Publications by authors named "Mikko Seppänen"

81 Publications

Mutation Is Associated with Increased STAT1 and STAT5 Activation in Two Family Members with Inflammatory Conditions and Lymphopenia.

Pharmaceuticals (Basel) 2021 Aug 13;14(8). Epub 2021 Aug 13.

Molecular Immunology Group, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.

Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional coregulator that has an important role in the regulation of the immune response. IRF2BP2 has been associated with the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, but its exact role remains elusive. Here, we identified a novel clinical variant, c.625_665del, from two members of a family with inflammatory conditions and investigated the function of IRF2BP2 and c.625_665del mutation in JAK-STAT pathway activation and inflammatory signaling. The levels of constitutive and cytokine-induced phosphorylation of STATs and total STAT1 in peripheral blood monocytes, T cells, and B cells from the patients and four healthy controls were measured by flow cytometry. Inflammation-related gene expression was studied in peripheral blood mononuclear cells using direct digital detection of mRNA (NanoString). Finally, we studied the relationship between IRF2BP2 and STAT1 activation using a luciferase reporter system in a cell model. Our results show that patients having the c.625_665del mutation presented overexpression of STAT1 protein and increased constitutive activation of STAT1. In addition, interferon-induced JAK-STAT signaling was upregulated, and several interferon-inducible genes were overexpressed. Constitutive phosphorylation of STAT5 was also found to be upregulated in CD4 T cells from the patients. Using a cell model, we show that IRF2BP2 was needed to attenuate STAT1 transcriptional activity and that IRF2BP2 c.625_665del mutation failed in this. We conclude that IRF2BP2 has an important role in suppressing immune responses elicited by STAT1 and STAT5 and suggest that aberrations in IRF2BP2 can lead to abnormal function of intrinsic immunity.
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http://dx.doi.org/10.3390/ph14080797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402006PMC
August 2021

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations.

J Allergy Clin Immunol 2021 Apr 23. Epub 2021 Apr 23.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany. Electronic address:

Background: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.

Objective: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.

Methods: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.

Results: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.

Conclusions: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.
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http://dx.doi.org/10.1016/j.jaci.2021.04.015DOI Listing
April 2021

Pulmonary Follow-Up Imaging in Cartilage-Hair Hypoplasia: a Prospective Cohort Study.

J Clin Immunol 2021 07 5;41(5):1064-1071. Epub 2021 Mar 5.

Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Stenbäckinkatu 9, P.O. Box 347, 00029 HUS, Helsinki, Finland.

Cartilage-hair hypoplasia is a syndromic immunodeficiency with short stature, chondrodysplasia, and variable degree of immune dysfunction. Patients with cartilage-hair hypoplasia are prone to recurrent respiratory tract infections, and the prevalence of bronchiectasis ranges from 29 to 52%. Pulmonary complications contribute significantly to the mortality; therefore, regular lung imaging is essential. However, the optimal schedule for repeated lung imaging remains unestablished. We determined the rate and correlates of progression of structural lung changes in a prospectively followed cohort of 16 patients with cartilage-hair hypoplasia. We analyzed clinical, laboratory, and pulmonary functional testing data and performed lung magnetic resonance imaging at a median interval of 6.8 years since previous imaging. Imaging findings remained identical or improved due to disappearance of inflammatory changes in all evaluated patients. Patients with subtle signs of bronchiectasis on imaging tended to have low immunoglobulin M levels, as well as suffered from pneumonia during the follow-up. In conclusion, our results suggest slow if any development of bronchiectasis in selected subjects with cartilage-hair hypoplasia.
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http://dx.doi.org/10.1007/s10875-021-01007-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249260PMC
July 2021

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

J Clin Immunol 2021 04 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

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

Herpes simplex virus 2 encephalitis in a patient heterozygous for a TLR3 mutation.

Neurol Genet 2020 Dec 25;6(6):e532. Epub 2020 Nov 25.

Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.

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http://dx.doi.org/10.1212/NXG.0000000000000532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720273PMC
December 2020

Somatic mutations and T-cell clonality in patients with immunodeficiency.

Haematologica 2020 12 1;105(12):2757-2768. Epub 2020 Dec 1.

Hematology Research Unit Helsinki, University of Helsinki, HUS, Helsinki, Finland.

