scholarly journals Effective anti-mycobacterial treatment for BCG disease in patients with Mendelian Susceptibility to Mycobacterial Disease (MSMD)

2021 ◽  
Author(s):  
Seyed Alireza Mahdaviani ◽  
Mazdak Fallahi ◽  
Mahnaz Jamee ◽  
Majid Marjani ◽  
Payam Tabarsi ◽  
...  
Keyword(s):  
Second Line ◽  
Mycobacterial Disease ◽  
Inborn Errors ◽  
Laboratory Findings ◽  
Post Vaccination ◽  
Purified Protein Derivative ◽  
Ifn Γ ◽  
Therapeutic Protocols ◽  
Gastric Washing

Abstract Background/purpose: Post-vaccination BCG disease typically attests to underlying inborn errors of immunity (IEIs), with the highest rates of complications in patients with Mendelian susceptibility to mycobacterial disease (MSMD). However, therapeutic protocols for the management of BCG-osis (disseminated) and persistent BCG-itis (localized) are still controversial. Methods: Twenty-four Iranian patients with MSMD (BCG-osis or BCG-itis), followed from 2009 to 2020 in Tehran, were included in the study. Their medical records were retrospectively reviewed for demographics, clinical features, laboratory findings, and molecular diagnosis. The therapeutic protocol sheets were prepared to contain the types and duration of anti-mycobacterial agents. Results: BCG disease either as BCG-itis (33.3%) or BCG-osis (66.7%) was confirmed in all patients by positive gastric washing test (54.2%), microbial smear and culture (58.3%), or purified protein derivative (PPD) test (4.2%). The duration between BCG-osis onset and MSMD diagnosis was 21.6 months. All except three patients were initiated on second-line anti-mycobacterial agents with either a fluoroquinolone (levofloxacin: 15 mg/kg/day, ciprofloxacin: 20 mg/kg/day, ofloxacin: 15 mg/kg/day), aminoglycoside (amikacin: 10-15 mg/kg/day, streptomycin: 15 mg/kg/day), and/or macrolide (clarithromycin: 15 mg/kg/day) along with oral rifampin (10 mg/kg/day), isoniazid (15 mg/kg/day), and ethambutol (20 mg/kg/day). Three patients showed a clinical response to rifampin, despite in vitro resistance. Fourteen (58.3%) patients received also adjuvant subcutaneous IFN-γ therapy, 50 µ/m2 every other day. At the end of survey, most patients (n=22, 91.7%) were alive and two patients died following BCG-osis and respiratory failure. Conclusion: We recommend the early instigation of second-line anti-mycobacterial agents in MSMD patients with BCG disease.

scholarly journals Effective anti-mycobacterial treatment for BCG disease in patients with Mendelian Susceptibility to Mycobacterial Disease (MSMD)

2021 ◽  
Author(s):  
Seyed Alireza Mahdaviani ◽  
Mazdak Fallahi ◽  
Mahnaz Jamee ◽  
Majid Marjani ◽  
Payam Tabarsi ◽  
...  
Keyword(s):  
Second Line ◽  
Mycobacterial Disease ◽  
Inborn Errors ◽  
Laboratory Findings ◽  
Post Vaccination ◽  
Purified Protein Derivative ◽  
Ifn Γ ◽  
Therapeutic Protocols ◽  
Gastric Washing

Abstract Background: Post-vaccination BCG disease typically attests to underlying inborn errors of immunity (IEIs), with the highest rates of complications in patients with Mendelian susceptibility to mycobacterial disease (MSMD). However, therapeutic protocols for the management of BCG-osis (disseminated) and persistent BCG-itis (localized) are still controversial. Methods: Twenty-four Iranian patients with MSMD (BCG-osis or BCG-itis), followed from 2009 to 2020 in Tehran, were included in the study. Their medical records were retrospectively reviewed for demographics, clinical features, laboratory findings, and molecular diagnosis. The therapeutic protocol sheets were prepared to contain the types and duration of anti-mycobacterial agents. Results: BCG disease either as BCG-itis (33.3%) or BCG-osis (66.7%) was confirmed in all patients by positive gastric washing test (54.2%), microbial smear and culture (58.3%), or purified protein derivative (PPD) test (4.2%). The duration between BCG-osis onset and MSMD diagnosis was 21.6 months. All except three patients were initiated on second-line anti-mycobacterial agents with either a fluoroquinolone (levofloxacin: 15 mg/kg/day, ciprofloxacin: 20 mg/kg/day, ofloxacin: 15 mg/kg/day), aminoglycoside (amikacin: 10-15 mg/kg/day, streptomycin: 15 mg/kg/day), and/or macrolide (clarithromycin: 15 mg/kg/day) along with oral rifampin (10 mg/kg/day), isoniazid (15 mg/kg/day), and ethambutol (20 mg/kg/day). Three patients showed a clinical response to rifampin, despite in vitro resistance. Fourteen (58.3%) patients received also adjuvant subcutaneous IFN-γ therapy, 50 µ/m2 every other day. At the end of survey, most patients (n=22, 91.7%) were alive and two patients died following BCG-osis and respiratory failure. Conclusions: We recommend the early instigation of second-line anti-mycobacterial agents in MSMD patients with BCG disease.

