Publications by authors named "Steven M Holland"

513 Publications

miR-181c regulates MCL1 and cell survival in GATA2 deficient cells.

J Leukoc Biol 2021 Jul 16. Epub 2021 Jul 16.

Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland, USA.

GATA2 is a transcription factor critical for hematopoiesis. Germline mutations in GATA binding protein 2 (GATA2) led to haploinsufficiency, severe cytopenias of multiple cell lineages, susceptibility to infections and strong propensity to develop myelodysplastic syndrome, and acute myeloid leukemia. Mechanisms of progressive cytopenias remain unclear. MicroRNA (miRNA) represents a unique mechanism of post-transcriptional gene regulation. In this study, miRNA profiles were evaluated and eight miRNAs were found to be differentially expressed (≥2-fold, P ≤ 0.05) in patient-derived cell lines (N = 13) in comparison to controls (N = 10). miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582 showed increased expression, whereas miR-223 and miR-424-3p showed decreased expression. Cell death assays indicated that miR-181c potently induces cell death in lymphoid (Ly-8 and SP-53) and myeloid (HL-60) cell lines. miR-181c was predicted to target myeloid cell leukemia (MCL)1, which was confirmed by transfection assays, resulting in significantly reduced MCL1 mRNA and decreased live cell numbers. Bone marrow analysis of 34 GATA2 patients showed significantly decreased cellularity, CD34-positive cells, monocytes, dendritic cells, NK cells, B cells, and B cell precursors in comparison to healthy controls (N = 29; P < 0.001 for each), which was accompanied by decreased levels of MCL1 (P < 0.05). GATA2 expression led to significant repression of miR-181c expression in transfection experiments. Conversely, knockdown of GATA2 led to increased miR-181c expression. These findings indicate that miR-181c expression is increased and MCL1 levels decreased in GATA2 deficiency cells, and that GATA2 represses miR-181c transcription. Increased miR-181c may contribute to elevated cell death and cytopenia in GATA2 deficiency potentially through down-regulation of MCL1.
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http://dx.doi.org/10.1002/JLB.2A1220-824RDOI Listing
July 2021

Hematologically important mutations: X-linked chronic granulomatous disease (fourth update).

Blood Cells Mol Dis 2021 Jun 2;90:102587. Epub 2021 Jun 2.

Dept of Pediatrics and Laboratory for Leukocyte Function, Meir Medical Centre, Kfar Saba, Israel.

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe bacterial and fungal infections. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide and subsequently formed other reactive oxygen species (ROS) are instrumental in killing phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients in Europe and in about 20% in countries with a high ratio of parental consanguinity. This article lists all mutations identified in CYBB and should therefore help in genetic counseling of X-CGD patients' families. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of disease-causing mutations. In addition, we also include some mutations in G6PD, the gene on the X chromosome that encodes glucose-6-phosphate dehydrogenase, because inactivity of this enzyme may lead to shortage of NADPH and thus to insufficient activity of NADPH oxidase. Severe G6PD deficiency can induce CGD-like symptoms.
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http://dx.doi.org/10.1016/j.bcmd.2021.102587DOI Listing
June 2021

"One-two Punch": Synergistic β-lactam Combinations for Mycobacterium abscessus and Target Redundancy in the Inhibition of Peptidoglycan Synthesis Enzymes.

Clin Infect Dis 2021 Jun 11. Epub 2021 Jun 11.

Department of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Mycobacterium abscessus subsp. abscessus is one of the most difficult pathogens to treat and its incidence in disease is increasing. Dual β-lactam combinations act synergistically in vitro, but are not widely employed in practice. A recent study shows that a combination of imipenem and ceftaroline significantly lowers the minimum inhibitory concentration (MIC) of clinical isolates despite both drugs targeting the same peptidoglycan synthesis enzymes. The underlying mechanism of this effect provides a basis for further investigations of dual β-lactam combinations in the treatment of M. abscessus subsp. abscessus eventually leading to a clinical trial. Furthermore, dual β-lactam strategies may be explored for other difficult mycobacterial infections.
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http://dx.doi.org/10.1093/cid/ciab535DOI Listing
June 2021

Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21.

