Publications by authors named "Nina K Serwas"

10 Publications

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Global absence and targeting of protective immune states in severe COVID-19.

Nature 2021 03 25;591(7848):124-130. Epub 2021 Jan 25.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs) across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.
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http://dx.doi.org/10.1038/s41586-021-03234-7DOI Listing
March 2021

Visualizing Synaptic Transfer of Tumor Antigens among Dendritic Cells.

Cancer Cell 2020 06;37(6):786-799.e5

Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address:

Generation of tumor-infiltrating lymphocytes begins when tumor antigens reach the lymph node (LN) to stimulate T cells, yet we know little of how tumor material is disseminated among the large variety of antigen-presenting dendritic cell (DC) subsets in the LN. Here, we demonstrate that tumor proteins are carried to the LN within discrete vesicles inside DCs and are then transferred among DC subsets. A synapse is formed between interacting DCs and vesicle transfer takes place in the absence of free exosomes. DCs -containing vesicles can uniquely activate T cells, whereas DCs lacking them do not. Understanding this restricted sharing of tumor identity provides substantial room for engineering better anti-tumor immunity.
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http://dx.doi.org/10.1016/j.ccell.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671443PMC
June 2020

Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis.

Nat Commun 2019 07 15;10(1):3106. Epub 2019 Jul 15.

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11CTLA-4 vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.
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http://dx.doi.org/10.1038/s41467-019-10812-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629652PMC
July 2019

-Mutant Specific Granule Deficiency Correlates With Aberrant Granule Organization and Substantial Proteome Alterations in Neutrophils.

Front Immunol 2018 29;9:588. Epub 2018 Mar 29.

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.

Specific granule deficiency (SGD) is a rare disorder characterized by abnormal neutrophils evidenced by reduced granules, absence of granule proteins, and atypical bilobed nuclei. Mutations in () are one molecular etiology of the disease. Although C/EBPε has been studied extensively, the impact of mutations on neutrophil biology remains elusive. Here, we identified two SGD patients bearing a previously described heterozygous mutation (p.Val218Ala) in . We took this rare opportunity to characterize SGD neutrophils in terms of granule distribution and protein content. Granules of patient neutrophils were clustered and polarized, suggesting that not only absence of specific granules but also defects affecting other granules contribute to the phenotype. Our analysis showed that remaining granules displayed mixed protein content and lacked several glycoepitopes. To further elucidate the impact of mutant , we performed detailed proteomic analysis of SGD neutrophils. Beside an absence of several granule proteins in patient cells, we observed increased expression of members of the linker of nucleoskeleton and cytoskeleton complex (nesprin-2, vimentin, and lamin-B2), which control nuclear shape. This suggests that absence of these proteins in healthy individuals might be responsible for segmented shapes of neutrophilic nuclei. We further show that the heterozygous mutation p.Val218Ala in causes SGD through prevention of nuclear localization of the protein product. In conclusion, we uncover that absence of nuclear C/EBPε impacts on spatiotemporal expression and subsequent distribution of several granule proteins and further on expression of proteins controlling nuclear shape.
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http://dx.doi.org/10.3389/fimmu.2018.00588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884887PMC
May 2019

Novel Mutation in CECR1 Leads to Deficiency of ADA2 with Associated Neutropenia.

J Clin Immunol 2018 04 21;38(3):273-277. Epub 2018 Mar 21.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Purpose: Adenosine deaminase 2 (ADA2) have been reported to cause vasculitic diseases and immunodeficiency recently. Patients present with stroke episodes and rashes mimicking polyarteritis nodosa (PAN). We report a patient who has been followed up with severe neutropenia and found an unexpectedly revealed novel mutation in CECR1 affecting ADA2.

Methods: We reviewed medical records and clinical history of the patient. No mutations in other known neutropenia genes such as ELA, G6PC3, HAX1, AP3B1, LAMTOR2, VPS13B, VPS45, GFI1, JAGN1, or WAS could be detected. Sanger sequencing was used to confirm the genetic variants in the patient and relatives.

Results: Genetic analysis by exome sequencing revealed a novel mutation in the gene CECR1 (c.G962A; p.G321E) which segregated perfectly in the relatives.