scholarly journals Coordinated In Vitro Release of Granulysin, Perforin and IFN-γ in TB and HIV/TB Co-Infection Associated with Clinical Outcomes before and after Anti-TB Treatment

Pathogens ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 655
Author(s):  
Nada Pitabut ◽  
Panadda Dhepakson ◽  
Shinsaku Sakurada ◽  
Naoto Keicho ◽  
Srisin Khusmith
Keyword(s):  
Clinical Outcomes ◽  
Mononuclear Cells ◽  
Granzyme B ◽  
In Vitro Release ◽  
Peripheral Blood Mononuclear ◽  
Purified Protein Derivative ◽  
Tb Treatment ◽  
Before And After ◽  
Ifn Γ

Granule-associated killing molecules released from cytotoxic T lymphocytes participate as a crucial step in immunity against tuberculosis (TB), but the role of coordinated production remains controversial. Coordinated release of effector molecules in vitro after stimulating peripheral blood mononuclear cells (PBMCs) of active TB or HIV/TB coinfection patients with PPD, purified protein derivative of tuberculin and avirulent Mtb, H37Ra, an attenuated strain were investigated in association with clinical outcomes. Perforin, granzyme-B, granulysin and IFN-γ were measured using ELISA. Before anti-TB treatment, PBMCs of TB stimulated with PPD or H37Ra released higher perforin, granzyme-B, and granulysin levels than in HIV/TB and released significantly higher IFN-γ (p = 0.045, p = 0.022). Granulysin positively correlated with perforin in TB (p = 0.042, r = 0.385), HIV/TB coinfection (p = 0.003, r = 0.941) after PPD stimulation, and after H37Ra stimulation in TB (p = 0.005, r = 0.549), but negatively correlated with granzyme B in TB (p = 0.042, r = −0.386), HIV/TB coinfection (p = 0.042, r = 0.754) were noted. After anti-TB treatment, increased levels of perforin, granulysin and IFN-γ in TB or HIV/TB upon PPD or H37Ra stimulation, and decreased granzyme-B levels after PPD (p = 0.003) or H37Ra (p = 0.028) stimulation in TB were observed. These results suggest that granulysin may act synergistic with perforin and IFN-γ in TB, indicating its crucial function in host immunity to tuberculosis. Future studies with larger numbers of patients ought to be conducted in the future.

scholarly journals Phenotypic and immune functional profiling of patients with suspected Mendelian Susceptibility to Mycobacterial Disease in South Africa

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Ansia van Coller ◽  
Brigitte Glanzmann ◽  
Helena Cornelissen ◽  
Marlo Möller ◽  
Craig Kinnear ◽  
...  
Keyword(s):  
South Africa ◽  
Molecular Diagnosis ◽  
Mycobacterial Disease ◽  
Management Options ◽  
Mycobacterial Infections ◽  
Functional Assays ◽  
High Prevalence ◽  
Functional Profiling ◽  
Ifn Γ

