinghino, Suryanarayan Somanathan
Summary: Treatment of monogenetic disorders using AAV-based vectors is a popular research topic. This study examined the risk of complement activation in AAV-mediated gene therapies when sera from seropositive donors were exposed to AAV9 capsid. The findings showed that preexisting neutralizing antibodies activated complement, and this risk could be mitigated by immunosuppression strategies.
HUMAN GENE THERAPY
(2023)
Review
Immunology
Martin Kolev, Tara Barbour, Scott Baver, Cedric Francois, Pascal Deschatelets
Summary: C3 is a crucial complement protein involved in the immune response and dysregulation of this protein is linked to many diseases. The development of C3-targeted therapeutics has faced challenges due to its high concentration in blood and increased risk of infections. This review compares the mechanism of action of pegcetacoplan and eculizumab in paroxysmal nocturnal hemoglobinuria and discusses potential complement-mediated diseases that could be treated with C3 inhibition.
IMMUNOLOGICAL REVIEWS
(2023)
Review
Immunology
Tetsuhiro Kajikawa, Dimitrios C. Mastellos, Hatice Hasturk, Georgios A. Kotsakis, Despina Yancopoulou, John D. Lambris, George Hajishengallis
Summary: Periodontitis, if not properly treated, can lead to tooth loss and affect overall health. This review focuses on the potential use of a complement-targeting drug called AMY-101 in the treatment of periodontal disease and peri-implant inflammatory conditions.
SEMINARS IN IMMUNOLOGY
(2022)
Article
Clinical Neurology
Frauke Stascheit, Omar Chuquisana, Christian W. Keller, Philip Alexander Ambrose, Sarah Hoffmann, Catharina C. Gross, Sophie Lehnerer, Heinz Wiendl, Nick Willcox, Andreas Meisel, Jan D. Luenemann
Summary: In patients with AChR-Ab(+) MG, there is significantly increased activation of the complement system, which remains present even under standard immunosuppressive therapies but is not evident in patients with MuSK-Abs or seronegative MG. Further exploration of complement inhibition proximal to C5 cleavage is suggested for potential therapeutic benefits in AChR-Ab(+) MG.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Review
Immunology
Anqi Tang, Xin Zhao, Tian Tao, Dengpiao Xie, Bojun Xu, Youqun Huang, Mingquan Li
Summary: Anti-GBM disease is a rare but life-threatening autoimmune disorder. Complement activation plays a significant role in the pathogenesis of the disease, and certain complement factors are associated with the severity of renal injury and act as risk factors for renal outcomes. Patients with both ANCA and anti-GBM antibodies exhibit a unique clinical phenotype, suggesting that complement activation may be a bridge between these two diseases.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Cell Biology
Junping Li, Zhigang Zhu, Yuan Zhu, Jinqing Li, Kangbao Li, Weijie Zhong
Summary: The aberrant downregulation of C1qA is related to Rituximab resistance in DLBCL cells. METTL3 and YTHDF2 mediate the m6A methylation of C1qA mRNA in DLBCL cells, offering a potential strategy for inhibiting Rituximab resistance in DLBCL.
CELL DEATH DISCOVERY
(2023)
Article
Chemistry, Multidisciplinary
Huan Wang, Shiqi Lin, Songli Wang, Zhuxuan Jiang, Tianhao Ding, Xiaoli Wei, Ying Lu, Feng Yang, Changyou Zhan
Summary: In this study, folic acid-functionalized lipodiscs (FA-Disc) were successfully constructed to avoid opsonization by IgM and achieve folate targeting. FA-Disc retained folate binding activity and could effectively target folate receptor positive tumors in vivo. This study provides a solution to avoid negative regulation by IgM and achieve folate-enabled targeting by exploring disc-shaped nanocarriers.
Review
Immunology
Solaf Al-Awadhi, Marc Raynaud, Kevin Louis, Antoine Bouquegneau, Jean-Luc Taupin, Olivier Aubert, Alexandre Loupy, Carmen Lefaucheur
Summary: In this systematic review, meta-analysis, and critical appraisal, the impact of complement-activating anti-HLA DSAs on solid organ transplant outcomes was investigated. The study found that complement-activating anti-HLA DSAs were associated with an increased risk of allograft loss and rejection. These findings demonstrate the significant deleterious impact and independent prognostic value of circulating complement-activating anti-HLA DSAs.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Immunology
Corinne J. J. Smith, Nikki Ross, Ali Kamal, Kevin Y. Kim, Elizabeth Kropf, Pascal Deschatelets, Cedric Francois, William J. Quinn, Inderpal Singh, Anna Majowicz, Federico Mingozzi, Klaudia Kuranda
Summary: AAV gene transfer shows promise in treating genetic diseases, but the host immune response poses challenges. This study characterizes the innate immune response to AAV in human whole blood, finding that high levels of neutralizing antibodies can increase inflammation and vector uptake. Inhibiting the complement pathway may be a strategy for reducing immunogenicity in AAV-based therapies.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Courtney M. Barkoff, Shaker A. Mousa
Summary: COVID-19, caused by SARS-CoV-2, has led to over one million deaths worldwide. The complement system, a key part of the immune response, may also contribute to inflammation, tissue damage, and thrombosis in COVID-19 patients. This review discusses the potential impact of complement activation in COVID-19 and potential treatments targeting this system.