Common variable immunodeficiency and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is however implicated. To study whether somatic mutations in CD4+ and CD8+ T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset common variable immunodeficiency and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2533 immune-associated genes from CD4+ and CD8+ cells. Deep T-cell receptor beta sequencing was used to characterize CD4+ and CD8+ T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in common variable immunodeficiency and 48% in controls. Clonal hematopoiesis-associated variants in both CD4+ and CD8+ cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immune- and proliferative functions, such as STAT5B (two patients), C5AR1 (two patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, common variable immunodeficiency patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4+ and CD8+ cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.
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http://dx.doi.org/10.3324/haematol.2019.220889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716374PMC
December 2020

Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis.

J Clin Immunol 2020 11 16;40(8):1156-1162. Epub 2020 Sep 16.

Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.

Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.
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http://dx.doi.org/10.1007/s10875-020-00834-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567724PMC
November 2020

Behçet disease (BD) and BD-like clinical phenotypes: NF-κB pathway in mucosal ulcerating diseases.

Scand J Immunol 2020 Nov 10;92(5):e12973. Epub 2020 Oct 10.

Rare Disease and Pediatric Research Centers, Hospital for Children and Adolescents and Adult Immunodeficiency Unit, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.

Behçet's disease (BD) is a heterogeneous multi-organ disorder in search of a unified pathophysiological theory and classification. The disease frequently has overlapping features resembling other disease clusters, such as vasculitides, spondyloarthritides and thrombophilias with similar genetic risk variants, namely HLA-B*51, ERAP1, IL-10, IL-23R. Many of the BD manifestations, such as unprovoked recurrent episodes of inflammation and increased expression of IL-1, IL-6 and TNFα, overlap with those of the hereditary monogenic autoinflammatory syndromes, positioning BD at the crossroads between autoimmune and autoinflammatory syndromes. BD-like disease associates with various inborn errors of immunity, including familial Mediterranean fever, conditions related to dysregulated NF-κB activation (eg TNFAIP3, NFKB1, OTULIN, RELA, IKBKG) and either constitutional trisomy 8 or acquired trisomy 8 in myelodysplastic syndromes. We review here the recent advances in the immunopathology of BD, BD-like diseases and the NF-κB pathway suggesting new elements in the elusive BD etiopathogenesis.
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http://dx.doi.org/10.1111/sji.12973DOI Listing
November 2020

Global systematic review of primary immunodeficiency registries.

Expert Rev Clin Immunol 2020 07;16(7):717-732

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

Introduction: During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear.

Areas Covered: Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients.

Expert Opinion: Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.
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http://dx.doi.org/10.1080/1744666X.2020.1801422DOI Listing
July 2020

Tonsillar granuloma associated with hypogammaglobulinemia.

Allergy Asthma Clin Immunol 2020 29;16:43. Epub 2020 May 29.

Research Unit of Biomedicine, University of Oulu, Oulu, Finland.

Background: Rare tonsillar granulomas may be caused for example by infections, malignancies or sarcoidosis. Granulomas also occur in inborn errors of immunity (IEI) such as common variable immunodeficiency (CVID) with B cell maturation defects and hypogammaglobulinemia. CVID shares various features with sarcoidosis and drug-induced secondary hypogammaglobulinemia; careful consideration of differential diagnosis between these conditions is warranted.

Case Presentation: A 29-year-old female with epilepsy developed dysphagia, dyspnea and impaired exercise tolerance. Obstruction caused by swollen lingual tonsil and edema in the epiglottis and arytenoid mucosa were found. Lingual tonsil and epiglottis biopsies displayed non-necrotizing granulomas. There was no evidence of viral, bacterial, mycobacterial or fungal infections. Chest X-ray, computerized tomography of chest and ultrasound of neck and abdomen remained unremarkable. Positron emission tomography/computed tomography (PET/CT) showed laryngeal enhancement. Empiric antimicrobials combined with prednisolone were insufficient to control her disease. In immunological evaluation, the patient had normal counts of B and T cells. Proportions of CD27 memory B cells (30.3%) and IgDIgMCD27 switched memory B cells (7.2%; normal range 6.5-29.2%) were normal. Percentage of activated CD21 B cells was high (6.6%; normal range 0.6-3.5%). IgG (3.5 g/L; normal range 6.77-15.0 g/l) and all IgG subclass concentrations were low. Anti-polysaccharide responses were impaired, with 3/10 serotypes reaching a level of 0.35 µg/ml after immunization with Pneumovax. The findings were consistent with hypogammaglobulinemia resembling CVID, possibly secondary to antiepileptic medication. Her dyspnea and dysphagia responded favorably to subcutaneous IgG and rituximab.

