Research

Alternative UNC13D Promoter Encodes a Functional Munc13-4 Isoform Predominantly Expressed in Lymphocytes and Platelets.

June 26, 2020 By Manish Butte

Alternative UNC13D Promoter Encodes a Functional Munc13-4 Isoform Predominantly Expressed in Lymphocytes and Platelets.

Front Immunol. 2020;11:1154

Authors: Galgano D, Soheili T, Voss M, Torralba-Raga L, Tesi B, Cichocki F, Andre I, Rettig J, Cavazzana M, Bryceson Y

Abstract
Autosomal recessive mutations in genes required for cytotoxicity are causative of a life-threatening, early-onset hyperinflammatory syndrome termed familial hemophagocytic lymphohistiocytosis (FHL). Mutations in UNC13D cause FHL type 3. UNC13D encodes Munc13-4, a member of the Unc13 protein family which control SNARE complex formation and vesicle fusion. We have previously identified FHL3-associated mutations in the first intron of UNC13D which control transcription from an alternative transcriptional start site. Using isoform specific antibodies, we demonstrate that this alternative Munc13-4 isoform with a unique N-terminus is preferentially expressed in human lymphocytes and platelets, as compared to the conventional isoform that was mostly expressed in monocytes and neutrophils. The distinct N-terminal of the two isoforms did not impact on Munc13-4 localization or trafficking to the immunological synapse of cytotoxic T cells. Moreover, ectopic expression of both isoforms efficiently restored exocytosis by FHL3 patient-derived Munc13-4 deficient T cells. Thus, we demonstrate that the conventional and alternative Munc13-4 isoforms have different expression pattern in hematopoietic cell subsets, but display similar localization and contribution to T cell exocytosis. The use of an alternative transcriptional starting site (TSS) in lymphocytes and platelets could be selected for increasing the overall levels of Munc13-4 expression for efficient secretory granule release.

PMID: 32582217 [PubMed – in process]

Live Cell Imaging Demonstrates Multiple Routes Toward a STAT1 Gain-of-Function Phenotype.

June 26, 2020 By Manish Butte

Live Cell Imaging Demonstrates Multiple Routes Toward a STAT1 Gain-of-Function Phenotype.

Front Immunol. 2020;11:1114

Authors: Giovannozzi S, Lemmens V, Hendrix J, Gijsbers R, Schrijvers R

Abstract
Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations result in a primary immunodeficiency (PID) characterized typically by chronic mucocutaneous candidiasis (CMC), but a wider phenotypic range is reported and remains unexplained from a pathophysiological point-of-view. We hypothesized that different STAT1 GOF mutations may result in distinct molecular mechanisms, possibly explaining the variable phenotypes observed in patients. We selected STAT1 GOF mutants (R274W, R321S, T419R, and N574I) that are spread over the protein and studied their dynamic behavior in vitro in U3A and HeLa cell lines. All GOF mutants showed increased STAT1 phosphorylation compared to STAT1 WT. Real-time imaging demonstrated three underlying mechanisms for STAT1 GOF: (i) R274W showed a faster nuclear accumulation, (ii) both R321S and N574I showed a reduced nuclear mobility and slower dephosphorylation, whereas (iii) T419R was near-immobile in the nucleus, potentially due to enhanced binding to chromatin.

PMID: 32582194 [PubMed – in process]

Actinotignum schaalii Abscess in a Patient with Common Variable Immunodeficiency.

June 26, 2020 By Manish Butte

Actinotignum schaalii Abscess in a Patient with Common Variable Immunodeficiency.

Pathogens. 2020 Jun 22;9(6):

Authors: Panganiban CM, Gupta S

Abstract
Actinotignum schaalii is an anaerobic, gram-positive commensal organism of the urogenital tract. A. schaalii typically causes urinary tract infections, predominantly in the elderly. Here, we describe the first case of A. schaalii infection presenting as cellulitis and abscess in a patient with common variable immunodeficiency. The patient was successfully treated with an incision and drainage and a prolonged antibiotic course. A. schaalii infection should be considered in sterile abscesses, and anaerobic cultures should be requested in the absence of positive routine cultures.