Conclusion: This is the first DADA2 patient presenting with severe neutropenia. We suggest that in patients with unexplained cytopenias combined with immunodeficiency, fevers of unknown origin and high inflammation markers, DADA2 should be considered.
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http://dx.doi.org/10.1007/s10875-018-0487-xDOI Listing
April 2018

Multiple Presentations of LRBA Deficiency: a Single-Center Experience.

J Clin Immunol 2017 Nov 27;37(8):790-800. Epub 2017 Sep 27.

Department of Pediatric Allergy and Immunology, Ankara University School of Medicine, Cebeci, 06590, Ankara, Turkey.

Introduction: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency categorized as common variable immunodeficiency associated with autoimmune manifestations and inflammatory bowel diseases; however, the clinical spectrum has been extended. Here, we present our cohort of Turkish LRBA-deficient patients from a single center, demonstrating a diversity of clinical manifestations.

Method: Seven affected individuals from five families were assessed retrospectively in this study.

Results: Of the seven patients with LRBA deficiency, four had homozygous, and two had compound heterozygous mutations. One patient remained disease free until the last follow-up (age 17 years). The most common clinical manifestations of the six symptomatic patients were organomegaly (6/6), autoimmunity (6/6), and chronic diarrhea (5/6). Recurrent infectious episodes were observed in three patients. None of the patients had hypogammaglobulinemia at presentation. B cell subpopulation analysis revealed low numbers of switched-memory B cell numbers in two of the four tested patients. During the disease course, three of the patients died, two of them underwent successful hematopoietic stem cell transplantation (HSCT) from matched sibling donors, and one is under abatacept therapy.

Conclusion: LRBA defects should always be kept in mind as a differential diagnosis for patients with autoimmune disease affecting multiple organs, chronic diarrhea, and organomegalies. In our experience, early HSCT is a life-saving therapeutic strategy.
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http://dx.doi.org/10.1007/s10875-017-0446-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086713PMC
November 2017

CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis.

N Engl J Med 2017 07 28;377(1):52-61. Epub 2017 Jun 28.

From the Section of Molecular Development of the Immune System, Laboratory of Immunology (A.O., W.A.C., A.R.M., H.F.M., M.J.L.), the Clinical Genomics Program (A.O., W.A.C., A.R.M., Y.Z., H.F.M., H.C.S., M.J.L.), and the Human Immunological Diseases Section, Laboratory of Host Defenses (Y.Z., H.C.S.), National Institute of Allergy and Infectious Diseases, the Laboratory of Pathology, National Cancer Institute (S.P.), and Radiology and Imaging Sciences, Clinical Center (L.R.F.), National Institutes of Health, Bethesda, MD; the Department of Pediatrics, Division of Allergy and Immunology (A.O., E.K.-A., S.B., A. Kiykim, I.O.), and the Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition (E.T., D.E.), Marmara University, Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases (A.O., E.K.-A., S.B., A. Kiykim, I.O.), and the Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, İstanbul University Cerrahpaşa Faculty of Medicine (Ö.F.B., T.E.), Istanbul, and the Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Gazi University (B.D., S.S.), the Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, Başkent University (F.O., Z.B., M.G.), and the Pediatric Gastroenterology Clinic, Dr. Sami Ulus Children's Hospital (A.U.A.), Ankara - all in Turkey; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases and the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (R.C.A., C.D.C., N.K.S., A. Krolo, K.B.), Clinical Institute of Pathology (R.K.), the Department of Pediatrics and Adolescent Medicine (K.B.), and St. Anna Kinderspital and Children's Cancer Research Institute, Department of Pediatrics (K.B.), Medical University of Vienna, Vienna; Merck Research Laboratories (J.J.M.), and the Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Harvard Medical School (S.B.S.), Boston; and the Department of Pediatric Gastroenterology, University Medical Center-Wilhelmina Children's Hospital (R.H.J.H.), and the Department of Rheumatology and Clinical Immunology, University Medical Center (H.L.L.), Utrecht, the Netherlands.

Background: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies.

Methods: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55.

Results: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation.

Conclusions: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
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http://dx.doi.org/10.1056/NEJMoa1615887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690356PMC
July 2017

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.