Article
Immunology
Lisanne de Vor, Coco R. R. Beudeker, Anne Flier, Lisette M. M. Scheepmaker, Piet C. C. Aerts, Daniel C. C. Vijlbrief, Mireille N. N. Bekker, Frank J. J. Beurskens, Kok P. M. van Kessel, Carla J. C. de Haas, Suzan H. M. Rooijakkers, Michiel van der Flier
Summary: Central line associated bloodstream infections (CLABSI) caused by Staphylococcus epidermidis are a significant morbidity factor in neonates. This study explores the use of monoclonal antibodies (mAbs) to induce phagocytic killing of S. epidermidis by human neutrophils. The researchers found that complement activation is crucial for efficient phagocytosis and that Fc mutations enhancing IgG1 hexamerization improve complement activation and phagocytic killing. In addition, the mAbs greatly enhanced phagocytosis of S. epidermidis in neonatal plasma conditions, indicating their potential as prophylactic agents for neonatal CLABSI.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Kathryn J. Brayer, Joshua A. Hanson, Shashank Cingam, Cathleen Martinez, Scott A. Ness, Ian Rabinowitz
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a poor prognosis cancer associated with alterations in the pancreas microbiome, including the presence of Malassezia. Up-regulation of immune- and inflammatory-related genes in PDAC suggests their involvement in tumor progression.
Review
Pharmacology & Pharmacy
Christina Lamers, Dimitrios C. Mastellos, Daniel Ricklin, John D. Lambris
Summary: This review discusses the importance of the complement system in the treatment of clinical conditions and the development of treatment methods, focusing on targeted therapy of C3 activation and highlighting the critical role of pegcetacoplan as a C3 inhibitor in treating complement diseases.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2022)
Article
Oncology
Sergio Ortiz-Espinosa, Xabier Morales, Yaiza Senent, Diego Alignani, Beatriz Tavira, Irati Macaya, Borja Ruiz, Haritz Moreno, Ana Remirez, Cristina Sainz, Alejandro Rodriguez-Pena, Alvaro Oyarbide, Mikel Ariz, Maria P. Andueza, Karmele Valencia, Alvaro Teijeira, Kai Hoehlig, Axel Vater, Barbara Rolfe, Trent M. Woodruff, Jose Maria Lopez-Picazo, Silvestre Vicent, Grazyna Kochan, David Escors, Ignacio Gil-Bazo, Jose Luis Perez-Gracia, Luis M. Montuenga, John D. Lambris, Carlos Ortiz de Solorzano, Fernando Lecanda, Daniel Ajona, Ruben Pio
Summary: This study reveals that C5a can enhance the capacity of PMN-MDSCs to promote tumor growth and metastasis by inducing the formation of NETs. The formation of NETs is dependent on the production of HMGB1 by cancer cells. Inhibiting C5a, C5aR1, or NETosis can reduce the number of circulating tumor cells and the metastatic burden in a mouse lung metastasis model. The translational relevance of these findings is supported by the stimulation of migration and NETosis in PMN-MDSCs obtained from lung cancer patients.
Review
Immunology
Tom E. Mollnes, Benjamin S. Storm, Ole L. Brekke, Per H. Nilsson, John D. Lambris
Summary: The complement system, initially thought to protect the host from infection, has been shown to have numerous other functions and plays a major role in various diseases. Traditional reductionistic models of complement research are limited, and there is a need for holistic models that retain complement activity and allow for the study of interactions with other inflammatory systems. Two such models using anticoagulated whole blood are described here, which will be useful in further understanding complement-driven diseases.
SEMINARS IN IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Ewelina Golec, Alexander Ekstrom, Maciej Noga, Muhmmad Omar-Hmeadi, Per-Eric Lund, Bruno O. Villoutreix, Ulrika Krus, Katarzyna Wozniak, Olle Korsgren, Erik Renstrom, Sebastian Barg, Ben C. King, Anna M. Blom
Summary: The study finds that splice variants of CD59 exist in human and mouse pancreatic islets. These variants are associated with insulin granules and insulin secretion. In type 2 diabetes patients, the expression of these variants is significantly reduced, which may contribute to insulin deficiency.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Panagiotis Skendros, Georgios Germanidis, Dimitrios C. Mastellos, Christina Antoniadou, Efstratios Gavriilidis, Georgios Kalopitas, Anna Samakidou, Angelos Liontos, Akrivi Chrysanthopoulou, Maria Ntinopoulou, Dionysios Kogias, Ioanna Karanika, Andreas Smyrlis, Dainora Cepaityte, Iliana Fotiadou, Nikoleta Zioga, Ioannis Mitroulis, Nikolaos K. Gatselis, Charalampos Papagoras, Simeon Metallidis, Haralampos Milionis, George N. Dalekos, Loek Willems, Barbro Persson, Vivek Anand Manivel, Bo Nilsson, E. Sander Connolly, Simona Iacobelli, Vasileios Papadopoulos, Rodrigo T. Calado, Markus Huber-Lang, Antonio M. Risitano, Despina Yancopoulou, Konstantinos Ritis, John D. Lambris
Summary: Complement C3 activation plays a role in the pathology of COVID-19, and targeting C3 has emerged as a promising therapeutic strategy. This study provides interim data from the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 patients. The results show that AMY-101 is safe and well tolerated, and it appears to have a potential benefit in reducing disease severity.
