Manish Butte

Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical and Genetic Features of 32 Iranian Patients.

J Clin Immunol. 2020 Jun 30;:

Authors: Mahdaviani SA, Mansouri D, Jamee M, Zaki-Dizaji M, Aghdam KR, Mortaz E, Khorasanizadeh M, Eskian M, Movahedi M, Ghaffaripour H, Baghaie N, Hassanzad M, Chavoshzadeh Z, Mansouri M, Mesdaghi M, Ghaini M, Noori F, Eskandarzadeh S, Kahkooi S, Poorabdolah M, Tabarsi P, Moniri A, Farnia P, Karimi A, Boisson-Dupuis S, Rezaei N, Marjani M, Casanova JL, Bustamante J, Velayati AA

Abstract
Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-β1 (IL-12Rβ1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.

PMID: 32602053 [PubMed – as supplied by publisher]

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Prevalence of Immunological Defects in a Cohort of 97 Rubinstein-Taybi Syndrome Patients.

J Clin Immunol. 2020 Jun 27;:

Authors: Saettini F, Herriot R, Prada E, Nizon M, Zama D, Marzollo A, Romaniouk I, Lougaris V, Cortesi M, Morreale A, Kosaki R, Cardinale F, Ricci S, Domínguez-Garrido E, Montin D, Vincent M, Milani D, Biondi A, Gervasini C, Badolato R

Abstract
Although recurrent infections in Rubinstein-Taybi syndrome (RSTS) are common, and probably multifactorial, immunological abnormalities have not been extensively described with only isolated cases or small case series of immune deficiency and dysregulation having been reported. The objective of this study was to investigate primary immunodeficiency (PID) and immune dysregulation in an international cohort of patients with RSTS. All published cases of RSTS were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Ninety-seven RSTS patients were identified. For 45 patients, we retrieved data from the published reports while for 52 patients, a clinical update was provided. Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. Manifestations of immune dysfunctions, affecting mostly B cells, are more common than previously recognized in patients with RSTS. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment. Graphical Abstract.

PMID: 32594341 [PubMed – as supplied by publisher]

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Discontinuation of Immunoglobulin Replacement Therapy in Patients with Secondary Antibody Deficiency.

Expert Rev Clin Immunol. 2020 Jun 26;:

Authors: Patel V, Cowan J

Abstract
INTRODUCTION: Secondary immunodeficiency is becoming a greater medical concern as the usage of immunosuppressive and biological treatments has increased. Individuals with certain medical conditions, such as hematological malignancies, can also have secondary immunodeficiency. Immunoglobulin replacement therapy (IGRT), which has been used for decades in inherited or primary immunodeficiency, provides some protection to patients with acquired and predominant antibody deficiency, i.e. secondary antibody deficiency (SAD). However, IGRT is costly, and supplies are limited. Although there are clinical guidelines on when to initiate IGRT, there is no guideline on when to discontinue it.
AREAS COVERED: The authors reviewed existing literature and provided an overview of the current state of knowledge regarding IGRT discontinuation in SAD patients.
EXPERT OPINION: Long-term supplementary immunoglobulin may not be necessary. Although it is possible to successfully transition away from IGRT in individuals with SAD, evidence-based practices are limited. Without clear guidelines and reliable prognostic markers, IGRT discontinuation practices are restricted to clinical judgment. For this reason, additional research should be conducted to identify markers that indicate the recovery of humoral immunity. Furthermore, the derivation and validation of a set of combined clinical and laboratory criteria to allow safe and timely IGRT discontinuation is warranted.

PMID: 32588670 [PubMed – as supplied by publisher]

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Evaluation of Radiation Sensitivity in Patients with Hyper IgM Syndrome.

Immunol Invest. 2020 Jun 25;:1-17

Authors: Fekrvand S, Mozdarani H, Delavari S, Sohani M, Nazari F, Kiaee F, Bagheri Y, Azizi G, Hassanpour G, Mozdarani S, Abolhassani H, Aghamohammadi A, Yazdani R

Abstract
BACKGROUND: HIGM syndrome is a rare form of primary immunodeficiencies characterized by normal/increased amounts of serum IgM and decreased serum levels of other switched immunoglobulin classes. Since the affected patients are continuously infected with various types of pathogens and are susceptible for cancers, diagnostic and therapeutic tests including imaging techniques are recommended for the diagnosis and treatment of these patients, which predispose them to higher accumulated doses of radiation. Given the evidence of class switching recombination machinery defect and its association with an increased rate of DNA repair, we aimed to evaluate radiation sensitivity among a group of patients diagnosed with HIGM syndrome.
METHODS: 19 HIGM patients (14 CD40 L and 3 AID deficiencies and 2 unsolved cases without known genetic defects) and 17 control subjects (10 healthy subjects as negative control group, 7 ataxia-telangiectasia patients as positive control group) were enrolled. G2 assay was carried out for the determination of radiosensitivity.
RESULTS: Based on radiation-induced chromosomal changes among the studied HIGM patients and their comparison with the controls, almost all (95%) the patients had degrees of radiosensitivity: 6 patients with low to moderate, 1 patient with moderate, 11 patients with severe and 1 patient without radiation sensitivity.
CONCLUSION: Today, X-ray radiation plays a very important role in diagnostic and therapeutic procedures; while increased exposure has devastating effects especially in radiosensitive patients. Considering higher sensitivity in HIGM patients, utilizing radiation-free techniques could partly avoid unnecessary and high-level exposure to radiation, thus preventing or reducing its harmful effects on the affected patients.

PMID: 32584193 [PubMed – as supplied by publisher]

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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]

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