J Allergy Clin Immunol 2021 Jun 2. Epub 2021 Jun 2.

Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, National Institutes of Health (NIH), Bethesda, Md. Electronic address:

Background: Pediatric endogenous Cushing syndrome (eCs) is mainly caused by pituitary corticotropin-producing adenomas, and most glucocorticoid-dependent effects progressively regress upon tumor removal. eCs reproduces long-term, high-dose glucocorticoid therapy, representing a clean, natural, and unbiased model in which to study glucocorticoid bona fide effects on immunity.

Objective: We performed extensive immunologic studies in otherwise healthy pediatric patients with eCs before and 6 to 13 months after tumor resection, as well as in in vitro glucocorticoid-treated control cells.

Methods: Flow cytometry, immunoblotting, enzyme-linked immunosorbent assay, real-time quantitative PCR, and RNA-Seq techniques were used to characterize patients' and in vitro glucocorticoid treated cells.

Results: Reduced thymic output, decreased naive T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery; all these defects eventually normalized after tumor removal in patients. In vitro studies also showed increased T-cell apoptosis, with correspondingly diminished NF-κB signaling and IL-21 levels. In this setting, IL-21 addition upregulated antiapoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway-dependent manner. Similar and reproducible findings were confirmed in eCs patient cells as well.

Conclusions: We identified decreased thymic output and lymphocyte proliferation, together with increased apoptosis, as the underlying causes to T-cell lymphopenia in eCs patients. IL-21 was decreased in both natural and in vitro long-term, high-dose glucocorticoid environments, and in vitro addition of IL-21 counteracted the proapoptotic effects of glucocorticoid therapy. Thus, our results suggest that administration of IL-21 in patients receiving long-term, high-dose glucocorticoid therapy may contribute to ameliorate lymphopenia and the complications associated to it.
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http://dx.doi.org/10.1016/j.jaci.2021.05.031DOI Listing
June 2021

Pulmonary Manifestations of GATA2 Deficiency.

Chest 2021 Jun 3. Epub 2021 Jun 3.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Background: GATA2 deficiency is a genetic disorder of hematopoiesis, lymphatics, and immunity caused by autosomal dominant or sporadic mutations in GATA2. The disease has a broad phenotype encompassing immunodeficiency, myelodysplasia, leukemia, and vascular or lymphatic dysfunction as well as prominent pulmonary manifestations.

Research Question: What are the pulmonary manifestations of GATA2 deficiency?

Study Design And Methods: A retrospective review was conducted of clinical medical records, diagnostic imaging, pulmonary pathologic specimens, and tests of pulmonary function.

Results: Of 124 patients (95 probands and 29 ascertained), the lung was affected in 56%. In addition to chronic infections, pulmonary alveolar proteinosis (11 probands) and pulmonary arterial hypertension (nine probands) were present. Thoracic CT imaging found small nodules in 54% (54 probands and 12 relatives), reticular infiltrates in 40% (45 probands and four relatives), paraseptal emphysema in 25% (30 probands and one relative), ground-glass opacities in 35% (41 probands and two relatives), consolidation in 21% (23 probands and two relatives), and a typical crazy-paving pattern in 7% (eight probands and no relatives). Nontuberculous mycobacteria were the most frequent organisms associated with chronic infection. Allogeneic hematopoietic stem cell transplantation successfully reversed myelodysplasia and immune deficiency and also improved pulmonary hypertension and pulmonary alveolar proteinosis in most patients.

Interpretation: GATA2 deficiency has prominent pulmonary manifestations. These clinical observations confirm the essential role of hematopoietic cells in many aspects of pulmonary function, including infections, alveolar proteinosis, and pulmonary hypertension, many of which precede the formal diagnosis, and many of which respond to stem cell transplantation.
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http://dx.doi.org/10.1016/j.chest.2021.05.046DOI Listing
June 2021

Nodular regenerative hyperplasia in X-linked agammaglobulinemia: An underestimated and severe complication.

J Allergy Clin Immunol 2021 Jun 1. Epub 2021 Jun 1.

Liver Diseases Branch, National Institute of Diabetes and Digestive & Kidney Diseases, NIH, Bethesda, Md. Electronic address:

Background: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited.

