Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

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I SPI1 something needed for B cells

Wahlster, Lara;Sankaran, Vijay G.

2021 The Journal of Experimental Medicine

doi: 10.1084/jem.20210572pmid: 33978700

In this issue, Le Coz et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20201750) describe a novel immunodeficiency syndrome caused by mutations in SPI1. Through a series of in-depth studies, the authors provide insights into how SPI1 affects blood lineage specification, highlighting the important role of master transcription factors as cellular fate determinants.

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A positive feedback loop reinforces the allergic immune response in human peanut allergy

Zhou, Xiaoying;Yu, Wong;Lyu, Shu-Chen;Macaubas, Claudia;Bunning, Bryan;He, Ziyuan;Mellins, Elizabeth D.;Nadeau, Kari C.

2021 The Journal of Experimental Medicine

doi: 10.1084/jem.20201793pmid: 33944900

Food allergies are a leading cause of anaphylaxis, and cellular mechanisms involving antigen presentation likely play key roles in their pathogenesis. However, little is known about the response of specific antigen-presenting cell (APC) subsets to food allergens in the setting of food allergies. Here, we show that in peanut-allergic humans, peanut allergen drives the differentiation of CD209+ monocyte-derived dendritic cells (DCs) and CD23+ (FcєRII) myeloid dendritic cells through the action of allergen-specific CD4+ T cells. CD209+ DCs act reciprocally on the same peanut-specific CD4+ T cell population to reinforce Th2 cytokine expression in a positive feedback loop, which may explain the persistence of established food allergy. In support of this novel model, we show clinically that the initiation of oral immunotherapy (OIT) in peanut-allergic patients is associated with a decrease in CD209+ DCs, suggesting that breaking the cycle of positive feedback is associated with therapeutic effect.

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CD1a selectively captures endogenous cellular lipids that broadly block T cell response

Cotton, Rachel N.;Wegrecki, Marcin;Cheng, Tan-Yun;Chen, Yi-Ling;Veerapen, Natacha;Le Nours, Jérôme;Orgill, Dennis P.;Pomahac, Bohdan;Talbot, Simon G.;Willis, Richard;Altman, John D.; de Jong, Annemieke; Van Rhijn, Ildiko;Clark, Rachael A.;Besra, Gurdyal S.;Ogg, Graham;Rossjohn, Jamie;Moody, D. Branch

2021 The Journal of Experimental Medicine

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Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain

Navia-Pelaez, Juliana M.;Choi, Soo-Ho;dos Santos Aggum Capettini, Luciano;Xia, Yining;Gonen, Ayelet;Agatisa-Boyle, Colin;Delay, Lauriane;Gonçalves dos Santos, Gilson;Catroli, Glaucilene F.;Kim, Jungsu;Lu, Jenny W.;Saylor, Benjamin;Winkels, Holger;Durant, Christopher P.;Ghosheh, Yanal;Beaton, Graham;Ley, Klaus;Kufareva, Irina;Corr, Maripat;

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GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension

Drzewiecki, Kaela;Choi, Jungmin;Brancale, Joseph;Leney-Greene, Michael A.;Sari, Sinan;Dalgiç, Buket;Ünlüsoy Aksu, Aysel;Evirgen Şahin, Gülseren;Ozen, Ahmet;Baris, Safa;Karakoc-Aydiner, Elif;Jain, Dhanpat;Kleiner, David;Schmalz, Michael;Radhakrishnan, Kadakkal;Zhang, Junhui;Hoebe, Kasper;Su, Helen C.;Pereira, João P.;

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Analyzing signaling activity and function in hematopoietic cells

Kull, Tobias;Schroeder, Timm

2021 The Journal of Experimental Medicine

doi: 10.1084/jem.20201546pmid: 34129015

Cells constantly sense their environment, allowing the adaption of cell behavior to changing needs. Fine-tuned responses to complex inputs are computed by signaling pathways, which are wired in complex connected networks. Their activity is highly context-dependent, dynamic, and heterogeneous even between closely related individual cells. Despite lots of progress, our understanding of the precise implementation, relevance, and possible manipulation of cellular signaling in health and disease therefore remains limited. Here, we discuss the requirements, potential, and limitations of the different current technologies for the analysis of hematopoietic stem and progenitor cell signaling and its effect on cell fates.

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Open Access Collection

Sterilizing immunity: New opportunities for rational TB vaccine design

Sher, Alan;Flynn, Joanne L.

2021 The Journal of Experimental Medicine

doi: 10.1084/jem.20210454pmid: 34037668

Recent studies have revealed situations of high-level naturally acquired and vaccine-induced immunity against Mycobacterium tuberculosis in animal models along with examples of significantly protective immunization in humans. These discoveries offer immunologists new opportunities to define effector mechanisms that when triggered by appropriately engineered vaccines could end TB’s deadly reign.