Abstract Background Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a primary immunodeficiency (PID) characterised by a predisposition to infection by weakly-pathogenic mycobacteria. In countries with a high prevalence of tuberculosis (TB), individuals with MSMD are also prone to infections by Mycobacterium tuberculosis. Several MSMD-associated genes have been described, all resulting in a disruption of IL-12 and IFN-γ cytokine axis, which is essential for control of mycobacterial infections. An accurate molecular diagnosis, confirmed by phenotypic and functional immune investigations, is essential to ensure that the patient receives optimal treatment and prophylaxis for infections. The aim of this study was to implement a set of functional assays to assess the integrity of the IL-12-IFN-γ cytokine pathways in patients presenting with severe, persistent, unusual and/or recurrent TB, mycobacterial infections or other clinical MSMD-defining infections such as Salmonella. Methods Blood was collected for subsequent PBMC isolation from 16 participants with MSMD-like clinical phenotypes. A set of flow cytometry (phenotype and signalling integrity) and ELISA-based (cytokine production) functional assays were implemented to assess the integrity of the IL-12-IFN-γ pathway. Results The combination of the three assays for the assessment of the integrity of the IL-12-IFN-γ pathway was successful in identifying immune deficits in the IL-12-IFN-γ pathway in all of the participants included in this study. Conclusions The data presented here emphasise the importance of investigating PID and TB susceptibility in TB endemic regions such as South Africa as MSMD and other previously described PIDs relating to TB susceptibility may present differently in such regions. It is therefore important to have access to in vitro functional investigations to better understand the immune function of these individuals. Although functional assays alone are unlikely to always provide a clear diagnosis, they do give an overview of the integrity of the IL-12-IFN-γ pathway. It would be beneficial to apply these assays routinely to patients with suspected PID relating to mycobacterial susceptibility. A molecular diagnosis with confirmed functional impairment paves the way for targeted treatment and improved disease management options for these patients.

Impaired in-vitro responses to IL-12 and IFN-γ in Iranian patients with Mendelian susceptibility to mycobacterial disease

2015 ◽  
Vol 43 (5) ◽  
pp. 456-460 ◽  
Author(s):  
N. Parvaneh ◽  
B. Pourakbari ◽  
N. Rezaei ◽  
A. Omidvar ◽  
F. Sabouni ◽  
...  
Keyword(s):  
Mycobacterial Disease ◽  
Ifn Γ ◽  
Iranian Patients

Production of Mycobacterium bovis Antigens Included in Recombinant Occlusion Bodies of Baculovirus

2019 ◽  
Vol 29 (1-6) ◽  
pp. 83-90
Author(s):  
Luciana Villafañe ◽  
Marina Andrea Forrellad ◽  
María Gabriela López ◽  
Sergio Garbaccio ◽  
Carlos Garro ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Intradermal Injection ◽  
In Vitro Assays ◽  
Chimeric Proteins ◽  
Purified Protein Derivative ◽  
E Coli ◽  
Occlusion Bodies ◽  
Ifn Γ ◽  
High Level

Bovine tuberculosis (bTB) is a disease produced by <i>Mycobacterium bovis</i> that affects livestock, wild animals, and humans. The classical diagnostic method to detect bTB is measuring the response induced with the intradermal injection of purified protein derivative of <i>M. bovis</i> (PPDb). Another ancillary bTB test detects IFN-γ produced in whole blood upon stimulation with PPDb, protein/peptide cocktails, or individual antigens. Among the most used <i>M. bovis</i> antigens in IFN-γ assays are the secreted proteins ESAT-6 and CFP-10, which together with antigen Rv3615c improve the sensitivity of the test in comparison to PPDb. Protein reagents for immune stimulation are generally obtained from <i>Escherichia coli</i>, because this bacterium produces a high level of recombinant proteins. However, <i>E. coli</i> recombinant antigens are in general contaminated with lipopolysaccharides and other components that produce non-specific IFN-γ secretion in in vitro assays. In this work, we produced the relevant ESAT-6, CFP-10, and Rv3615c <i>M. bovis</i> antigens as fusions to the polyhedrin protein from the baculovirus AcMNPV. We obtained chimeric proteins effectively incorporated to the occlusion bodies and easily purified the recombinant polyhedra with no reactive contaminants. In an IFN-γ assay, these fusion proteins showed equivalent sensibility but better specificity than the same <i>M. bovis</i> proteins produced in <i>E. coli</i>.

scholarly journals Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

2014 ◽  
Vol 26 (6) ◽  
pp. 454-470 ◽  
Author(s):  
Jacinta Bustamante ◽  
Stéphanie Boisson-Dupuis ◽  
Laurent Abel ◽  
Jean-Laurent Casanova
Keyword(s):  
Clinical Features ◽  
Mycobacterial Disease ◽  
Inborn Errors ◽  
Ifn Γ

scholarly journals Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

2020 ◽  
Author(s):  
Rui Yang ◽  
Federico Mele ◽  
Lisa Worley ◽  
David Langlais ◽  
Jérémie Rosain ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Target Genes ◽  
Γδ T Cells ◽  
Chromatin Accessibility ◽  
Mycobacterial Disease ◽  
Inborn Errors ◽  
Ifn Γ ◽  
Low Levels ◽  
Mycobacterial Antigens