Objectives: This study sought to describe NRH prevalence, associated features, and impact in patients with XLA.

Methods: Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons.

Results: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per μL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002).

Conclusions: NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.
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http://dx.doi.org/10.1016/j.jaci.2021.05.028DOI Listing
June 2021

Bortezomib treatment for refractory nontuberculous mycobacterial infection in the setting of interferon gamma autoantibodies.

J Transl Autoimmun 2021 4;4:100102. Epub 2021 May 4.

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Interferon-γ autoantibodies increase the risk of disseminated nontuberculous mycobacterial infections. Addition of rituximab to antibiotics accelerates and improves outcomes, but refractory infections can occur due to persistent production of autoantibodies. We combined bortezomib with rituximab to reduce autoantibodies leading to clinical and radiographic improvement in infection.
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http://dx.doi.org/10.1016/j.jtauto.2021.100102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141761PMC
May 2021

Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer.

Cancer Immunol Res 2021 Jul 14;9(7):790-810. Epub 2021 May 14.

Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumor-associated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287091PMC
July 2021

Hematopoietic Cell Transplantation and Outcomes Related to Human Papillomavirus Disease in GATA2 Deficiency.

Transplant Cell Ther 2021 05 3;27(5):435.e1-435.e11. Epub 2021 Jan 3.

Immune Deficiency-Cellular Therapy Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

GATA2 deficiency is a bone marrow failure syndrome effectively treated with hematopoietic cell transplantation (HCT), which also addresses the predisposition to many infections (prominently mycobacterial). However, many GATA2-deficient persons who come to HCT also have prevalent and refractory human papilloma virus disease (HPVD), which can be a precursor to cancer. We analyzed 75 HCT recipients for the presence of HPVD to identify patient characteristics and transplantation results that influence HPVD outcomes. We assessed the impact of cellular recovery and iatrogenic post-transplantation immunosuppression, as per protocol (PP) or intensified/prolonged (IP) graft-versus-host disease (GVHD) prophylaxis or treatment, on the persistence or resolution of HPVD. Our experience with 75 HCT recipients showed a prevalence of 49% with anogenital HPVD, which was either a contributing or primary factor in the decision to proceed to HCT. Of 24 recipients with sufficient follow-up, 13 had resolution of HPVD, including 8 with IP and 5 with PP. Eleven recipients had persistent HPVD, including 5 with IP and 6 with PP immunosuppression. No plausible cellular recovery group (natural killer cells or T cells) showed a significant difference in HPV outcomes. One recipient died of metastatic squamous cell carcinoma, presumably of anogenital origin, at 33 months post-transplantation after prolonged immunosuppression for chronic GVHD. Individual cases demonstrate the need for continued aggressive monitoring, especially in the context of disease prevalent at transplantation or prior malignancy. HCT proved curative in many cases in which HPVD was refractory and recurrent prior to transplantation, supporting a recommendation that HPVD should be considered an indication rather than contraindication to HCT, but post-transplantation monitoring should be prolonged with a high level of vigilance for new or recurrent HPVD.
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http://dx.doi.org/10.1016/j.jtct.2020.12.028DOI Listing
May 2021

Gastrointestinal Computed Tomography Findings in Chronic Granulomatous Disease with Subgroup Clinicopathologic Analysis.

Dig Dis Sci 2021 May 1. Epub 2021 May 1.

Abdominal Imaging, Division of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency which can lead to gastrointestinal (GI) complications including inflammatory bowel disease. Radiographic findings in this cohort have not been well described.

Aims: To describe the frequency and spectrum of gastrointestinal abnormalities seen on computed tomography (CT) in patients with CGD and determine whether radiography was predictive of endoscopic or histopathologic inflammatory findings.

Methods: A retrospective review was conducted on 141 consecutive CGD patients seen at the National Institutes of Health between 1988 and 2011. All corresponding CTs were reviewed for gastrointestinal abnormalities including wall thickening. Endoscopic and histopathologic findings were reviewed in subjects with documented endoscopy within 30 days of an imaging study. Findings were compared between patients with and without wall thickening on CT to determine whether bowel wall thickening was predictive of endoscopic or histologic inflammatory findings.

