Publications by authors named "Kaan Boztug"

133 Publications

TMC8 mutation in a Turkish family with epidermodysplasia verruciformis including laryngeal papilloma and recurrent skin carcinoma.

J Cosmet Dermatol 2021 Aug 20. Epub 2021 Aug 20.

Pediatric Immunology Department, Hacettepe University Faculty of Medicine, Ankara, Turkey.

The vast majority of primary immunodeficiencies (PIDs) occur due to the defects in cells originating from hematopoietic stem cells, while in some PIDs, there are defects in various genes responsible for non-leucocyte immune response such as seen in epidermodysplasia verruciformis (EV). EV caused by the mutations in TMC6, TMC8, and CIB1 genes is called "typical." "Atypical" EV may develop in patients with primary immunodeficiencies originating from hematopoietic stem cells, which include severe T-cell failure, caused by inactivating biallelic mutations of STK4, RHOH, CORO1A, ITK, TPP2, DCLRE1C, LCK, RASGRP1, or DOCK8 genes. Here, we present a family with TMC8 gene mutation leading to disseminated epidermodysplasia verruciformis including laryngeal papilloma and recurrent cutaneous squamous cell carcinomas. Typical EV with impaired local, keratinocyte-intrinsic immune response should be considered when routine immunological examinations are normal in patients presenting with clinical signs of EV. Although it is not possible to prevent EV lesions, early and appropriate surveillance for malignancy is mandatory.
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http://dx.doi.org/10.1111/jocd.14393DOI Listing
August 2021

Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.

Allergy 2021 Jul 20. Epub 2021 Jul 20.

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

Background: Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations.

Methods: The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cT ) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape.

Results: Mean age at disease onset was 38 ± 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4 T cells, Treg, and cT cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years).

Conclusion: This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.
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http://dx.doi.org/10.1111/all.15010DOI Listing
July 2021

Impaired respiratory burst contributes to infections in PKCδ-deficient patients.

J Exp Med 2021 Sep 15;218(9). Epub 2021 Jul 15.

Department of Pediatrics, Division of Allergy and Clinical Immunology, Tehran University of Medical Sciences, Tehran, Iran.

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.
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http://dx.doi.org/10.1084/jem.20210501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288504PMC
September 2021

Actin Dynamics at the T Cell Synapse as Revealed by Immune-Related Actinopathies.

Front Cell Dev Biol 2021 24;9:665519. Epub 2021 Jun 24.

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria.

The actin cytoskeleton is composed of dynamic filament networks that build adaptable local architectures to sustain nearly all cellular activities in response to a myriad of stimuli. Although the function of numerous players that tune actin remodeling is known, the coordinated molecular orchestration of the actin cytoskeleton to guide cellular decisions is still ill defined. T lymphocytes provide a prototypical example of how a complex program of actin cytoskeleton remodeling sustains the spatio-temporal control of key cellular activities, namely antigen scanning and sensing, as well as polarized delivery of effector molecules, via the immunological synapse. We here review the unique knowledge on actin dynamics at the T lymphocyte synapse gained through the study of primary immunodeficiences caused by mutations in genes encoding actin regulatory proteins. Beyond the specific roles of individual actin remodelers, we further develop the view that these operate in a coordinated manner and are an integral part of multiple signaling pathways in T lymphocytes.
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http://dx.doi.org/10.3389/fcell.2021.665519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266300PMC
June 2021

Morphological profiling of human T and NK lymphocytes by high-content cell imaging.

Cell Rep 2021 Jul;36(1):109318

Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM UMR1291, CNRS UMR5051, Toulouse III Paul Sabatier University, Toulouse, France; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria; Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address:

The immunological synapse is a complex structure that decodes stimulatory signals into adapted lymphocyte responses. It is a unique window to monitor lymphocyte activity because of development of systematic quantitative approaches. Here we demonstrate the applicability of high-content imaging to human T and natural killer (NK) cells and develop a pipeline for unbiased analysis of high-definition morphological profiles. Our approach reveals how distinct facets of actin cytoskeleton remodeling shape immunological synapse architecture and affect lytic granule positioning. Morphological profiling of CD8 T cells from immunodeficient individuals allows discrimination of the roles of the ARP2/3 subunit ARPC1B and the ARP2/3 activator Wiskott-Aldrich syndrome protein (WASP) in immunological synapse assembly. Single-cell analysis further identifies uncoupling of lytic granules and F-actin radial distribution in ARPC1B-deficient lymphocytes. Our study provides a foundation for development of morphological profiling as a scalable approach to monitor primary lymphocyte responsiveness and to identify complex aspects of lymphocyte micro-architecture.
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http://dx.doi.org/10.1016/j.celrep.2021.109318DOI Listing
July 2021

A novel homozygous mutation is associated with severe combined immunodeficiency and neurological presentations.