Conclusions: Tonsillar granulomas can be the presenting and only clinical feature of B cell deficiency, highlighting the diversity of symptoms and findings in primary or secondary immunodeficiencies.
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http://dx.doi.org/10.1186/s13223-020-00441-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257222PMC
May 2020

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

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

J Allergy Clin Immunol 2020 10 9;146(4):901-911. Epub 2020 Apr 9.

Primary Immunodeficiencies Unit, Hospital Dona Estefania, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.

Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes.

Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations.

Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling.

Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents.

Conclusions: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
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http://dx.doi.org/10.1016/j.jaci.2019.11.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246418PMC
October 2020

Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency.

J Clin Immunol 2020 04 19;40(3):503-514. Epub 2020 Feb 19.

Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.

Hypomorphic IL2RG mutations may lead to milder phenotypes than X-SCID, named variably as atypical X-SCID or X-CID. We report an 11-year-old boy with a novel c. 172C>T;p.(Pro58Ser) mutation in IL2RG, presenting with atypical X-SCID phenotype. We also review the growing number of hypomorphic IL2RG mutations causing atypical X-SCID. We studied the patient's clinical phenotype, B, T, NK, and dendritic cell phenotypes, IL2RG and CD25 cell surface expression, and IL-2 target gene expression, STAT tyrosine phosphorylation, PBMC proliferation, and blast formation in response to IL-2 stimulation, as well as protein-protein interactions of the mutated IL2RG by BioID proximity labeling. The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis. His total lymphocyte counts have remained normal despite skewed T and B cells subpopulations, with very low numbers of plasmacytoid dendritic cells. Surface expression of IL2RG was reduced on his lymphocytes. This led to impaired STAT tyrosine phosphorylation in response to IL-2 and IL-21, reduced expression of IL-2 target genes in patient CD4+ T cells, and reduced cell proliferation in response to IL-2 stimulation. BioID proximity labeling showed aberrant interactions between mutated IL2RG and ER/Golgi proteins causing mislocalization of the mutated IL2RG to the ER/Golgi interface. In conclusion, IL2RG p.(Pro58Ser) causes X-CID. Failure of IL2RG plasma membrane targeting may lead to atypical X-SCID. We further identified another carrier of this mutation from newborn SCID screening, lost to closer scrutiny.
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http://dx.doi.org/10.1007/s10875-020-00745-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142052PMC
April 2020

European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management.

J Clin Immunol 2020 05 17;40(4):576-591. Epub 2020 Feb 17.

Immunodeficiency Centre for Wales, Cardiff University & University Hospital of Wales, Cardiff, UK.

This guideline aims to describe the complement system and the functions of the constituent pathways, with particular focus on primary immunodeficiencies (PIDs) and their diagnosis and management. The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components. There are three distinct enzymatic cascade pathways within the complement system, the classical, alternative and lectin pathways, which converge with the cleavage of central C3. Complement deficiencies account for ~5% of PIDs. The clinical consequences of inherited defects in the complement system are protean and include increased susceptibility to infection, autoimmune diseases (e.g., systemic lupus erythematosus), age-related macular degeneration, renal disorders (e.g., atypical hemolytic uremic syndrome) and angioedema. Modern complement analysis allows an in-depth insight into the functional and molecular basis of nearly all complement deficiencies. However, therapeutic options remain relatively limited for the majority of complement deficiencies with the exception of hereditary angioedema and inhibition of an overactivated complement system in regulation defects. Current management strategies for complement disorders associated with infection include education, family testing, vaccinations, antibiotics and emergency planning.
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http://dx.doi.org/10.1007/s10875-020-00754-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253377PMC
May 2020

A Family With A20 Haploinsufficiency Presenting With Novel Clinical Manifestations and Challenges for Treatment.

J Clin Rheumatol 2020 Jan 21. Epub 2020 Jan 21.

Clinicum, Faculty of Medicine, University of Helsinki, Helsinki.