SummaryInborn errors of human IFN-γ immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, including IFNG, by altering chromatin accessibility and DNA methylation in CD4+ T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of non-mycobacterial-reactive classic TH1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-γ. Other IFN-γ-producing lymphocyte subsets however develop normally, but with low levels of IFN-γ production, with exception of Vδ2− γδ T lymphocytes, which produce normal amounts of IFN-γ in response to non-mycobacterial stimulation, and non-classic TH1 (TH1*) lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-γ production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells), with mycobacterial-specific, IFN-γ-producing, purely adaptive αβ TH1* cells unable to compensate for this deficit.

scholarly journals Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease

2021 ◽  
Vol 118 (15) ◽  
pp. e2102804118
Author(s):  
Tom Le Voyer ◽  
Anna-Lena Neehus ◽  
Rui Yang ◽  
Masato Ogishi ◽  
Jérémie Rosain ◽  
...  
Keyword(s):  
Cell Lines ◽  
Myeloid Cell ◽  
Stress Granules ◽  
Lymphoid Cells ◽  
Loss Of Function ◽  
Mycobacterial Disease ◽  
Inborn Errors ◽  
Cell Responses ◽  
Hela Cell Lines ◽  
Ifn Γ

Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette–Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.

scholarly journals Neutralization of Interleukin-10 Significantly Enhances Gamma Interferon Expression in Peripheral Blood by Stimulation with Johnin Purified Protein Derivative and by Infection with Mycobacterium avium subsp. paratuberculosis in Experimentally Infected Cattle with Paratuberculosis

2004 ◽  
Vol 72 (4) ◽  
pp. 2425-2428 ◽  
Author(s):  
Joram J. Buza ◽  
Hirokazu Hikono ◽  
Yasuyuki Mori ◽  
Reiko Nagata ◽  
Sachiyo Hirayama ◽  
...  
Keyword(s):  
Mycobacterium Avium ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Interleukin 10 ◽  
Suppressive Effect ◽  
Gamma Interferon ◽  
Peripheral Blood Mononuclear ◽  
Purified Protein Derivative ◽  
Ifn Γ

ABSTRACT Monoclonal antibody neutralization of interleukin-10 (IL-10) increased Johnin purified protein derivative-induced whole-blood gamma interferon (IFN-γ) secretion 23-fold and also increased IFN-γ secretion ninefold following in vitro Mycobacterium avium subsp. paratuberculosis infection of peripheral blood mononuclear cells. These results demonstrate the suppressive effect of IL-10 on immune responses to M. avium subsp. paratuberculosis infection in cattle.

Electron Microscopy of Fibroblasts from Myotonic Muscular Dystrophy Patients

1981 ◽  
Vol 39 ◽  
pp. 498-499
Author(s):  
S. E. Miller ◽  
G. B. Hartwig ◽  
R. A. Nielsen ◽  
A. P. Frost ◽  
A. D. Roses
Keyword(s):  
Electron Microscopy ◽  
Muscular Dystrophy ◽  
Genetic Diseases ◽  
Skin Fibroblasts ◽  
Inborn Errors ◽  
Cytoplasmic Inclusions ◽  
Cultured Skin ◽  
Myotonic Muscular Dystrophy ◽  
Glycosaminoglycan Metabolism

Many genetic diseases can be demonstrated in skin cells cultured in vitro from patients with inborn errors of metabolism. Since myotonic muscular dystrophy (MMD) affects many organs other than muscle, it seems likely that this defect also might be expressed in fibroblasts. Detection of an alteration in cultured skin fibroblasts from patients would provide a valuable tool in the study of the disease as it would present a readily accessible and controllable system for examination. Furthermore, fibroblast expression would allow diagnosis of fetal and presumptomatic cases. An unusual staining pattern of MMD cultured skin fibroblasts as seen by light microscopy, namely, an increase in alcianophilia and metachromasia, has been reported; both these techniques suggest an altered glycosaminoglycan metabolism An altered growth pattern has also been described. One reference on cultured skin fibroblasts from a different dystrophy (Duchenne Muscular Dystrophy) reports increased cytoplasmic inclusions seen by electron microscopy. Also, ultrastructural alterations have been reported in muscle and thalamus biopsies from MMD patients, but no electron microscopical data is available on MMD cultured skin fibroblasts.

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