PMID: 32580346 [PubMed]

Adipokines and Inflammation Alter the Interaction Between Rheumatoid Arthritis Synovial Fibroblasts and Endothelial Cells.

June 26, 2020 By Manish Butte

Adipokines and Inflammation Alter the Interaction Between Rheumatoid Arthritis Synovial Fibroblasts and Endothelial Cells.

Front Immunol. 2020;11:925

Authors: Hasseli R, Frommer KW, Schwarz M, Hülser ML, Schreiyäck C, Arnold M, Diller M, Tarner IH, Lange U, Pons-Kühnemann J, Schönburg M, Rehart S, Müller-Ladner U, Neumann E

Abstract
Objective: The long-distance migration of rheumatoid arthritis synovial fibroblasts (RASFs) in the severe combined immunodeficiency (SCID) mouse model of rheumatoid arthritis (RA) suggests that an interaction between RASFs and endothelial cells (EC) is critical in this process. Our objective was to assess whether immunomodulatory factors such as adipokines and antirheumatic drugs affect the adhesion of RASFs to ECs or the expression of surface molecules. Methods: Primary ECs or human umbilical vein endothelial cell (HUVEC) and primary RASFs were stimulated with adiponectin (10 μg/mL), visfatin (100 ng/mL), and resistin (20 ng/mL) or treated with methotrexate (1.5 and 1,000 μM) and the glucocorticoids prednisolone (1 μM) and dexamethasone (1 μM), respectively. The expression of adhesion molecules was analyzed by real-time polymerase chain reaction. The interaction of both cell types was analyzed under static (cell-to-cell binding assay) and dynamic conditions (flow-adhesion assay). Results: Under static conditions, adipokines increased mostly binding of RASFs to EC (adiponectin: 40%, visfatin: 28%, tumor necrosis factor α: 49%). Under flow conditions, visfatin increased RASF adhesion to HUVEC (e.g., 0.5 dyn/cm2: 75.2%). Reduced adhesion of RASFs to E-selectin was observed after treatment with dexamethasone (e.g., 0.9 dyn/cm2: -40%). In ECs, tumor necrosis factor α (TNF-α) increased expression of intercellular adhesion molecule 1 (20-fold) and vascular cell adhesion molecule 1 (77-fold), whereas P-selectin was downregulated after stimulation with TNF-α (-6-fold). Conclusion: The adhesion of RASFs to EC was increased by visfatin under static and flow conditions, whereas glucocorticoids were able to decrease adhesion to E-selectin. The process of migration and adhesion of RASFs to ECs could be enhanced by adipokines via adhesion molecules and seems to be targeted by therapeutic intervention with glucocorticoids.

PMID: 32582145 [PubMed – in process]

Childhood-onset cerebellar ataxia in Japan: A questionnaire-based survey.

June 26, 2020 By Manish Butte

Childhood-onset cerebellar ataxia in Japan: A questionnaire-based survey.

Brain Behav. 2019 10;9(10):e01392

Authors: Ono H, Shimizu-Motohashi Y, Maruo K, Takeshita E, Ishiyama A, Saito T, Komaki H, Nakagawa E, Sasaki M