Allergol Immunopathol (Madr) 2021 1;49(4):91-97. Epub 2021 Jul 1.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Introduction And Objectives: Severe combined immunodeficiency (SCID) is a subset of primary immunodeficiency diseases caused by a hereditary deficiency of the adaptive immune system. Mutation in recombination activating gene () is known as the underlying genetic cause of SCID. RAG protein plays a pivotal role in V(D)J recombination which is the main process to assemble lymphocyte antigen receptors during T- and B-cell development. The patients are characterized by recurrent infections, failure to thrive, chronic diarrhea, and fever, in early infancy. Herein, we present a case of SCID with rare neurological manifestations affected by a mutation in

Patients And Methods: The patient was a 15-month-old infant born to a consanguineous family. She was presented with neurological abnormalities including facial nerve palsy, seizure, and decreased consciousness. Next-generation sequencing (NGS)-based primary immunodeficiency disease (PID)-gene panel screen and Sanger sequencing were performed to identify the genetic mutation.

Results: We found a novel homozygous missense mutation in , c.1210C>T,p.Arg404Trp, which was predicted to be deleterious (combined annotation dependent depletion, CADD score of 27.4). Both parents were heterozygous carriers for this mutation. According to her laboratory data, both T cell and B cell numbers were decreased and the patient was diagnosed as - SCID.

Conclusions: SCID is a pediatric emergency with a variety of manifestations in infants. Therefore, accurate diagnosis importantly in the case of rare manifestations must be considered in these patients. Our findings point toward the importance of genetic assessment for early diagnosis and timely treatment of this disorder.
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http://dx.doi.org/10.15586/aei.v49i4.194DOI Listing
July 2021

Immunologically relevant aspects of the new COVID-19 vaccines-an ÖGAI (Austrian Society for Allergology and Immunology) and AeDA (German Society for Applied Allergology) position paper.

Allergo J Int 2021 Jun 18:1-14. Epub 2021 Jun 18.

Institute of Pathophysiology and Allergy Research, Centre for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

Background: The vaccines against the coronavirus disease 2019 (COVID-19) approved in the European Union represent a decisive step in the fight against the pandemic. The application of these available vaccines to patients with pre-existing immunological conditions leads to a multitude of questions regarding efficacy, side effects and the necessary patient information.

Results: This review article provides insight into mechanisms of action of the currently available severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and summarises the current state of science as well as expert recommendations regarding tolerability of the vaccines. In addition, the potential to develop protective immune responses is determined. A special focus is given on patients under immunosuppression or in treatment with immunomodulatory drugs. Special groups of the population such as children, pregnant women and the elderly are also considered.

Conclusion: Despite the need for a patient-specific risk-benefit assessment, the consensus among experts is that patients with immunological diseases in particular benefit from the induced immune protection after COVID-19 vaccination and do not have an increased risk of side effects.
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http://dx.doi.org/10.1007/s40629-021-00178-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212077PMC
June 2021

Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature.

J Allergy Clin Immunol Pract 2021 Oct 17;9(10):3752-3766.e4. Epub 2021 Jun 17.

Department of Pediatric Immunology, Hacettepe University Medical School, Ankara, Turkey; Department of Pediatric Immunology, Institute of Child Health, Hacettepe University Medical School, Ankara, Turkey.

Background: Serine/threonine kinase-4 (STK4) deficiency is an autosomal recessive combined immunodeficiency.

Objective: We aimed to define characteristic clinical and laboratory features to aid the differential diagnosis and determine the most suitable therapy.

Methods: In addition to nine STK4 deficiency patients, we reviewed 15 patients from the medical literature. We compared B lymphocyte subgroups of the cohort with age-matched healthy controls.