Results: Two hundred and ninety-two CTs were reviewed. GI wall thickening was present on CT in 61% of patients (n = 86). Among a subgroup of 20 patients who underwent endoscopy at the time of their imaging, there was a statistically significant correlation between radiographic gastrointestinal wall thickening and endoscopic inflammation in the same intestinal segment (p = 0.035). Additionally, there was a significant correlation between radiographic gastrointestinal wall thickening and inflammatory features on histopathology (p = 0.02).

Conclusions: GI abnormalities are commonly observed on CT in CGD patients. Bowel wall thickening correlates with endoscopic and histopathologic evidence of inflammation. These findings may be used to better facilitate directed endoscopic assessment and histopathologic sampling in patients with CGD.
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http://dx.doi.org/10.1007/s10620-021-06978-4DOI Listing
May 2021

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.

J Exp Med 2021 07;218(7)

Pediatric Medicine Unit, University Hospital of Besançon, Besançon, France.

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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http://dx.doi.org/10.1084/jem.20210554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077172PMC
July 2021

SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.

Blood 2021 Apr 19. Epub 2021 Apr 19.

Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States.

SAM and SH3 domain-containing 3 (SASH3), also called SH3-containing Lymphocyte Protein (SLY1) is a putative adaptor protein that is postulated to play an important role in the organization of signaling complexes and propagation of signal transduction cascades in lymphocytes. The SASH3 gene is located on the X-chromosome. Here, we identified three novel SASH3 deleterious variants in four unrelated male patients with a history of combined immunodeficiency and immune dysregulation manifesting as recurrent sinopulmonary, cutaneous and mucosal infections, and refractory autoimmune cytopenias. Patients exhibited CD4+ T cell lymphopenia, decreased T cell proliferation and cell cycle progression, and increased T cell apoptosis in response to mitogens. In vitro T-cell differentiation of CD34+ cells and molecular signatures of rearrangements at the T-cell receptor alpha (TRA) locus were indicative of impaired thymocyte survival. These patients also manifested neutropenia and B and NK cell lymphopenia. Lentivirus-mediated transfer of the SASH3 cDNA corrected protein expression, in vitro proliferation and signaling in SASH3-deficient Jurkat and patient-derived T cells. These findings define a new type of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in Sly1-/- and Sly1D/Dmutant mice, highlighting an important role of SASH3 in human lymphocyte function and survival.
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http://dx.doi.org/10.1182/blood.2020008629DOI Listing
April 2021

Safety and Efficacy of Ustekinumab in the Inflammatory Bowel Disease of Chronic Granulomatous Disease.

Clin Gastroenterol Hepatol 2021 Apr 1. Epub 2021 Apr 1.

Translational Hepatology Section, Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address:

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by mutations encoding the NADPH oxidase complex. Those affected are at increased risk of bacterial and fungal infections and require antimicrobial prophylaxis. Dysregulated inflammation may cause inflammatory bowel disease (IBD), termed CGD-associated IBD or CGD colitis, a distinct entity from Crohn's disease (CD) or ulcerative colitis (UC).
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http://dx.doi.org/10.1016/j.cgh.2021.03.039DOI Listing
April 2021

, a Pathogen from Patients with Chronic Granulomatous Disease, Produces a Penta-Acylated Hypostimulatory Glycero-D-talo-oct-2-ulosonic Acid-Lipid A Glycolipid (Ko-Lipid A).

Int J Mol Sci 2021 Mar 24;22(7). Epub 2021 Mar 24.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