Abstract
OBJECTIVE: The diagnosis of childhood-onset cerebellar ataxia (CA) is often challenging due to variations in symptoms and etiologies. Despite the known regional differences in the prevalence of etiologies underlying CA, the frequency and characteristics of CA in Japan remain unclear. We conducted a questionnaire-based survey to identify the clinical characteristics of childhood-onset CA in the Japanese population.
MATERIALS AND METHODS: Questionnaires were sent to 1,103 board-certified pediatric neurologists in Japan from 2016 to 2017. The primary survey requested the number of patients with CA under care, and the follow-up secondary questionnaire requested additional clinical characteristics of the patients.
RESULTS: The primary survey obtained 578 responses (response rate, 52.4%) on 385 patients with CA, including 171 diagnosed and 214 undiagnosed cases (diagnostic rate, 44.4%). The most frequent etiology was dentatorubropallidoluysian atrophy (DRPLA), followed by mitochondrial disorders and encephalitis. The secondary survey obtained the clinical characteristics of 252 cases (119 diagnosed and 133 undiagnosed cases). Multiple logistic regression analysis revealed that a younger age at onset, hearing issues, and short stature were associated with a higher risk of remaining undiagnosed with CA in Japan.
CONCLUSIONS: The diagnostic rate of childhood-onset CA in the current study was comparable to those reported in other countries. The high prevalence of autosomal dominant ataxia, especially DRPLA, was a signature of CA in Japan. These data offer insights into the characteristics of childhood-onset CA in the Japanese population.

PMID: 31469254 [PubMed – indexed for MEDLINE]

Pearls and pitfalls in the diagnosis of hereditary angioedema.

June 26, 2020 By Manish Butte

Pearls and pitfalls in the diagnosis of hereditary angioedema.

Allergy Asthma Proc. 2019 07 01;40(4):282-284

Authors: Li HH

Abstract
Hereditary angioedema is a very disabling and even life-threatening chronic condition. A timely and proper diagnosis of the condition is critical in disease management. Unfortunately, there is the potential for misdiagnosis when using the current laboratory diagnostic tools. Physicians should understand the limitations of each diagnostic assay and judiciously establish this life-altering diagnosis.

PMID: 31262383 [PubMed – indexed for MEDLINE]

Hereditary angioedema: Screening of first-degree blood relatives and earlier diagnosis.

June 26, 2020 By Manish Butte

Hereditary angioedema: Screening of first-degree blood relatives and earlier diagnosis.

Allergy Asthma Proc. 2019 07 01;40(4):279-281

Authors: Valle SOR, Alonso MLO, Tortora RP, Abe AT, Levy SAP, Dortas SD

Abstract
Background: Hereditary angioedema (HAE) with C1 inhibitor (C1INH) deficiency is an inherited disease characterized by sudden, recurrent episodes of edema that involve the skin, gastrointestinal tract, respiratory tract, and other organs. Objective: Because it takes a long time from the first symptoms to diagnosis, we aimed to identify HAE in untested first-degree blood relatives among some of our patients with HAE in our outpatient clinic at Hospital Universitário Clementino Fraga (HUCFF), Federal University of Rio de Janeiro. Methods: Untested first-degree relatives of patients with HAE C1INH, even those who were asymptomatic, were identified and invited to participate. Those who agreed to participate answered a specific questionnaire and had a blood sample collected for complement testing. Results: Fifty untested first-degree relatives of 30 index patients with HAE C1INH were identified, and both groups were analyzed. The mean ± standard deviation (SD) age of the index patients group was 37.08 ± 16.56 years (range, 13-73 years), with a high frequency in women (n = 24 [80.0%]). Most of them had severe (n = 23 [76.7%]) and moderate (n = 7 [23.3%]) attacks. None were asymptomatic. The mean ± SD time between the first symptoms and diagnosis was 20.2 ± 11.06 years (range, 0-48 years) in that group. In the first-degree relatives group, 30 new cases of HAE C1INH (60%) were identified. Conclusion: We found that there was a long time between early manifestations and a diagnosis of HAE. First-degree relatives of patients with HAE patients are at risk for having the disease. Sixty percent were newly diagnosed with HAE and with C1INH deficiency in our study. So, screening of family members, including individuals who were asymptomatic, is the key for earlier diagnosis and effective treatment.

PMID: 31262382 [PubMed – indexed for MEDLINE]

Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences.

June 26, 2020 By Manish Butte

Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences.