Background: Tumor necrosis factor α-induced protein 3 gene (TNFAIP3, also called A20) haploinsufficiency (HA20) leads to autoinflammation and autoimmunity. We have recently shown that a p.(Lys91*) mutation in A20 disrupts nuclear factor κB signaling, impairs protein-protein interactions of A20, and leads to inflammasome activation.

Methods: We now describe the clinical presentations and drug responses in a family with HA20 p.(Lys91*) mutation, consistent with our previously reported diverse immunological and functional findings.

Results: We report for the first time that inflammasome-mediated autoinflammatory lung reaction caused by HA20 can be treated with interleukin 1 antagonist anakinra. We also describe severe anemia related to HA20 successfully treated with mycophenolate. In addition, HA20 p.(Lys91*) was found to associate with autoimmune thyroid disease, juvenile idiopathic arthritis, psoriasis, liver disease, and immunodeficiency presenting with specific antibody deficiency and genital papillomatosis.

Conclusions: We conclude that HA20 may lead to combination of inflammation, immunodeficiency, and autoimmunity. The condition may present with variable and unpredictable symptoms with atypical treatment responses.
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http://dx.doi.org/10.1097/RHU.0000000000001268DOI Listing
January 2020

Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score.

J Allergy Clin Immunol 2020 05 27;145(5):1452-1463. Epub 2019 Dec 27.

Department of Bone Marrow Transplantation, Hadassah, Hebrew University Medical Centre, Jerusalem, Israel.

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant.

Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant.

Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices.

Results: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome.

Conclusion: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.
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http://dx.doi.org/10.1016/j.jaci.2019.12.896DOI Listing
May 2020

Novel TMEM173 Mutation and the Role of Disease Modifying Alleles.

Front Immunol 2019 5;10:2770. Epub 2019 Dec 5.

Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

Upon binding to pathogen or self-derived cytosolic nucleic acids cyclic GMP-AMP synthase (cGAS) triggers the production of cGAMP that further activates transmembrane protein STING. Upon activation STING translocates from ER via Golgi to vesicles. Monogenic STING gain-of-function mutations cause early-onset type I interferonopathy, with disease presentation ranging from fatal vasculopathy to mild chilblain lupus. Molecular mechanisms underlying the variable phenotype-genotype correlation are presently unclear. Here, we report a novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and features of STING-associated vasculopathy with onset in infancy (SAVI), such as livedo reticularis, skin vasculitis, nasal septum perforation, facial erythema, and bacterial infections. Polymorphism in and showed variable penetrance in the affected family, implying contribution to varying phenotype spectrum. The G207E mutation constitutively activates inflammation-related pathways , and causes aberrant interferon signature and inflammasome activation in patient PBMCs. Treatment with Janus kinase 1 and 2 (JAK1/2) inhibitor baricitinib was beneficiary for a vasculitic ulcer, induced hair regrowth and improved overall well-being in one patient. Protein-protein interactions propose impaired cellular trafficking of G207E mutant. These findings reveal the molecular landscape of STING and propose common polymorphisms in and as likely modifiers of the phenotype.
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http://dx.doi.org/10.3389/fimmu.2019.02770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907089PMC
November 2020

Nagashima-type palmoplantar keratosis in Finland caused by a SERPINB7 founder mutation.

J Am Acad Dermatol 2020 Aug 7;83(2):643-645. Epub 2019 Nov 7.

Department of Dermatology, Skin and Allergy Hospital, University of Helsinki, ERN-skin, and Helsinki University Hospital, Helsinki, Finland.

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http://dx.doi.org/10.1016/j.jaad.2019.11.004DOI Listing
August 2020

Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease.

NPJ Genom Med 2019 27;4:14. Epub 2019 Jun 27.

1Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

Mutations in several proteins functioning as endolysosomal components cause monogenic autoimmune diseases, of which pathogenesis is linked to increased endoplasmic reticulum stress, inefficient autophagy, and defective recycling of immune receptors. We report here a heterozygous p.G307D missense mutation, detected by whole-exome sequencing, in two related patients presenting with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. The index patient suffered from recurrent respiratory tract infections and oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia, as well as an antibody deficiency. Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris. Consistent with previous knowledge on TOM1 protein function, we detected impaired autophagy and enhanced susceptibility to apoptosis in patient-derived cells. In addition, we noted diminished STAT and ERK1/2 signaling in patient fibroblasts, as well as poor IFN-γ and IL-17 secretion in T cells. The mutant TOM1 failed to interact with TOLLIP, a protein required for IL-1 recycling, PAMP signaling and autophagosome maturation, further strengthening the link between the candidate mutation and patient pathophysiology. In sum, we report here an identification of a novel gene, , associating with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. Other patient cases from unrelated families are needed to firmly establish a causal relationship between the genotype and the phenotype.
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http://dx.doi.org/10.1038/s41525-019-0088-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597545PMC
June 2019

Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy.

