An alarming increase in children presenting with fever, hyperinflammation and multiorgan dysfunction frequently requiring intensive care has been observed after SARS-CoV-2 infection. The illness resembles Kawasaki Disease (KD) with coronary dilatation and aneurysm occurring in some. However, the cardiovascular manifestations were typically on the severe end of the KD spectrum with cardiogenic shock a common presentation together with other features. This led to defining a unique syndrome named multisystem inflammatory syndrome in Children (MIS-C). In this issue of the JCI, Lee and Day-Lewis et al. and Diorio et al. explored the clinical profiles associated with COVID-19 in children. We posit that while splitting MIS-C into a separate disease may aid clinical management decisions, lumping it into the KD pot may better serve to understand pathobiology.
Rae S.M. Yeung, Polly J. Ferguson
Allogeneic hematopoietic cell transplantation (alloHCT) benefits increasing numbers of patients with otherwise lethal diseases. Graft-versus-host disease (GVHD), however, remains one of the most potentially life-threatening complications due to its own comorbidities and the side effects of its treatment. In this issue of the JCI, two groups have turned dogma on its head by providing evidence for alternative mechanisms of acute GVHD (aGVHD) in humans. The principle of donor T cell reactivity elicited by host antigen-presenting cells (APCs) expressing MHC-encoded major HLA disparities or expressing minor histocompatibility antigen (miHA) differences presented by identical HLA molecules remains intact. These reports, however, demonstrate that GVHD can additionally result from peripheral host T cells resident in skin and gut being stimulated against donor APCs in the form of monocyte-derived macrophages. Moreover, these donor monocyte-derived macrophages can themselves mediate cytopathic effects against resident host T cells in skin explants and against a keratinocyte-derived cell line.
James W. Young
The signals maintaining quiescence of the reproductive endocrine axis during childhood before its reawakening at puberty had been enigmatic. Studies in patients with abnormal puberty have illuminated the identity of the signals; kisspeptin has emerged as a major stimulator of puberty, and makorin RING finger protein 3 (MKRN3) as an inhibitory signal that prevents premature initiation of puberty. In this issue of the JCI, Abreu et al. investigated the mechanism by which MKRN3 regulates pubertal onset. The authors found that a reduction in MKRN3 alleviated the constraint on kisspeptin-expressing neurons to allow pubertal initiation, a phenomenon observed across species, including nonhuman primates. Further, the ubiquitinase activity of MKRN3 required its RING finger domain, in order to repress the promoter activity of genes encoding kisspeptin and neurokinin B. These data advance our understanding of the regulation of kisspeptin-expressing neurons by MKRN3 to initiate puberty.
Ali Abbara, Waljit S. Dhillo
Atherosclerosis is an inflammatory condition of the arteries that has profound incidence and increasing prevalence. Although endothelial cells detect changes in blood flow, how endothelial activation contributes to atherogenic inflammation is not well understood. In this issue of the JCI, Alfaidi et al. used mouse models to explore flow-induced endothelial activation. The authors revealed a role for Nck1 and a specific activator of the innate immune response, the downstream interleukin receptor–associated kinase-1 (IRAK-1) in NF-κB–mediated inflammation and atherosclerosis susceptibility. These results link disturbed blood flow to NF-κB–mediated inflammation, which promotes atherosclerosis, and provide Nck1 as a potential target for the treatment of atherosclerosis.
Mary Wines-Samuelson, Sayantani Chowdhury, Bradford C. Berk
Retinitis pigmentosa (RP), the most common form of rod-cone dystrophy, is caused by greater than 3100 mutations in more than 71 genes, many of which are preferentially expressed in rod photoreceptors. Cone death generally follows rod loss regardless of the underlying pathogenic mutation. Preventing the secondary loss of cone photoreceptors would preserve central visual acuity and substantially improve patients’ quality of life. In this issue of the JCI, Wang et al. demonstrate that adeno-associated virus–mediated overexpression of TGF-β1 promoted cone survival and function in 3 distinct RP models with rod-specific mutations. TGF-β1 induces microglia to metabolically tune from a glycolytic phenotype (M1) to an oxidative phenotype (M2), which associates with neuroprotection and the antiinflammatory ecosystem. Consolidating the results of this study with our current understanding of how TGF-β1 regulates microglia polarization, we highlight cell-specific metabolome reprogramming as a promising non–gene-specific therapeutic avenue for inherited retinal degenerations.