Results: In the cohort, median age at symptom onset and age at diagnosis were 6 years 8 months (range, 6-248 months) and 7 years 5 months (range, 6-260 months), respectively. The main clinical findings were infections (in all nine patients [9 of 9]), autoimmune or inflammatory diseases (7 of 9), and atopy (4 of 9). CD4 lymphopenia (9 out 9), lymphopenia (7 out 9), intermittent eosinophilia (4 out 9), transient neutropenia (3 out 9), low IgM (4 out 9), and high IgE (4 out 9) were common. Decreased recent thymic emigrants, naive and central memory T cells, but increased effector memory T cells were present. The increase in plasmablasts (P = .003) and decrease in switched memory B cells (P = .022) were significant. When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent. Lymphopenia, CD4 lymphopenia, high IgG, IgA, and IgE were common laboratory characteristics.

Conclusions: The differential diagnosis with autosomal recessive hyper-IgE syndrome is crucial. Because, atopy and CD4 lymphopenia are common in both diseases. Immunoglobulins, antibacterial, and antiviral prophylaxis are the mainstays of treatment. Clinicians may use immunomodulatory therapies during inflammatory or autoimmune complications. However, more data are needed to recommend hematopoietic stem cell transplantation as a safe therapy.
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http://dx.doi.org/10.1016/j.jaip.2021.05.032DOI Listing
October 2021

Single-Center Study of 72 Patients with Severe Combined Immunodeficiency: Clinical and Laboratory Features and Outcomes.

J Clin Immunol 2021 Oct 10;41(7):1563-1573. Epub 2021 Jun 10.

Department of Pediatric Immunology and Allergy, BMT Unit, Ankara University Medical School, Mamak Street, Dikimevi, 06100, Ankara, Turkey.

Severe combined immunodeficiency is an inborn error of immunity characterized by impairments in the numbers and functions of T and B lymphocytes due to various genetic causes, and if it remains untreated, patients succumb to infections during the first 2 years of life.

Purpose And Methods: This study reported retrospective data from 72 infants diagnosed with SCID including their major clinical features, HSCT characteristics, and outcomes over a 20-year period (1997-2017).

Results: Sixty-one of 72 SCID patients in the study underwent HSCT from 1997 to 2017. Median ages at the time of diagnosis and transplantation were 3.5 months and 5 months, respectively. Consanguinity was present in 68% of the patients, and T - B - NK + phenotype was predominantly identified. The overall survival was 80.3% over a 20-year period. However, the patients transplanted during an active infection had a lower survival rate of 73.9% compared to 100% for patients transplanted infection-free or with a previous infection that had resolved. The survival rate was significantly higher among recipients of HLA-identical transplants (92.9%), compared to recipients of mismatched related transplants (70%). The overall survival increased from 50 (1997-2006) to 85% (2007-2017) during the last 10 years.

Conclusions: This is one of the largest single-center studies in Turkey with extensive experience about SCID patients. Early diagnosis of SCID patients before the onset of an infection and early transplantation are shown to be extremely important factors affecting the outcome and increasing the survival regardless of the donor type based on the results of this study.
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http://dx.doi.org/10.1007/s10875-021-01062-yDOI Listing
October 2021

Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity.

J Allergy Clin Immunol 2021 May 12. Epub 2021 May 12.

Department of Immunology, Great Ormond Street (GOS) Hospital for Children NHS Foundation Trust, London, United Kingdom.

Background: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms.

Objectives: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions.

Methods: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs.

Results: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification.

Conclusions: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities.
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http://dx.doi.org/10.1016/j.jaci.2021.04.033DOI Listing
May 2021

Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency.

J Clin Immunol 2021 Aug 30;41(6):1272-1290. Epub 2021 Apr 30.

Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.
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http://dx.doi.org/10.1007/s10875-021-01031-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086229PMC
August 2021

The VRNetzer platform enables interactive network analysis in Virtual Reality.

Nat Commun 2021 04 23;12(1):2432. Epub 2021 Apr 23.