N Engl J Med 2015 Jun;372(25):2409-22

From the Division of Immunology (K.D., J.C., S.K., M.J.M., K.C., K.F., T.A.C., R.S.G., L.D.N.) and Manton Center for Orphan Disease Research (L.D.N.), Boston Children's Hospital, and Department of Molecular Biology, Massachusetts General Hospital (T.K.O.), Boston, Harvard Stem Cell Institute, Harvard University, Cambridge (L.D.N.), and Department of Pediatrics, University of Massachusetts Medical School, Worcester (A.M.C.) - all in Massachusetts; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (C.D.C., I.B., N.K.S., M.S., C.B., K.B.), Department of Pediatrics and Adolescent Medicine, Medical University of Vienna (K.B.), and CeRUD Vienna Center for Rare and Undiagnosed Diseases (K.B.) - all in Vienna; St. Giles Laboratory of Human Genetics of Infectious Disease, Rockefeller Branch, Rockefeller University (S.-Y.Z., M.A., S.O., B.B., Y.I., L.A., J.-L.C.), and Institute for Genomic Medicine, Columbia University (S. Petrovski, D.B.G.) - both in New York; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM Unité 1163 (S.-Y.Z., V.P., L.A., J.-L.C.), Paris Descartes University, Sorbonne Paris Cité, Imagine Institute (S.-Y.Z., F.R., P.L., L.A., J.-L.C.), and Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children (J.-L.C.) - all in Paris; Howard Hughes Medical Institute, Chevy Chase, MD (J.-L.C.); Department of Molecular and Translational Medicine, University of Brescia, Brescia (S. Parolini, O.P., G.T.), and Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genoa, Genoa (A.M.) - both in Italy; Folkhälsan Institute of Genetics and Research Programs Unit, Molecular Neurology (E.H.), Institute for Molecular Medicine Finland (J.S.), Children's Hospital (M.K.), Research Programs Unit, Diabetes and Obesity Research Program (M.K.), and Folkhälsan Research Center (M.K.), University of Helsinki and Helsinki University Central Hospital, Helsinki, Tampere Center

Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1413462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480434PMC
June 2015

Clinical features of interleukin 10 receptor gene mutations in children with very early-onset inflammatory bowel disease.

J Pediatr Gastroenterol Nutr 2015 Mar;60(3):332-8

*Department of Pediatric Gastroenterology, Hepatology and Nutrition, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey †CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences ‡Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Objectives: In the present study, we studied a cohort of patients with very early onset inflammatory bowel disease (IBD) to determine the frequency of mutations in the interleukin 10 (IL10) receptor genes as a cause of early-onset IBD.

Methods: Sanger sequencing was performed to determine the presence of IL10 and/or IL10 receptor mutations in 17 patients with a diagnosis of very early onset IBD (disease onset <2 years of age in 15 patients, between 3 and 4 years in the other 2). Mutation screening was performed including all of the coding regions of the IL10, IL10RA, and IL10RB genes. We then compared the follow-up findings of the patients with IL10 receptor mutations in terms of demographic, clinical, laboratory, and treatment response properties with those of patients diagnosed as having very early onset IBD with no mutation.

Results: We identified 3 patients bearing mutations in the IL10 or IL10 receptor genes, including 1 mutation in IL10RB that has been described recently (c.G477A, p.Trp159*) and 2 novel mutations affecting the IL10RA gene (c.T192G, p.Tyr64 and c.T133G, p.Trp45Gly). Collectively, these mutations thus provided genetic etiology for 17.6% of the cohort under investigation. The presence of a family history of IBD and the clinical course of Crohn disease differed between patients with mutations in the IL-10 pathway and those without such mutations. Although perianal fistulas were found in all of the patients with IL10 receptor mutations, they were found in only 14.3% of those without such mutations. The lower values of weight-for-age and height-for-age z scores, necessity for more intensive therapy, achievement of longer periods until remission, and frequent relapses in the patients bearing mutations in the IL10 receptor genes all underlined the severity of the disease and its relatively poor response to treatment.

Conclusions: In spite of the small number of patients with mutations affecting the IL-10 signaling pathway in our study, in all of the patients with IL10 receptor mutations, the disease onset occurs at an early age, the prognosis is poor, and the response to treatment is insufficient.
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http://dx.doi.org/10.1097/MPG.0000000000000621DOI Listing
March 2015