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

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.

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

10.21203/rs.3.rs-432750/v2 ◽

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2102804118 ◽

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.

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Inborn errors of IL-12/23- and IFN-γ-mediated immunity: molecular, cellular, and clinical features

Seminars in Immunology ◽

10.1016/j.smim.2006.07.010 ◽

2006 ◽

Vol 18 (6) ◽

pp. 347-361 ◽

Cited By ~ 311

Author(s):

Orchidée Filipe-Santos ◽

Jacinta Bustamante ◽

Ariane Chapgier ◽

Guillaume Vogt ◽

Ludovic de Beaucoudrey ◽

...

Keyword(s):

Clinical Features ◽

Inborn Errors ◽

Ifn Γ

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Corrigendum to “Inborn errors of IL-12/23- and IFN-γ-mediated immunity: Molecular, cellular, and clinical features” [Semin. Immunol. 18 (2006) 347–361]

Seminars in Immunology ◽

10.1016/j.smim.2007.02.002 ◽

2007 ◽

Vol 19 (2) ◽

pp. 136-137

Author(s):

Orchidée Filipe-Santos ◽

Jacinta Bustamante ◽

Ariane Chapgier ◽

Guillaume Vogt ◽

Ludovic de Beaucoudrey ◽

...

Keyword(s):

Clinical Features ◽

Inborn Errors ◽

Ifn Γ

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

10.21203/rs.3.rs-432750/v1 ◽

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.

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Pulmonary Nontuberculous Mycobacterial Disease Prevalence and Clinical Features

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.201003-0503oc ◽

2010 ◽

Vol 182 (7) ◽

pp. 977-982 ◽

Cited By ~ 241

Author(s):

Kevin L. Winthrop ◽

Erin McNelley ◽

Brian Kendall ◽

Allison Marshall-Olson ◽

Christy Morris ◽

...

Keyword(s):

Clinical Features ◽

Disease Prevalence ◽

Mycobacterial Disease

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

BMC Immunology ◽

10.1186/s12865-021-00452-6 ◽

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.

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