J Neurosci. 2019 08 07;39(32):6378-6394

Authors: Song X, Ma F, Herrup K

Abstract
ATM (ataxia-telangiectasia mutated) is a PI3K-like kinase best known for its role in the DNA damage response (DDR), especially after double-strand breaks. Mutations in the ATM gene result in a condition known as ataxia-telangiectasia (A-T) that is characterized by cancer predisposition, radiosensitivity, neurodegeneration, sterility, and acquired immune deficiency. We show here that the innate immune system is not spared in A-T. ATM-deficient microglia adopt an active phenotype that includes the overproduction of proinflammatory cytokines that are toxic to cultured neurons and likely contribute to A-T neurodegeneration. Causatively, ATM dysfunction results in the accumulation of DNA in the cytoplasm of microglia as well as a variety of other cell types. In microglia, cytoplasmic DNA primes an antiviral response via the DNA sensor, STING (stimulator of interferon genes). The importance of this response pathway is supported by our finding that inhibition of STING blocks the overproduction of neurotoxic cytokines. Cytosolic DNA also activates the AIM2 (absent in melanoma 2) containing inflammasome and induces proteolytic processing of cytokine precursors such as pro-IL-1β. Our study furthers our understanding of neurodegeneration in A-T and highlights the role of cytosolic DNA in the innate immune response.SIGNIFICANCE STATEMENT Conventionally, the immune deficiencies found in ataxia-telangiectasia (A-T) patients are viewed as defects of the B and T cells of the acquired immune system. In this study, we demonstrate the microglia of the innate immune system are also affected and uncover the mechanism by which this occurs. Loss of ATM (ataxia-telangiectasia mutated) activity leads to a slowing of DNA repair and an accumulation of cytoplasmic fragments of genomic DNA. This ectopic DNA induces the antivirus response, which triggers the production of neurotoxic cytokines. This expands our understanding of the neurodegeneration found in A-T and offers potentially new therapeutic options.

PMID: 31189575 [PubMed – indexed for MEDLINE]

Swiss newborn screening for severe T and B cell deficiency with a combined TREC/KREC assay – management recommendations.

June 25, 2020 By Manish Butte

Swiss newborn screening for severe T and B cell deficiency with a combined TREC/KREC assay – management recommendations.

Swiss Med Wkly. 2020 Jun 15;150:w20254

Authors: Trück J, Prader S, Natalucci G, Hagmann C, Brotschi B, Kelly J, Bassler D, Steindl K, Rauch A, Baumgartner M, Fingerhut R, Hauri-Hohl M, Güngör T, Pachlopnik Schmid J, Berger C, Reichenbach J

Abstract
The recent introduction of newborn screening for severe primary T and B cell deficiencies in Switzerland allows rapid identification of patients with severe combined immunodeficiency (SCID). Outcomes for SCID are greatly improved by early diagnosis and treatment with allogeneic haematopoietic stem cell transplantation or, in selected cases, gene therapy. National centralised newborn screening is performed in Switzerland since January 2019 using a combined T cell receptor excision circles (TREC) / κ-deleting recombination excision circles (KREC) assay, also revealing infants with non-SCID severe T and B cell disorders, who are often diagnosed with a substantial delay. Here, we outline the screening procedure currently performed in Switzerland and give recommendations for diagnostic evaluations and precautionary measures against infection in children with abnormal screening test results.

PMID: 32579701 [PubMed – as supplied by publisher]

Correction to: A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

June 25, 2020 By Manish Butte

Correction to: A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

J Clin Immunol. 2020 Jun 23;:

Authors: Coignard-Biehler H, Mahlaoui N, Pilmis B, Barlogis V, Brosselin P, De Vergnes N, Debré M, Malphettes M, Frange P, Catherinot E, Pellier I, Durieu I, Perlat A, Royer B, Quellec AL, Jeziorski E, Fischer A, Lortholary O, CEREDIH French PID study group

Abstract
The original version of the article contained error regarding the presentation of the institutional authors in the PDF and html versions.

PMID: 32578002 [PubMed – as supplied by publisher]