J Allergy Clin Immunol 2019 11 13;144(5):1364-1376. Epub 2019 Jun 13.

Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.

Background: CCAAT enhancer-binding protein epsilon (C/EBPε) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality.

Objective: The aim of this study was to molecularly characterize the effects of C/EBPε transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome.

Methods: Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed.

Results: Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages.

Conclusion: We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBPε. Mutated C/EBPε acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPε. Similar multiomics approaches should also be used in studying other transcription factor-associated diseases.
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http://dx.doi.org/10.1016/j.jaci.2019.06.003DOI Listing
November 2019

Primary Immunodeficiency, a Possible Cause of Neutrophilic Necrotizing Dermatosis.

JAMA Dermatol 2019 07;155(7):863-864

Rare Disease Center, New Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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http://dx.doi.org/10.1001/jamadermatol.2019.1201DOI Listing
July 2019

Novel DSP Spectrin 6 Region Variant Causes Neonatal Erythroderma, Failure to Thrive, Severe Herpes Simplex Infections and Brain Lesions.

Acta Derm Venereol 2019 Jul;99(9):789-796

Children's Hospital, University of Helsinki and Helsinki University Hospital, FIN-00290 Helsinki, Finland.

Desmoplakin (DSP) and Desmoglein 1 (DSG1) variants result in skin barrier defects leading to erythroderma, palmoplantar keratoderma and variable [AQ4] other features. Some DSG1 variant carriers present with SAM syndrome (Severe dermatitis, multiple Allergies, Metabolic wasting) and a SAM-like phenotype has been reported in 4 subjects with different heterozygous DSP variants. We report here a patient with a novel DSP spectrin region (SR) 6 variant c.1756C>T, p.(His586Tyr), novel features of brain lesions and severe recurrent mucocutaneous herpes simplex virus infections, with a favourable response to ustekinumab. Through a review of reported cases of heterozygous variants in DSP SR6 (n = 15) and homozygous or compound heterozygous variants in DSG1 (n = 12) and SAM-like phenotype, we highlight phenotypic variability. Woolly hair, nail abnormalities and cardiomyopathy characterize patients with DSP variants, while elevated immunoglobulin E and food allergies are frequent in patients with DSG1 variants. Clinicians should be aware of the diverse manifestations of desmosomopathies.
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http://dx.doi.org/10.2340/00015555-3203DOI Listing
July 2019

X-linked agammaglobulinemia (XLA):Phenotype, diagnosis, and therapeutic challenges around the world.

World Allergy Organ J 2019 22;12(3):100018. Epub 2019 Mar 22.

Department of Medicine and Sciences of Aging, University "G. d'Annunzio" of Chieti-Pescara, Italy.

Background: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features.

Methods: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries.

Results: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians.

Conclusions: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.
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http://dx.doi.org/10.1016/j.waojou.2019.100018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439403PMC
March 2019

Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

Nat Commun 2019 03 19;10(1):1252. Epub 2019 Mar 19.

Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, CH-4031, Switzerland.

Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.
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http://dx.doi.org/10.1038/s41467-019-09198-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424975PMC
March 2019

A High Prevalence of Gastrointestinal Manifestations in Common Variable Immunodeficiency.

Am J Gastroenterol 2019 04;114(4):648-655

Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objectives: Common variable immunodeficiency (CVID) is associated with a spectrum of autoimmune complications. We studied the prevalence of gastrointestinal (GI) manifestations and infections in patients with CVID.

Methods: Complete clinical data of 132 Finnish patients with CVID (106 probable and 26 possible CVID) followed up between 2007 and 2016 were collected to a structured database. Data on endoscopies, histology, and laboratory studies were retrieved from patient files.