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

Networks provide a powerful representation of interacting components within complex systems, making them ideal for visually and analytically exploring big data. However, the size and complexity of many networks render static visualizations on typically-sized paper or screens impractical, resulting in proverbial 'hairballs'. Here, we introduce a Virtual Reality (VR) platform that overcomes these limitations by facilitating the thorough visual, and interactive, exploration of large networks. Our platform allows maximal customization and extendibility, through the import of custom code for data analysis, integration of external databases, and design of arbitrary user interface elements, among other features. As a proof of concept, we show how our platform can be used to interactively explore genome-scale molecular networks to identify genes associated with rare diseases and understand how they might contribute to disease development. Our platform represents a general purpose, VR-based data exploration platform for large and diverse data types by providing an interface that facilitates the interaction between human intuition and state-of-the-art analysis methods.
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http://dx.doi.org/10.1038/s41467-021-22570-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065164PMC
April 2021

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.

Nat Genet 2021 04 29;53(4):500-510. Epub 2021 Mar 29.

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.
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http://dx.doi.org/10.1038/s41588-021-00803-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245161PMC
April 2021

Occurrence of autoimmune pancreatitis after chronic immune thrombocytopenia in a Caucasian adolescent.

Clin J Gastroenterol 2021 Jun 20;14(3):918-922. Epub 2021 Mar 20.

Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Kinderspitalgasse 6, 1090, Vienna, Austria.

Autoimmune pancreatitis is a rare, distinct and increasingly recognized form of chronic inflammatory pancreatic disease secondary to an underlying autoimmune mechanism. We report on a 14-year-old boy who developed autoimmune pancreatitis, while he was under treatment with eltrombopag for chronic immune thrombocytopenia. Therapy with corticosteroids resulted in complete remission of both. This is the first report on the co-occurrence of autoimmune pancreatitis and chronic immune thrombocytopenia in childhood, and clinicians should be aware of this rare association, because early diagnosis and therapy of autoimmune pancreatitis may prevent severe complications.
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http://dx.doi.org/10.1007/s12328-021-01383-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154769PMC
June 2021

Adenosine Deaminase Type II Deficiency: Severe Chronic Neutropenia, Lymphoid Infiltration in Bone Marrow, and Inflammatory Features.

Immunol Invest 2020 Dec 2:1-9. Epub 2020 Dec 2.

Department of Pediatric Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Deficiency of adenosine deaminase type 2 (DADA2) is an autoinflammatory disease characterized with immunologic, hematologic, and neurological features. Here, we presented two patients with severe persistent chronic neutropenia, which required differential diagnosis of congenital and autoimmune neutropenia, myelodysplastic syndrome (MDS), and primary immunodeficiency diseases, including autoimmune lymphoproliferative disease. The therapy of the disease except hematopoietic stem cell transplantation is a challenging experience.
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http://dx.doi.org/10.1080/08820139.2020.1853153DOI Listing
December 2020

Novel mutation in X-linked agammaglobulinemia: Report of a 17-year-old male.

Allergol Immunopathol (Madr) 2021 1;49(2):80-83. Epub 2021 Mar 1.

Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.

Introduction And Objectives: X-linked agammaglobulinemia (XLA), the first known primary immunodeficiency, is caused by rare mutations in Bruton's tyrosine kinase (BTK) gene. Mutations in the BTK gene lead to a failure in the development and maturation of B-cell linage. A decreased number of B-cells results in agammaglobulinemia and increased susceptibility to a variety of infections. Therefore, patients with XLA usually manifest with repetitive bacterial infections, such as upper respiratory tract infections, septic arthritis, osteomyelitis, and urinary tract infections, since their infancy.

Patients: We report a 17-year-old Iranian boy with XLA, referred to us with a history of severe and recurrent episodes of bacterial infections for a period of six years.

Results: Genetic analysis using the whole Exome sequencing revealed a hemizygous missense mutation in the BTK gene (c.428 A > T, p.His143Leu).

Conclusion: To our knowledge, c.428 A > T has not been reported in the BTK gene.
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http://dx.doi.org/10.15586/aei.v49i2.62DOI Listing
March 2021

Novel Variants of DOCK8 Deficiency in a Case Series of Iranian Patients.

Endocr Metab Immune Disord Drug Targets 2021 Feb 26. Epub 2021 Feb 26.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran. Iran.

Background: Dedicator of Cytokinesis 8 (DOCK8) deficiency, the most frequent cause of autosomal recessive hyper immunoglobulin (Ig)E syndrome, is a rare combined immunodeficiency.

Objective: In this study, we report seven patients with consanguineous parents with five novel variants within the DOCK8 gene.