can infect patients with chronic granulomatous disease, an immunodeficiency caused by reduced phagocyte NADPH oxidase function. Intact () is hypostimulatory compared to , i.e., cytokine production in human blood requires 10-100 times more CFU/mL than . To better understand the pathogenicity of , we isolated its lipopolysaccharide (LPS) and characterized its lipid A. Unlike with typical , the release of presumptive Gb lipid A from its LPS required a strong acid. NMR and mass spectrometry demonstrated that the carbohydrate portion of the isolated glycolipid consists of α-Man-(1→4)-β-GlcN3N-(1→6)-α-GlcN-(1⇿1)-α-GlcA tetra-saccharide substituted with five acyl chains: the amide-linked N-3' 14:0(3-OH), N-2' 16:0(3-O16:0), and N-2 18:0(3-OH) and the ester-linked O-3 14:0(3-OH) and 16:0. The identification of glycero-d-talo-oct-2-ulosonic acid (Ko) as the first constituent of the core region of the LPS that is covalently attached to GlcpN3N of the lipid backbone may account for the acid resistance of LPS. In addition, the presence of Ko and only five acyl chains may explain the >10-fold lower proinflammatory potency of Ko-lipidA compared to lipid A, as measured by cytokine induction in human blood. These unusual structural properties of the Ko-lipid A glycolipid likely contribute to immune evasion during pathogenesis and resistance to antimicrobial peptides.
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http://dx.doi.org/10.3390/ijms22073303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036547PMC
March 2021

The response to vedolizumab in chronic granulomatous disease-related inflammatory bowel disease.

Gastroenterol Rep (Oxf) 2020 Oct 10;8(5):404-406. Epub 2020 Mar 10.

Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1093/gastro/goaa005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603867PMC
October 2020

Recurrent nodular regenerative hyperplasia post-liver transplantation in common variable immunodeficiency.

Hepatology 2021 Feb 27. Epub 2021 Feb 27.

Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.

Liver involvement is well described in common variable immunodeficiency (CVID) and is an important prognostic marker. While multiple etiologies for liver disease have been reported, nodular regenerative hyperplasia (NRH) is being increasingly recognized with an overall prevalence above 5% (1). In this case series we describe the pre and post-transplant evolution of CVID-related liver disease (CVID-ld). (Table 1.).
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http://dx.doi.org/10.1002/hep.31775DOI Listing
February 2021

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee.

J Clin Immunol 2021 Apr 18;41(3):666-679. Epub 2021 Feb 18.

Department of Immunology and Microbiology, Laboratory for Inborn Errors of Immunity, Department of Pediatrics, University Hospitals Leuven and KU Leuven, 3000, Leuven, Belgium.

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.
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http://dx.doi.org/10.1007/s10875-021-00980-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889474PMC
April 2021

Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine.

J Exp Med 2021 04;218(4)

Laboratory of Immunology, University of Paris, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.
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http://dx.doi.org/10.1084/jem.20202486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871457PMC
April 2021

Genome-wide association study in patients with pulmonary complex disease.

Eur Respir J 2021 Feb 4. Epub 2021 Feb 4.

Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.

Rationale: Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear.

Objectives: We aimed to identify host susceptibility loci for complex (MAC), the most common NTM pathogen.

Methods: This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping.

Results: The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64E-13, odds ratio=0.54), which is in an intronic region of the calcineurin like EF-hand protein 2 (). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. This SNP was also significantly associated with the disease in patients of Korean (p=2.18E-12, odds ratio=0.54) and European (p=5.12E-03, odds ratio=0.63) ancestry.

Conclusions: We identified rs109592 in the locus as a susceptibility marker for pulmonary MAC disease.
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http://dx.doi.org/10.1183/13993003.02269-2019DOI Listing
February 2021

Disseminated cryptococcosis and anti-granulocyte-macrophage colony-stimulating factor autoantibodies: An underappreciated association.

Mycoses 2021 Jun 5;64(6):576-582. Epub 2021 Feb 5.

Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The development of disseminated cryptococcosis has historically occurred in patients living with advanced human immunodeficiency virus or other immunosuppressive conditions affecting T-cell function. Recently, patients with anti-cytokine neutralising autoantibodies have been recognised to be at risk for disseminated infections by opportunistic intracellular pathogens, including Cryptococcus species. Herein, we present a previously healthy 26-year-old man who was evaluated with disseminated cryptococcosis involving the bone, lung, mediastinum and brain. The patient's serum cryptococcal antigen titres were >1:1,100,000, and evaluation for an underlying immunodeficiency revealed high titres for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. We also review the literature of all published cases of disseminated cryptococcosis associated with the presence of anti-GM-CSF autoantibodies. Clinicians should have a heightened awareness of anti-cytokine autoantibodies in patients without a known immunodeficiency and development disseminated infections by opportunistic intracellular pathogens.
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http://dx.doi.org/10.1111/myc.13247DOI Listing
June 2021

Aberrant type 1 immunity drives susceptibility to mucosal fungal infections.

