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doi: 10.1084/jem.20191536pmid: 31645368
Futch, Hunter S.; McFarland, Karen N.; Moore, Brenda D.; Kuhn, M. Zino; Giasson, Benoit I.; Ladd, Thomas B.; Scott, Karen A.; Shapiro, Melanie R.; Nosacka, Rachel L.; Goodwin, Marshall S.; Ran, Yong; Cruz, Pedro E.; Ryu, Daniel H.; Croft, Cara L.; Levites, Yona; Janus, Christopher; Chakrabarty, Paramita; Judge, Andrew R.; Brusko, Todd M.; Kloet, Annette D. de; Krause, Eric G.; Golde, Todd E.
doi: 10.1084/jem.20190430pmid: 31467037
<jats:p>Hypothalamic–pituitary–adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high-affinity monoclonal antibody, CTRND05, targeting corticotropin-releasing factor (CRF). In mice, CTRND05 blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis. CTRND05 induces skeletal muscle hypertrophy and increases lean body mass, effects not previously reported with small-molecule HPA-targeting pharmacologic agents. Multiorgan transcriptomics demonstrates broad HPA axis target engagement through altering levels of known HPA-responsive transcripts such as Fkbp5 and Myostatin and reveals novel HPA-responsive pathways such as the Apelin-Apelin receptor system. These studies demonstrate the therapeutic potential of CTRND05 as a suppressor of the HPA axis and serve as an exemplar of a potentially broader approach to target neuropeptides with immunotherapies, as both pharmacologic tools and novel therapeutics.</jats:p>
Stoler-Barak, Liat; Biram, Adi; Davidzohn, Natalia; Addadi, Yoseph; Golani, Ofra; Shulman, Ziv
doi: 10.1084/jem.20190789pmid: 31492809
<jats:p>Germinal centers (GCs) are sites wherein B cells proliferate and mutate their immunoglobulins in the dark zone (DZ), followed by affinity-based selection in the light zone (LZ). Here, we mapped the location of single B cells in the context of intact lymph nodes (LNs) throughout the GC response, and examined the role of BCR affinity in dictating their position. Imaging of entire GC structures and proximal single cells by light-sheet fluorescence microscopy revealed that individual B cells that previously expressed AID are located within the LN cortex, in an area close to the GC LZ. Using in situ photoactivation, we demonstrated that B cells migrate from the LZ toward the GC outskirts, while DZ B cells are confined to the GC. B cells expressing very-low-affinity BCRs formed GCs but were unable to efficiently disperse within the follicles. Our findings reveal that BCR affinity regulates B cell positioning during the GC response.</jats:p>
Shi, Yang; Manis, Melissa; Long, Justin; Wang, Kairuo; Sullivan, Patrick M.; Serrano, Javier Remolina; Hoyle, Rosa; Holtzman, David M.
doi: 10.1084/jem.20190980pmid: 31601677
<jats:p>Chronic activation of brain innate immunity is a prominent feature of Alzheimer’s disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of ptau pathology is also driven by microglia. In addition, we found that APOE, the strongest genetic risk factor for AD, regulates neurodegeneration predominantly by modulating microglial activation, although a minor role of apoE in regulating ptau and insoluble tau formation independent of its immunomodulatory function was also identified. Our results suggest that therapeutic strategies targeting microglia may represent an effective approach to prevent disease progression in the setting of tauopathy.</jats:p>
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