Results: Most common referral indications were diarrhea and/or weight loss (47%-67%). Patients with probable CVID had higher fecal calprotectin and α1-antitrypsin and lower blood vitamin B12 than patients with possible CVID. Gastroscopy and colonoscopy were done to 71 (67%) and 63 (59%) patients with probable CVID, respectively. Endoscopies showed that 15% of them had chronic active gastritis and 17% atrophic gastritis and 3% had gastric adenocarcinoma. A celiac sprue-like condition was found in 7 patients (10%), of whom 3 responded to a gluten-free diet. Colonoscopies demonstrated unspecific colitis (14%), ulcerative colitis (8%), microscopic colitis (10%), and Crohn's disease (2%). Colonic polyps were noted in 30% of patients, and 3% had lower GI malignancies. Thirty-five patients with CVID had bacterial or parasitic gastroenteritis; chronic norovirus was detected in 4 patients with probable CVID. Patients with GI inflammation had higher levels of fecal calprotectin and blood CD8 T lymphocytes but lower counts of CD19CD27 memory B cells and/or CD19 B cells. Immunophenotype with low B-cell counts was associated with higher fecal calprotectin levels.

Discussion: Patients with CVID had a high prevalence of GI manifestations and infections of the GI tract. GI inflammation was associated with a distinct immunophenotype and elevated fecal calprotectin.
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http://dx.doi.org/10.14309/ajg.0000000000000140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455088PMC
April 2019

Rubella Virus-Associated Cutaneous Granulomatous Disease: a Unique Complication in Immune-Deficient Patients, Not Limited to DNA Repair Disorders.

J Clin Immunol 2019 01 3;39(1):81-89. Epub 2019 Jan 3.

Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Department of Pediatrics, University of Washington, Seattle, WA, USA.

The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.
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http://dx.doi.org/10.1007/s10875-018-0581-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739844PMC
January 2019

Haploinsufficiency of A20 impairs protein-protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation.

RMD Open 2018 17;4(2):e000740. Epub 2018 Oct 17.

Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.

Objectives: encodes A20 that negatively regulates nuclear factor kappa light chain enhancer of activated B cells (NF-κB), the major transcription factor coordinating inflammatory gene expression. polymorphisms have been linked with a spectrum of inflammatory and autoimmune diseases and, recently, loss-of-function mutations in A20 were found to cause a novel inflammatory disease 'haploinsufficiency of A20' (HA20). Here we describe a family with HA20 caused by a novel loss-of-function mutation and elucidate the upstream molecular mechanisms linking HA20 to dysregulation of NF-κB and the related inflammasome pathway.

Methods: NF-κB activation was studied in a mutation-expressing cell line using luciferase reporter assay. Physical and close-proximity protein-protein interactions of wild-type and p.(Lys91*) mutant A20 were analysed using mass spectrometry. NF-κB -dependent transcription, cytokine secretion and inflammasome activation were compared in immune cells of the HA20 patients and control subjects.

Results: The protein-protein interactome of p.(Lys91*) mutant A20 was severely impaired, including interactions with proteins regulating NF-κB activation, DNA repair responses and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The p.(Lys91*) mutant A20 failed to suppress NF-κB signalling, which led to increased NF-κB -dependent proinflammatory cytokine transcription. Functional experiments in the HA20 patients' immune cells uncovered a novel caspase-8-dependent mechanism of NLRP3 inflammasome hyperresponsiveness that mediated the excessive secretion of interleukin-1β and interleukin-18.

Conclusions: The current findings significantly deepen our understanding of the molecular mechanisms underlying HA20 and other diseases associated with reduced A20 expression or function, paving the way for future therapeutic targeting of the pathway.
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http://dx.doi.org/10.1136/rmdopen-2018-000740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203104PMC
October 2018

Novel cytoskeletal mutations with immunodeficiency: Why is the raven like a writing desk?

J Allergy Clin Immunol 2018 11 4;142(5):1444-1446. Epub 2018 Sep 4.

Rare Diseases Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.08.020DOI Listing
November 2018

Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders.

Orphanet J Rare Dis 2018 08 17;13(1):139. Epub 2018 Aug 17.

Rare Disease Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.

Methods: Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.

Results: In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.

Conclusions: Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.
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http://dx.doi.org/10.1186/s13023-018-0864-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097299PMC
August 2018
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