Methods: For genetic analysis, we performed Whole Exome Sequencing (WES), or targeted sequencing by means of Next-generation sequencing (NGS) for some of the patients. For others, Sanger sequencing, Fluorescence-activated cell sorting (FACS), or polymerase chain reaction (PCR) was used.

Results: We report five novel variants within the DOCK8 gene: three deletions (deletion of exons 4-12, 24-30, and 22-27), one frameshift (LRG_196:g.189315dup;p.(Leu1052Profs*7)), and a splice region variant (LRG_196t1:c.741+5G>T). Patients presented with skin lesions, food allergy, candidiasis, otitis, recurrent respiratory infections, short stature, aortic aneurism, gynecomastia, and coarse facial features. Patients had leukocytosis, eosinophilia, lymphopenia, and monocytosis, elevated IgE, IgG, IgA , reduced IgM and IgA levels. Patients had a low percentage of CD3+ and CD4+ cells, and a high percentage of CD19+, CD27+CD19+, and recent thymic emigrants T cells. The percentage of natural killer cells was increased in one of the patients while it was decreased in another patient. One patient died due to disseminated intravascular coagulation after hematopoietic stem cell transplantation.

Conclusion: We reported novel variants within the DOCK8 gene and highlighted risk of aneurysms in these patients, which have been rarely reported in these patients.
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http://dx.doi.org/10.2174/1871530321666210226143912DOI Listing
February 2021

RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis.

Blood 2021 04;137(15):2033-2045

St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.

Exocytosis of cytotoxic granules (CG) by lymphocytes is required for the elimination of infected and malignant cells. Impairments in this process underly a group of diseases with dramatic hyperferritinemic inflammation termed hemophagocytic lymphohistiocytosis (HLH). Although genetic and functional studies of HLH have identified proteins controlling distinct steps of CG exocytosis, the molecular mechanisms that spatiotemporally coordinate CG release remain partially elusive. We studied a patient exhibiting characteristic clinical features of HLH associated with markedly impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions, who beared biallelic deleterious mutations in the gene encoding the small GTPase RhoG. Experimental ablation of RHOG in a model cell line and primary CTLs from healthy individuals uncovered a hitherto unappreciated role of RhoG in retaining CGs in the vicinity of the plasma membrane (PM), a fundamental prerequisite for CG exocytotic release. We discovered that RhoG engages in a protein-protein interaction with Munc13-4, an exocytosis protein essential for CG fusion with the PM. We show that this interaction is critical for docking of Munc13-4+ CGs to the PM and subsequent membrane fusion and release of CG content. Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity and provides the molecular pathomechanism behind the identified here and previously unreported genetically determined form of HLH.
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http://dx.doi.org/10.1182/blood.2020008738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057258PMC
April 2021

BCGitis as the primary manifestation of chronic granulomatous disease.

IDCases 2021 29;23:e01038. Epub 2020 Dec 29.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Patients with primary immunodeficiency disease (PID) are not only vulnerable to mycobacterial disease, but are also more likely to develop adverse events following BCG vaccination. These events can range from regional disease (BCGitis) to disseminated disease (BCGosis). Chronic granulomatous disease (CGD), which is characterized by impaired leukocyte phagocytic function, is one of the many inherited PIDs that increase the body's susceptibility to recurrent bacterial and fungal infections. Here, we report a 6-year-old boy with no significant past medical history who presented with progressive lymphadenopathy six years after BCG vaccination. He was later diagnosed with CGD on further evaluation.
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http://dx.doi.org/10.1016/j.idcr.2020.e01038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785948PMC
December 2020

Novel Frameshift Autosomal Recessive Loss-of-Function Mutation in SMARCD2 Encoding a Chromatin Remodeling Factor Mediates Granulopoiesis.

J Clin Immunol 2021 01 6;41(1):59-65. Epub 2020 Oct 6.

Faculty of Medicine, Division of Pediatric Allergy/Immunology, Marmara University, Fevzi Çakmak Mah. No: 41, Pendik, Istanbul, Turkey.

Purpose: Recently, a new form of congenital neutropenia that is caused by germline biallelic loss-of-function mutations in the SMARCD2 gene was described in four patients. Given the rarity of the condition, the clinical spectrum of the disease has remained elusive. We here report a new patient with a novel frameshift mutation and compare our patient with the previously reported SMARCD2-mutant patients, aiming to provide a more comprehensive understanding of the natural course of the disease.