Salvatore Caruso, Joseph Ryu, Peter M.J. Quinn, Stephen H. Tsang
Most patients with COVID-19 lack antibody to SARS-CoV-2 in the first 10 days of illness while the virus drives disease pathogenesis. SARS-CoV-2 antibody deficiency in the setting of a tissue viral burden suggests that using an antibody as a therapeutic agent would augment the antiviral immune response. In this issue of the JCI, Wang and collaborators describe the kinetics of viral load and antibody responses of 23 individuals with COVID-19 with mild and severe disease. The researchers found: 1) individuals with mild and severe disease produced neutralizing IgG to SARS-CoV-2 10 days after disease onset; 2) SARS-CoV-2 persisted longer in those with severe disease; and 3) there was cross-reactivity between antibodies to SARS-CoV-1 and SARS-CoV-2, but only antibodies from patients with COVID-19 neutralized SARS-CoV-2. These observations provide important information on the serological response to SARS-CoV-2 of hospitalized patients with COVID-19 that can inform the use of convalescent plasma therapy.
Arturo Casadevall, Michael J. Joyner, Liise-anne Pirofski
The lymph node (LN) is an intriguing site not only for inducing protective effector immunity but also for inducing tolerance against peripherally encountered antigens such as tissue-specific self-antigens that are regionally drained and through draining lymph nodes (DLNs). The dual functions of DLNs in immunity are attributable at least in part to fibroblastic reticular cells (FRCs), which are a major population of the nonhematopoietic compartment in the LN. In this issue of the JCI, Li, Zhao, and colleagues investigated DLNs in the transplantation setting. The authors demonstrated that, following skin transplantation, the donor mast cell–mediated senescence in FRCs was associated with collagen 1 deposition in DLNs. Systemic administration to mice of FRCs that were expanded ex vivo decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data implicate the DLN as a target for immunomodulatory therapy of transplant rejection.
Zhaoli Sun, James Burdick
New York City has been described as the epicenter of the COVID-19 pandemic in the United States. While health care workers are notably at increased risk for COVID-19 infection, the impact on resident physicians remains unclear. In this issue of the JCI, Breazzano et al. surveyed resident physicians for their exposure to COVID-19 during the exponential phase of the COVID-19 pandemic. The researchers also assessed how personal protective equipment (PPE) and COVID-19 testing protected health care workers (HCWs) from infection. This study highlights resident physician experiences of the first COVID-19 wave that can inform and improve preparedness for upcoming COVID-19 surges and other future epidemics.
Lauren I. Shapiro, Grace R. Kajita, Julia H Arnsten, Yaron Tomer
Neuromyelitis optica (NMO) is a central nervous system (CNS) inflammatory autoimmune disease caused by antibodies against aquaporin-4 (AQP4) expressed on astrocytes. Binding of AQP4-specific antibodies (NMO-IgG) triggers activation of the complement cascade, which is responsible for astrocyte loss and secondary demyelination. Although the role for the cytolytic complement proteins in astrocyte destruction in NMO is well established, little is known regarding the initial phase of astrocyte injury. In this issue of the JCI, Chen and colleagues evaluated the precytolytic phase when NMO-IgG binds astrocytes in vivo in the absence of exogenous complement. NMO-IgG alone caused astrocyte activation and AQP4 loss. Surprisingly, microglia, CNS-resident innate immune cells that produce endogenous complement, were required for clinical manifestations of disease, a finding that suggests microglia may serve as a therapeutic target in NMO.
Zahra Moinfar, Scott S. Zamvil
Allergic asthma is a chronic inflammatory lung disease associated with increased cytokine secretion. Aspects of airway inflammation are also linked to a common genetic variant that corresponds to the small GTPase, Rab27, a protein involved in vesicular trafficking in immune cells. However, the mechanisms by which Rab27 contributes to airway inflammation and cytokine release remain ambiguous. In this issue of the JCI, Okunishi et al. explored the role that the Rab27 effector, exophilin-5, has in allergic inflammation. Exophilin-5–deficient mice and asthma mouse models revealed that exophilin-5 regulates IL-33 production and the Th2 response. Notably, exophilin-5 deletion enhanced IL-33 release and pathogenic Th2 responsiveness through the mTOR pathway and altered intracellular IL-33 trafficking. This work provides insights into the molecular mechanisms that underlie inflammatory lung disease.
Michael Brusilovsky, Mark Rochman, Nurit P. Azouz, Lydia E. Mack, Marc E. Rothenberg
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