Science 2021 01;371(6526)

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.
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http://dx.doi.org/10.1126/science.aay5731DOI Listing
January 2021

Overview of nontuberculous mycobacterial disease in children.

J Paediatr Child Health 2021 01 6;57(1):15-18. Epub 2021 Jan 6.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States.

Nontuberculous mycobacteria (NTM) are ubiquitous organisms in our surrounding environment. Four distinct clinical syndromes associated with NTM infection have been described: skin and soft tissue disease, lymphadenitis, disseminated disease and pulmonary disease. In children, lymphadenitis is the most common NTM clinical entity, particularly affecting those aged 1-5 years who have no known risk factors for disease. Optimal management of NTM lymphadenitis is not entirely clear, although surgical intervention is likely a definitive therapy. Disseminated NTM disease is uncommon and only seen in the setting of immunocompromise. In previously well children, this presentation should always lead to consideration of an underlying immune defect, such as Mendelian susceptibility to mycobacterial disease. Identification of the underlying cause enables more targeted therapy and better prognostic understanding. Pulmonary NTM disease is fundamentally different to the other clinical syndromes, presenting in different hosts, who have different comorbidities, and follow a different clinical course.
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http://dx.doi.org/10.1111/jpc.15257DOI Listing
January 2021

Venetoclax/decitabine for a pediatric patient with chronic myelomonocytic leukemia.

Pediatr Blood Cancer 2021 03 27;68(3):e28865. Epub 2020 Dec 27.

Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, Maryland.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS)/myeloproliferative disorder most commonly seen in the elderly. We describe an adolescent with monosomy 7 CMML presenting as central diabetes insipidus (DI), who was treated with venetoclax and decitabine as a bridge to hematopoietic stem cell transplantation (HSCT). Central DI is a rare manifestation of monosomy 7-associated MDS including CMML, itself a rare manifestation of GATA2 deficiency, particularly in children. Venetoclax/decitabine was effective for treatment of CMML as a bridge to HSCT.
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http://dx.doi.org/10.1002/pbc.28865DOI Listing
March 2021

A Novel RAC2 Variant Presenting as Severe Combined Immunodeficiency.

J Clin Immunol 2021 Feb 13;41(2):473-476. Epub 2020 Nov 13.

Department of Pediatrics, Division of Allergy and Immunology, Penn State Children's Hospital, 600 University Drive, Hershey, PA, 17036, USA.

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http://dx.doi.org/10.1007/s10875-020-00915-2DOI Listing
February 2021

CT and clinical assessment in asymptomatic and pre-symptomatic patients with early SARS-CoV-2 in outbreak settings.

Eur Radiol 2021 May 4;31(5):3165-3176. Epub 2020 Nov 4.

Center for Interventional Oncology, Radiology and Imaging Sciences, NIH Clinical Center and National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA.

Objectives: The early infection dynamics of patients with SARS-CoV-2 are not well understood. We aimed to investigate and characterize associations between clinical, laboratory, and imaging features of asymptomatic and pre-symptomatic patients with SARS-CoV-2.

Methods: Seventy-four patients with RT-PCR-proven SARS-CoV-2 infection were asymptomatic at presentation. All were retrospectively identified from 825 patients with chest CT scans and positive RT-PCR following exposure or travel risks in outbreak settings in Japan and China. CTs were obtained for every patient within a day of admission and were reviewed for infiltrate subtypes and percent with assistance from a deep learning tool. Correlations of clinical, laboratory, and imaging features were analyzed and comparisons were performed using univariate and multivariate logistic regression.

Results: Forty-eight of 74 (65%) initially asymptomatic patients had CT infiltrates that pre-dated symptom onset by 3.8 days. The most common CT infiltrates were ground glass opacities (45/48; 94%) and consolidation (22/48; 46%). Patient body temperature (p < 0.01), CRP (p < 0.01), and KL-6 (p = 0.02) were associated with the presence of CT infiltrates. Infiltrate volume (p = 0.01), percent lung involvement (p = 0.01), and consolidation (p = 0.043) were associated with subsequent development of symptoms.

