Commentary
Abstract
IgE-mediated activation of mast cells is a hallmark of an anaphylactic reaction to allergen. In this issue of the JCI, Duan et al. describe an approach for suppressing IgE-dependent mast cell activation, thereby suppressing anaphylaxis. Specifically, the authors show that delivery of liposomes containing both the specific antigen recognized by the mast cell–bound IgE and a high-affinity glycan ligand of the inhibitory receptor CD33 (CD33L) to targeted mast cells inhibits antigen-induced, FcεRI-dependent spleen tyrosine kinase (Syk) phosphorylation and downstream protein tyrosine kinase (PTK) phosphorylation, Ca++ flux, and β-hexosaminidase release (i.e., degranulation). However, this strategy only worked if both the antigen (reactive with the mast cell–bound IgE) and CD33L were on the same liposome. This approach promises to rapidly reduce IgE-dependent mast cell activation in response to challenge with offending allergens.
Authors
Stephen J. Galli
Abstract
Despite advances in understanding systemic lupus erythematosus (SLE) pathogenesis, most clinical trials of new targeted therapies have been met with disappointment. The type I IFN pathway is believed to play an important role in SLE, and the proposed involvement of this pathway helps explain the frustration behind the failure at targeting either IFN-α or the type 1 IFN receptor itself. In this issue of the JCI, Furie et al. report on an intriguing phase 1b study that demonstrates an approach for inhibiting this pathway in the skin using an mAB (BIIB059) that targets the blood DC antigen 2 (BDCA-2) receptor on plasmacytoid DCs (pDCs). BIIB059 decreased IFN expression and improved cutaneous lupus disease activity, with a favorable safety profile. Whether or not this strategy will be effective in managing SLE in other organs remains unanswered. However, these results suggest that closing the door on targeting the type 1 IFN pathway in SLE may be premature and highlight the emerging question of whether an organ-specific approach toward lupus trials and treatment should be the wave of the future.
Authors
Yashaar Chaichian, Daniel J. Wallace, Michael H. Weisman
Abstract
Vascular smooth muscle cell (VSMC) phenotype switching from a contractile state to a synthetic phenotype has been implicated in intimal remodeling during vascular injury. While multiple studies have focused on dedifferentiation of VSMCs, prevention of VSMC-mediated excessive repair remains poorly understood. In this issue of the JCI, Zeng et al. identified a mechanism by which platelet-derived microRNA-223 (miRNA-223) reverses VSMC dedifferentiation. The authors show that suppression of proliferation occurs after platelet internalization by VSMCs. Moreover, they demonstrate that miRNA-223 inhibits dedifferentiation and intimal hyperplasia in diabetic mice by decreasing PDGFRβ expression in VSMCs. Together, these results identify platelet-derived miRNA-223 as a potential therapeutic target in vascular injury.
Authors
Elena V. Dolmatova, Kathy K. Griendling
Abstract
A variety of neurological procedures, including deep brain stimulation and craniotomies that require tissue removal near elegant cortices, require patients to remain awake and responsive in order to monitor function. Such procedures can produce anxiety and are poorly tolerated in some subjects. In this issue of the JCI, Bijanki and colleagues demonstrate that electrical stimulation of the left dorsal anterior cingulum bundle promoted a positive (mirthful) effect and reduced anxiety, without sedation, in three patients with epilepsy undergoing intracranial electrode monitoring. The results of this study highlight the need for further evaluation of anterior cingulum stimulation to reduce anxiety during awake surgery and as a possible approach for treating anxiety disorders.
Authors
Kelly A. Mills
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia, and its pathogenesis is initiated by the accumulation of amyloid-β (Aβ) into extracellular plaques. Apolipoprotein E4 (ApoE4) is the largest genetic risk factor for sporadic AD and contributes to AD pathogenesis by influencing clearance and seeding of the initial aggregation of Aβ. In this issue of the JCI, Tachibana et al. investigated the relationship between neuronal LRP1 expression and ApoE4-mediated seeding of Aβ and showed that knockout of neuronal LRP1 prevents the increase in Aβ pathology caused by ApoE4 expression. These findings give insight into potential therapeutic targets for the preclinical phase of AD and the pathogenesis of Aβ pathology.
