Brief Definitive Report
Alzheimer’s disease–related γ-secretase is a prime drug target whose brain regional expression and distribution remain largely unknown. This study describes the development of a molecular imaging probe to reveal γ-secretase in rodents and macaques with translational potentials in humans.
Neutralizing anti–IFN-γ autoantibodies are the underlying immunodeficiency that explains the susceptibility to Talaromyces marneffei infections in otherwise healthy individuals in epidemic regions. This finding reveals the critical role of the IFN-γ pathway in controlling this dimorphic fungus.
A germline homozygous loss-of-function mutation in NUAK2 causes human fetal death due to anencephaly. Our functional tests establish that NUAK2, operating on the Hippo signaling axis, is an essential kinase that regulates cytoskeletal processes that govern cell shape during neural tube closure.
NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation
Biallelic mutations in NCKAP1L, a regulator of the actin cytoskeleton, cause immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Impaired immune synapse formation, early T cell activation and leading edge formation, and defective neutrophil migration characterize this novel “actinopathy.”
This study reveals profound alteration in biology of blood unconventional T cells (MAIT, iNKT, and γδT) in severe COVID-19. Highly activated MAIT cells are found in abundance in the airways of mechanically ventilated patients. Activation levels of MAIT/iNKT cells at admission positively correlate with clinical improvement.
Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19
Radermecker et al. report the presence of neutrophil extracellular traps (NETs) in fixed lung tissues from severe COVID-19 patients. NETs infiltrate the airway, interstitial, and vascular compartments, supporting the hypothesis that they may drive several aspects of COVID-19 lung pathology and represent therapeutic targets.
The knowledge of COVID-19 pathophysiology is pivotal for the discovery of effective treatments. Here, we described that SARS-CoV-2 triggers the release of ACE2-depended neutrophil extracellular traps (NETs) that mediate lung pathology, supporting the use of NETs inhibitors for COVID-19 treatment.
Interleukin-17–induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer
IL17 cross-talk with pancreatic cancer cells orchestrates neutrophil recruitment and activation of Padi4-dependent NETosis, resulting in immune spatial remodeling and immunosuppression reversal. IL17 genetic or pharmacological inhibition overcomes resistance to checkpoint blockade in a CD8+ T cell–dependent fashion.
A Fas-4-1BB immunomodulatory fusion protein converts a pro-death to a pro-survival signal, enhancing T cell function and improving the efficacy of adoptive T cell therapy in immunocompetent murine models of liquid and solid tumors.
IFN-I provide a rapid antiviral defense, but they limit antigen availability during priming. Here, the authors demonstrate that short-term IFN-I blockade after primary viral infection improves adaptive immunity and protection against reinfection. This “adjuvant” effect is generalizable to viral vaccines.
Intestinal barrier dysfunction is a marker of disease progression during chronic viral infections, but its causes remain mostly unknown. This study demonstrates essential roles for type I IFN signaling and CD8 T cell responses in increasing intestinal permeability during chronic viral infection.
Intracerebral hemorrhage (ICH) provokes brain edema and causes high mortality and disability. This study has identified brain-bound natural killer cells as a key contributor to brain edema and neurological deterioration after ICH.
The APOBEC mutation signature is abundant in cancer, but its relationship to the multistep process of carcinogenesis is unclear. Studies by Law and colleagues demonstrate that APOBEC3A catalyzes mutagenesis and promotes tumorigenesis in two different murine systems in vivo.
Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis
IgG4 autoantibodies in autoimmune myasthenia gravis are functionally monovalent, requiring a high-affinity threshold to reach pathogenic capacity. This capacity is dependent on self-antigen driven maturation, which includes the accumulation of indispensable somatic mutations that may alter electrostatic interactions with the antigen.
Israelow et al. show that AAV-mediated expression of human ACE2 allows for SARS-CoV-2 infection and disease investigation in mice. This pathology is in part driven by type I interferon signaling, which recruits inflammatory immune cells without aborting viral replication.
Technical Advances and Resources
A network of immune and microbial modifications underlies viral persistence in the gastrointestinal tract
Macleod et al. uncover how chronic viral infection modulates gastrointestinal immune and microbial composition to foster persistence and long-term disease susceptibilities. The authors also identify the central role of regulatory T cells to maintain viral sanctuary in the intestinal tract.
Multi-omic comparison of Alzheimer’s variants in human ESC–derived microglia reveals convergence at APOE
Liu et al. compare epigenetic and expression profiles in isogenic ESC-derived human microglia-like cells (hMGLs) comprising Alzheimer’s disease (AD)–associated mutations. Using this model, convergent dysregulation at the APOE locus is observed with AD-associated mutations in SORL1 and TREM2.