Methods: Clinical and laboratory findings of all reported patients were reviewed. Next-generation sequencing was performed to identify the causative genetic defect. Data on the hematopoietic stem cell transplantation including stem cell sources, conditioning regimen, engraftment, graft-versus-host disease, and infections were also collected.

Results: An 11-year-old female patient had a variety of infections including sepsis, deep tissue abscesses, otitis, pneumonia, gingivitis, and diarrhea since infancy. A novel homozygous mutation in SMARCD2 (c.93delG, p.Ala32Argfs*80) was detected. Bone marrow examination showed hypocellularity and decreased neutrophils with diminished granules and myeloid dysplasia, but no blast excess as in previously reported patients. The neutropenia was non-responsive even to higher doses of granulocyte colony-stimulating factor (G-CSF); therefore, the patient was transplanted at 10 years of age from a HLA-A allele-mismatched unrelated donor using a reduced toxicity conditioning regimen and recovered successfully. Compared with the previous four cases, our patient showed longer survival before transplantation without blastic transformation.

Conclusion: Distinctive myeloid features and long-term follow-up including therapy options are presented for the newly described case of SMARCD2 deficiency. This disorder is apparent at infancy and requires early transplantation due to the unrelenting disease course despite conventional therapy.
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http://dx.doi.org/10.1007/s10875-020-00878-4DOI Listing
January 2021

CD70 Deficiency Associated With Chronic Epstein-Barr Virus Infection, Recurrent Airway Infections and Severe Gingivitis in a 24-Year-Old Woman.

Front Immunol 2020 4;11:1593. Epub 2020 Aug 4.

Department of Pediatric Pneumonology, Immunology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Most of the few patients with homozygous CD70 deficiency described to date suffered from EBV-related malignancies in early childhood. We present a woman with CD70 deficiency diagnosed in adulthood. She presented in childhood with recurrent airway infections due to encapsulated bacteria, herpes zoster and a fulminant EBV infection followed by chronic EBV infection with mild lymphoproliferation and severe gingivitis/periodontal disease with high EBV viral load in saliva and gingival plaques as an adult. Up to the age of 24 years she developed no malignancy despite constant EBV viremia since primary EBV infection 15 years previously. Immunologic evaluation in childhood showed hypogammaglobulinemia with impaired polysaccharide responsiveness. She has been stable on immunoglobulin substitution with no further severe viral infections and no bacterial airway infections in adulthood. Targeted panel sequencing at the age of 20 years revealed a homozygous missense mutation (ENST00000245903.3:c.2T>C). CD70 deficiency was confirmed by absent CD70 expression of B cells and activated T cell blasts. The patient finished high school, persues an academic career and has rarely sick days at college. The clinical course of our patient may help to counsel parents of CD70-deficient patients with regard to prognosis and therapeutic options including haematopoetic stem cell transplantation.
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http://dx.doi.org/10.3389/fimmu.2020.01593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417345PMC
April 2021

Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies.

Blood 2021 01;137(3):349-363

Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.

IKAROS is a transcription factor forming homo- and heterodimers and regulating lymphocyte development and function. Germline mutations affecting the IKAROS N-terminal DNA binding domain, acting in a haploinsufficient or dominant-negative manner, cause immunodeficiency. Herein, we describe 4 germline heterozygous IKAROS variants affecting its C-terminal dimerization domain, via haploinsufficiency, in 4 unrelated families. Index patients presented with hematologic disease consisting of cytopenias (thrombocytopenia, anemia, neutropenia)/Evans syndrome and malignancies (T-cell acute lymphoblastic leukemia, Burkitt lymphoma). These dimerization defective mutants disrupt homo- and heterodimerization in a complete or partial manner, but they do not affect the wild-type allele function. Moreover, they alter key mechanisms of IKAROS gene regulation, including sumoylation, protein stability, and the recruitment of the nucleosome remodeling and deacetylase complex; none affected in N-terminal DNA binding defects. These C-terminal dimerization mutations are largely associated with hematologic disorders, display dimerization haploinsufficiency and incomplete clinical penetrance, and differ from previously reported allelic variants in their mechanism of action. Dimerization mutants contribute to the growing spectrum of IKAROS-associated diseases displaying a genotype-phenotype correlation.
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http://dx.doi.org/10.1182/blood.2020007292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819759PMC
January 2021

Treatment and management of primary antibody deficiency: German interdisciplinary evidence-based consensus guideline.