Authors
Michael R. Strickland, David M. Holtzman
Abstract
Effector T cell responses directed toward cancer neoantigens mediate tumor regression following checkpoint blockade or adoptive T cell immunotherapy, but are generally “private”, thus requiring considerable effort for their identification. In this issue of the JCI, Malekzadeh et al. show that a fraction of patients with epithelial cancers mount antigen-specific T cell responses to “hot spot” p53 mutations that in some cases are shared among patients. This work suggests that other genes frequently mutated in human cancer can be immunogenic, thus offering a rapid way to screen for cancer neoantigens that can be targeted by subsequent T cell–based therapies.
Authors
Enrico Lugli, Pia Kvistborg, Giovanni Galletti
Abstract
Primary antibody deficiencies are the most common immunodeficiencies in humans; however, identification of the underlying genetic and biochemical basis for these diseases is often difficult, given that these deficiencies typically involve complex genetic etiologies. In this issue of the JCI, Bouafia et al. performed whole-exome sequencing on a pair of siblings with primary antibody deficiencies and identified genetic mutations that result in a deficiency of ARHGEF1, a hematopoietic intracellular signaling molecule that transmits signals from GPCRs. ARHGEF1-deficient lymphocytes from the affected siblings exhibited important functional deficits that indicate that loss of ARHGEF1 accounts for the observed primary antibody deficiency, which manifests in an inability to mount antibody responses to vaccines and pathogens. Thus, this report demonstrates an important role for ARHGEF1 in GPCR signal transduction required for appropriate adaptive immune responses in humans.
Authors
Divij Mathew, Kimberly N. Kremer, Raul M. Torres
Abstract
The heart relies on mitochondria-derived energy production for continuous contraction and relaxation; therefore, the maintenance of a pool of healthy mitochondria is essential for sustaining normal cardiac performance. Mitophagy serves as a critical process for maintaining mitochondrial quality control and involves the PTEN-induced kinase 1/Parkin (Pink1/Parkin) pathway and autophagosomes labeled with the autophagy proteins autophagy-related 7 (ATG) and light chain 3 (LC3). In this issue of the JCI, Saito and colleagues identify an alternative pathway for mitophagy that utilizes the serine/threonine protein kinase Unc-51–like kinase 1 (Ulk1) and the small GTPase Rab9 to clear damaged mitochondria independently of conventional autophagy proteins. Together, the results of this study reveal that Ulk1 phosphorylation of Rab9 at serine 179 is critical for alternative mitophagy and cardioprotection under energy stress conditions.
Authors
Rimpy Dhingra, Inna Rabinovich-Nikitin, Lorrie A. Kirshenbaum
Abstract
Achromatopsia is an inherited retinal degeneration characterized by the loss of cone photoreceptor function. In this issue of the JCI, Moshiri et al. characterize a naturally occurring model of the disease in the rhesus macaque caused by homozygous mutations in the phototransduction enzyme PDE6C. Using retinal imaging, and electrophysiologic and biochemical methods, the authors report a clinical phenotype nearly identical to the human condition. These findings represent the first genetic nonhuman primate model of an inherited retinal disease, and provide an ideal testing ground for the development of novel gene replacement, gene editing, and cell replacement therapies for cone dystrophies.
Authors
Katherine E. Uyhazi, Jean Bennett
Abstract
Necrotizing fasciitis and myositis caused by group A streptococci (GAS) are among the most fulminating infections, with a mortality rate of 20% to 30%. Although numerous regimens have been utilized in attempts to control these devastating infections, such as combinations of various antimicrobial agents and intravenous immunoglobulin (IVIG) as well as hyperbaric oxygen therapy, none have been the complete answer. Zhu and colleagues have utilized a transposon-directed insertion-site sequencing (TraDIS) protocol to identify 126 genes of M1 and 116 genes of M28 strains of GAS required for myositis, of which 25% encode transporters, which could be used as possible targets for future therapeutic protocols.
Authors
Harry R. Hill
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Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)