Conclusions: COVID-19 CT infiltrates pre-dated symptoms in two-thirds of patients. Body temperature elevation and laboratory evaluations may identify asymptomatic patients with SARS-CoV-2 CT infiltrates at presentation, and the characteristics of CT infiltrates could help identify asymptomatic SARS-CoV-2 patients who subsequently develop symptoms. The role of chest CT in COVID-19 may be illuminated by a better understanding of CT infiltrates in patients with early disease or SARS-CoV-2 exposure.

Key Points: • Forty-eight of 74 (65%) pre-selected asymptomatic patients with SARS-CoV-2 had abnormal chest CT findings. • CT infiltrates pre-dated symptom onset by 3.8 days (range 1-5). • KL-6, CRP, and elevated body temperature identified patients with CT infiltrates. Higher infiltrate volume, percent lung involvement, and pulmonary consolidation identified patients who developed symptoms.
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http://dx.doi.org/10.1007/s00330-020-07401-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610169PMC
May 2021

Everything a general paediatrician needs to know about primary immunodeficiencies.

J Paediatr Child Health 2020 Dec 16;56(12):1861-1864. Epub 2020 Oct 16.

Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States.

Primary immunodeficiencies (PID) are a heterogenous group of inherited diseases, arising from inborn errors of immunity. Although typically managed by specialist immunologists, general paediatricians are often the first point of referral for patients with clinical pictures that may be presentations of PID. Recurrent, severe or atypical infections are common, but autoimmunity, aberrant inflammation and malignancy may also occur. PID may occur with or without other syndromic features. Early diagnosis and implementation of treatment are important, particularly if curative bone marrow transplant is a possible treatment modality. Therefore, knowledge of PID phenotypes, recognition of presentations and an approach to investigation are essential. Advances in genetic testing have greatly enhanced the ability to diagnose PID and their underlying genetic defects.
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http://dx.doi.org/10.1111/jpc.15186DOI Listing
December 2020

Autoantibodies against type I IFNs in patients with life-threatening COVID-19.

Science 2020 10 24;370(6515). Epub 2020 Sep 24.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
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http://dx.doi.org/10.1126/science.abd4585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857397PMC
October 2020

Nocardiosis Associated with Primary Immunodeficiencies (Nocar-DIP): an International Retrospective Study and Literature Review.

J Clin Immunol 2020 11 12;40(8):1144-1155. Epub 2020 Sep 12.

Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker -Pasteur, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades University Hospital, Université de Paris, Paris, France.

Purpose: Nocardiosis is a life-threatening infectious disease. We aimed at describing nocardiosis in patients with primary immunodeficiency diseases (PID).

Methods: This international retrospective cohort included patients with PID and nocardiosis diagnosed and/or published from Jan 1, 2000, to Dec 31, 2016. To identify nocardiosis cases, we analyzed PID databases from the French National Reference Center for PID (Paris, France) and the National Institute of Health (NIH, United States of America) and we performed a literature review on PubMed.

Results: Forty-nine cases of nocardiosis associated with PID were included: median age at diagnosis of nocardiosis was 19 (0-56) years and most cases were observed among chronic granulomatous disease (CGD) patients (87.8%). Median time from symptoms to diagnosis of Nocardia infection was 20 (2-257) days. Most frequent clinical nocardiosis presentation was pneumonia (86.7%). Twelve-month mortality rate was 4.2%, and 11.9% of patients experienced a possible recurrence of infection. Nocardiosis more frequently led to the diagnosis of PID among non-CGD patients than in CGD patients. Non-CGD patients experienced more cerebral nocardiosis and more disseminated infections, but mortality and recurrence rates were similar. Highest incidences of nocardiosis among PID cohorts were observed among CGD patients (0.0057 and 0.0044 cases/patient-year in the USA and in France, respectively), followed by IL-12p40 deficiency.

Conclusions: Among 49 cases of nocardiosis associated with PID, most patients had CGD and lung involvement. Both mortality and recurrence rates were low.
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http://dx.doi.org/10.1007/s10875-020-00866-8DOI Listing
November 2020
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