Eur J Immunol 2020 10 9;50(10):1432-1446. Epub 2020 Sep 9.

Department of Immunology, Labor Berlin Charité - Vivantes GmbH, Berlin, Germany.

This evidence-based clinical guideline provides consensus-recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss, and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, and evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus-based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation, autoimmunity, and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g., antibiotic prophylaxis, management of bronchiectasis) and non-infectious manifestations (e.g., management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible, or unlikely benefit of IgG-replacement therapy. Summary and consensus-recommendations are provided for treatment indication, dosing, routes of administration, and adverse events of IgG-replacement therapy. Special aspects of concomitant impaired T-cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA-4-, and LRBA-deficiency).
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http://dx.doi.org/10.1002/eji.202048713DOI Listing
October 2020

The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity.

Sci Immunol 2020 07;5(49)

St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.

The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1 mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity.
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http://dx.doi.org/10.1126/sciimmunol.abc3979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116756PMC
July 2020

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.

Blood 2020 12;136(23):2638-2655

Dr von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.
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http://dx.doi.org/10.1182/blood.2020006738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735164PMC
December 2020

A rare case of syndromic severe congenital neutropenia: JAGN1 mutation.

Turk J Pediatr 2020 ;62(2):326-331

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, and Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Background: Neutrophils are essential innate cells to fight bacterial and fungal pathogens. Jagunal homolog 1 (JAGN1) mutations were recently defined as rare genetic defects causing severe congenital neutropenia. JAGN1 participates in the secretory pathway and is required for granulocyte colony-stimulating factor receptormediated signalling. This gene is required for normal ultrastructure and granulation of endoplasmic reticulum of myeloid progenitor cells. Its defect is related to increased predisposition to apoptosis. In the literature, a few cases have been reported with congenital anomalies such as cardiac and renal anomalies.

Case: Here we report a patient in which JAGN1 deficiency was found after several years. Apart from syndromic facial appearance we were unable to detect any other systemic malformations.

Conclusion: The causes of multisystemic features of mutations in JAGN1 gene remain unknown. JAGN1 mutations must be considered in patients with severe congenital neutropenia especially with facial dismorphism even in the absence of systemic manifestations.
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http://dx.doi.org/10.24953/turkjped.2020.02.022DOI Listing
August 2021

Supplementation of the ESID registry working definitions for the clinical diagnosis of inborn errors of immunity with encoded human phenotype ontology (HPO) terms.

J Allergy Clin Immunol Pract 2020 05;8(5):1778

Research Unit for Pediatric Hematology and Immunology, Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.02.019DOI Listing
May 2020

The TGF-b/SOX4 axis and ROS-driven autophagy co-mediate CD39 expression in regulatory T-cells.

FASEB J 2020 06 22;34(6):8367-8384. Epub 2020 Apr 22.

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

The ectonucleotidase CD39 on human regulatory T-cells (Treg) is an important immune regulator which is dysregulated in autoimmune diseases and cancer immunosuppression. We here define that CD39 expression on Treg is independent of the Treg-specific transcription factors FOXP3 and HELIOS and promoted by canonical TGF-b- and mTOR-signaling. Furthermore, the TGF-b mediated upregulation of CD39 is counteracted by reactive oxygen species (ROS)-driven autophagy. In line, CD39 peripheral blood Treg constitute a distinct lineage with low autophagic flux and absent ROS production. Patients with rare genetic defects in autophagy show supraphysiological levels of CD39 Treg, validating our observations in vivo. These biological processes rely on a distinct transcriptional program with CD39 Treg expressing low levels of two genes with putative involvement in autophagy, NEFL and PLAC8. Furthermore, the TGF-b downstream transcription factor SOX4 is selectively upregulated in CD39 Treg. Overexpression of SOX4 in Treg strongly increases CD39 expression, while Crispr/Cas9-mediated knockout of SOX4 in Treg has the opposing effect. Thus, we identify a crucial role of SOX4 in immune regulation and provide new insights involving the interplay of tolerogenic cues and autophagy in Treg.
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http://dx.doi.org/10.1096/fj.201902664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317981PMC
June 2020
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