Roles of endothelial cells during infection.

Endothelial cells (ECs) integrate immune and vascular functions to promote host defense against pathogens. While previously studied as forming passive flow conduits, ECs are now recognized as active contributors to maladaptive inflammation. During acute infection, ECs may promote tissue pathologies, including hypoxia, acidosis, electrolyte disturbances, and capillary barrier breakdown.

Early-life human CD8 T cells exhibit rapid, short-lived effector responses and a unique transcription factor landscape.

Neonates and infants are distinct in their clinical and cellular responses to viral infections, with neonatal CD8 T cells displaying innate-like characteristics and a low threshold for T cell receptor activation. However, specific molecular programs that drive these unique responses are incompletely understood, particularly in humans, and targetable pathways to modulate viral illness in this vulnerable population remain to be elucidated. Early-life immune responses may be developmentally programmed to prioritize avoidance of tissue immunopathology, especially while maternal immunoglobulin provides passive immunity.

A single-cell atlas of circulating immune cells over the first 2 months of age in extremely premature infants.

Extremely premature infants (EPIs) who are born before 30 weeks of gestation are susceptible to infection; however, the trajectory of their peripheral immunity is poorly understood. Here, we undertook longitudinal analyses of immune cells from 250 μl of whole blood at 1 week, 1 month, and 2 months from 10 EPIs and compared these with samples from healthy adults and with preterm and full-term cord blood samples. Single-cell suspensions from individual samples were split to perform single-cell RNA sequencing, T and B cell receptor sequencing, and phosphoprotein mass cytometry.

Decoding Immunobiology Through Genetic Errors of Immunity.

Throughout biology, the pursuit of genotype-phenotype relationships has provided foundational knowledge upon which new concepts and hypotheses are built. Genetic perturbation, whether occurring naturally or in experimental settings, is the mainstay of mechanistic dissection in biological systems. The unbiased discovery of causal genetic lesions via forward genetics in patients who have a rare disease elucidates a particularly impactful set of genotype-phenotype relationships.

PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells.

The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens.

Human genetic errors of immunity illuminate an adaptive arsenal model of rapid defenses.

New discoveries in the field of human monogenic immune diseases highlight critical genes and pathways governing immune responses. Here, I describe how the ~500 currently defined human inborn errors of immunity help shape what I propose is an 'adaptive arsenal model of rapid defenses', emphasizing the set of immunological defenses poised for rapid responses in the natural environment. This arsenal blurs the lines between innate and adaptive immunity and is established through molecular relays between cell types, often traversing from sensors (pathogen detection) to intermediates to executioners (pathogen clearance) via soluble factors.

"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease.

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses.

Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.

Purpose: We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants.

Methods: The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells.

Results: Biallelic variants in CRELD1 were found in 18 participants from 14 families.

Variable CD18 expression in a 22-year-old female with leukocyte adhesion deficiency I: Clinical case and literature review.

Key Clinical Message: Partial leukocyte adhesion deficiency type 1 (LAD-1) deficiency is extremely rare condition with milder infectious manifestation and immune system imbalance leads to increased risks of autoinflammatory complications, such as pyoderma gangrenosum, that can be triggered by trauma or pregnancy. In patients with spice-site ITGB2 variants, partial expression can occur due to different β2 integrin isophorms expression.

Abstract: LAD-1, OMIM ID #116920 is a rare, autosomal recessive disorder that results from mutations in the gene that encodes the CD18 β2 integrin subunit.

Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis.

Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination.

SARS-CoV-2 mRNA vaccines decouple anti-viral immunity from humoral autoimmunity.

mRNA-based vaccines dramatically reduce the occurrence and severity of COVID-19, but are associated with rare vaccine-related adverse effects. These toxicities, coupled with observations that SARS-CoV-2 infection is associated with autoantibody development, raise questions whether COVID-19 vaccines may also promote the development of autoantibodies, particularly in autoimmune patients. Here we used Rapid Extracellular Antigen Profiling to characterize self- and viral-directed humoral responses after SARS-CoV-2 mRNA vaccination in 145 healthy individuals, 38 patients with autoimmune diseases, and 8 patients with mRNA vaccine-associated myocarditis.

A multiple sclerosis-protective coding variant reveals an essential role for HDAC7 in regulatory T cells.

Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. However, identification and functional characterization of causal variants remain challenging. Here, we focused on the immunomodulatory role of a protective variant of histone deacetylase 7 (HDAC7).

A retrospective cohort analysis of the Yale pediatric genomics discovery program.

The Pediatric Genomics Discovery Program (PGDP) at Yale uses next-generation sequencing (NGS) and translational research to evaluate complex patients with a wide range of phenotypes suspected to have rare genetic diseases. We conducted a retrospective cohort analysis of 356 PGDP probands evaluated between June 2015 and July 2020, querying our database for participant demographics, clinical characteristics, NGS results, and diagnostic and research findings. The three most common phenotypes among the entire studied cohort (n = 356) were immune system abnormalities (n = 105, 29%), syndromic or multisystem disease (n = 103, 29%), and cardiovascular system abnormalities (n = 62, 17%).

The role of PI3Kγ in the immune system: new insights and translational implications.

Over the past two decades, new insights have positioned phosphoinositide 3-kinase-γ (PI3Kγ) as a context-dependent modulator of immunity and inflammation. Recent advances in protein structure determination and drug development have allowed for generation of highly specific PI3Kγ inhibitors, with the first now in clinical trials for several oncology indications. Recently, a monogenic immune disorder caused by PI3Kγ deficiency was discovered in humans and modelled in mice.

Maximizing insights from monogenic immune disorders.

Monogenic immune disorders provide unprecedented insights into the consequences of disrupting single genes in humans, thereby informing our understanding of fundamental immune function and disease. Genomics has accelerated monogenic disease discovery while also revealing the complexity of human disease, where several factors beyond the genome can govern pathogenesis. At this juncture, the optimal path forward will focus on maximizing basic and translational immunology insights from these disorders.

Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation.

Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli.

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.

Purpose: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2.

Infections in activated PI3K delta syndrome (APDS).

Activated PI3K-delta Syndrome (APDS), also called PI3K-delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI), is an autosomal dominant disorder caused by inherited or de novo gain-of-function mutations in one of two genes encoding subunits of the phosphoinositide-3-kinase delta (PI3Kδ) complex. This largely leukocyte-restricted protein complex regulates cell growth, activation, proliferation, and survival. Patients who harbor these mutations have early onset immunodeficiency with recurrent infections, lymphadenopathy, and autoimmunity.

SARS-CoV-2-related MIS-C: A key to the viral and genetic causes of Kawasaki disease?

Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection.

Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction.

Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection in otherwise healthy children. Here, we define immune abnormalities in MIS-C compared to adult COVID-19 and pediatric/adult healthy controls using single-cell RNA sequencing, antigen receptor repertoire analysis, unbiased serum proteomics, and assays. Despite no evidence of active infection, we uncover elevated S100A-family alarmins in myeloid cells and marked enrichment of serum proteins that map to myeloid cells and pathways including cytokines, complement/coagulation, and fluid shear stress in MIS-C patients.