Article
Immunology
Hui Wang, Hidetaka Ideguchi, Tetsuhiro Kajikawa, Dimitrios C. Mastellos, John D. Lambris, George Hajishengallis
Summary: The complement and Th17 cells play crucial roles in periodontitis. Complement activation generates critical cytokines, including IL-6 and IL-23, which are necessary for the expansion of Th17 cells. Additionally, IL-6 is important for inflammation and bone loss in periodontitis.
JOURNAL OF IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Christina Lamers, Xiaoguang Xue, Martin Smiesko, Henri van Son, Bea Wagner, Nadja Berger, Georgia Sfyroera, Piet Gros, John D. Lambris, Daniel Ricklin
Summary: The authors provide molecular-level insight into the mode-of-action, target selectivity, and species specificity of the compstatin family of complement inhibitors, which entered the clinic in 2021.
NATURE COMMUNICATIONS
(2022)
Review
Hematology
Christina Lamers, Daniel Ricklin, John D. Lambris
Summary: The number of complement inhibitors approved for therapeutic use or in late-stage clinical trials has expanded rapidly in recent years. The sudden emergence of this area in biotech start-ups and pharmaceutical companies is surprising considering the well-established involvement of the complement system in various clinical conditions. However, the complement system has unique characteristics that have delayed its recognition as a traditional drug target, such as concerns about safety and the complexity of its involvement in biological processes.
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Article
Cell Biology
Amelie Kuhn, Jana Riegger, Graciosa Q. Teixeira, Markus Huber-Lang, John D. Lambris, Cornelia Neidlinger-Wilke, Rolf E. Brenner
Summary: Terminal complement complex deposition was found in human degenerated discs. The study investigated the mechanisms and effects of terminal complement activation in annulus fibrosus (AF) cells. Complement inhibitors effectively suppressed anaphylatoxin generation and TCC deposition induced by zymosan. Gene expression of ADAMTS4, MMP1, and COX2 was influenced by C3 and C5 blockade. Degenerated endplate tissue secreted soluble factors that enhanced direct C5 cleavage. These findings suggest the functional involvement of terminal complement activation in disc degeneration and the role of degenerated tissue in complement activation.
Article
Immunology
Michael S. Diamond, John D. Lambris, Jenny P. Ting, John S. Tsang
Summary: In early 2022, a workshop focusing on the innate immune response to SARS-CoV-2 was organized by staff from the NIAID at the NIH. This Viewpoint article features the thoughts of organizers and invited speakers on the key outcomes of the meeting. While the media has mainly focused on adaptive immunity during the COVID-19 pandemic, immunologists have been trying to understand how SARS-CoV-2 infection affects our innate immune system.
NATURE REVIEWS IMMUNOLOGY
(2022)
Article
Endocrinology & Metabolism
Tegehall Angie, Ingvast Sofie, Melhus Asa, Skog Oskar, Korsgren Olle
Summary: This study reveals the development of acute inflammation in rats after instillation of heat-inactivated bacteria in the ductal compartment of the pancreas. Although the inflammation subsided after three weeks, a subset of rats exhibited accumulation of T cells around the affected islets, resembling the insulitis seen in human T1D. These findings highlight the interplay between innate and acquired immunity in the pathogenesis of T1D.
ACTA DIABETOLOGICA
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
Ole-Lars Brekke, Joost Grond, Anne Landsem, Dorte Christiansen, Judith Krey Ludviksen, Corinna Lau, Trent M. Woodruff, John Lambris, Terje Espevik, Tom Eirik Mollnes
MOLECULAR IMMUNOLOGY
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
Christina Lamers, Martin Smiesko, Xiaoguang Xue, H. Van Son, Bea Wagner, G. Sfyroera, Nadja Berger, Piet Gros, John D. Lambris, Daniel Ricklin
MOLECULAR IMMUNOLOGY
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
Richard Pouw, Joyce de Paula Souza, Jonas Kost, Said Rabbani, John Lambris, Daniel Ricklin
MOLECULAR IMMUNOLOGY
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
Ekaterina Umnyakova, Clement Bechtler, Richard Pouw, John Lambris, Daniel Ricklin
MOLECULAR IMMUNOLOGY
(2022)