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The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma

Verma, Mukesh;Michalec, Lidia;Sripada, Anand;McKay, Jerome;Sirohi, Kapil;Verma, Divya;Sheth, Dipa;Martin, Richard;Dyjack, Nathan;Seibold, Max A.;Knapp, Jennifer R.;Tu, Ting-Hui;O’Connor, Brian P.;Gorska, Magdalena M.;Alam, Rafeul

2021 The Journal of Experimental Medicine

doi: 10.1084/jem.20201354pmid:

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Antibodies against human endogenous retrovirus K102 envelope activate neutrophils in systemic lupus erythematosus

Tokuyama, Maria;Gunn, Bronwyn M.;Venkataraman, Arvind;Kong, Yong;Kang, Insoo;Rakib, Tasfia;Townsend, Michael J.;Costenbader, Karen H.;Alter, Galit;Iwasaki, Akiko

2021 The Journal of Experimental Medicine

doi: 10.1084/jem.20191766pmid: 34019642

Neutrophil activation and the formation of neutrophil extracellular traps (NETs) are hallmarks of innate immune activation in systemic lupus erythematosus (SLE). Here we report that the expression of an endogenous retrovirus (ERV) locus ERV-K102, encoding an envelope protein, was significantly elevated in SLE patient blood and correlated with autoantibody levels and higher interferon status. Induction of ERV-K102 in SLE negatively correlated with the expression of epigenetic silencing factors. Anti-ERV-K102 IgG levels in SLE plasma correlated with higher interferon stimulated gene expression, and further promoted enhanced neutrophil phagocytosis of ERV-K102 envelope protein through immune complex formation. Finally, phagocytosis of ERV-K102 immune complexes resulted in the formation of NETs consisting of DNA, neutrophil elastase, and citrullinated histone H3. Together, we identified an immunostimulatory ERV-K envelope protein that in an immune complex with SLE IgG is capable of activating neutrophils.

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Immunologic Research BMC Immunology

doi: 10.1084/jem.20202699pmid: 33961028

We optimized lipidomics methods to broadly detect endogenous lipids bound to cellular CD1a proteins. Whereas membrane phospholipids dominate in cells, CD1a preferentially captured sphingolipids, especially a C42, doubly unsaturated sphingomyelin (42:2 SM). The natural 42:2 SM but not the more common 34:1 SM blocked CD1a tetramer binding to T cells in all human subjects tested. Thus, cellular CD1a selectively captures a particular endogenous lipid that broadly blocks its binding to TCRs. Crystal structures show that the short cellular SMs stabilized a triad of surface residues to remain flush with CD1a, but the longer lipids forced the phosphocholine group to ride above the display platform to hinder TCR approach. Whereas nearly all models emphasize antigen-mediated T cell activation, we propose that the CD1a system has intrinsic autoreactivity and is negatively regulated by natural endogenous inhibitors selectively bound in its cleft. Further, the detailed chemical structures of natural blockers could guide future design of therapeutic blockers of CD1a response.

Yaksh, Tony L.;

Miller, Yury I.

2021 The Journal of Experimental Medicine

doi: 10.1084/jem.20202059pmid: 33970188

Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naive mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1–deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia or reverse CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling the TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.

Lenardo, Michael J.;

Lifton, Richard P.;

Vilarinho, Sílvia

2021 The Journal of Experimental Medicine

doi: 10.1084/jem.20201745pmid: 33956074

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

34076685

Repetitive exposure of Rag1−/− mice to the Alternaria allergen extract generated a form of memory that elicited an asthma-like response upon a subthreshold recall challenge 3–15 wk later. This memory was associated with lung ICOS+ST2+ ILC2s. Genetic, pharmacologic, and antibody-mediated inhibition and adoptive transfer established an essential role for ILC2s in memory-driven asthma. ATAC-seq demonstrated a distinct epigenetic landscape of memory ILC2s and identified Bach2 and AP1 (JunD and Fosl2) motifs as major drivers of altered gene accessibility. scRNA-seq, gene knockout, and signaling studies suggest that repetitive allergenic stress induces a gene repression program involving Nr4a2, Zeb1, Bach2, and JunD and a preparedness program involving Fhl2, FosB, Stat6, Srebf2, and MPP7 in memory ILC2s. A mutually regulated balance between these two programs establishes and maintains memory. The preparedness program (e.g., Fhl2) can be activated with a subthreshold cognate stimulation, which down-regulates repressors and activates effector pathways to elicit the memory-driven phenotype.