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Mendelian susceptibility to mycobacterial diseases: state of the art
Kosuke Noma1, Yoko Mizoguchi1, Miyuki Tsumura1
1Department of Pediatrics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
Background:
Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to infections caused by intracellular pathogens, such as mycobacteria, due to impaired IFN-γ immunity. To date, 18 different genes associated with MSMD have been reported.
Objectives:
This review describes recent discoveries, a 2020-2021 update, in MSMD through the introduction of three novel genetic disorders, namely, AR IFN-γ, T-bet, and ZNFX1 complete deficiency, as well as molecular mechanisms underlying multifocal osteomyelitis in patients with this condition.
Sources:
PubMed databases were searched for reports of MSMD since January 2020. Relevant articles and their references were screened.
Content:
The review covers a general overview, known genes, classifications, symptoms, and treatments for MSMD. MSMD is classified into two groups: isolated MSMD and syndromic MSMD. Among the 18 genes responsible, 13 cause isolated MSMD, which is characterized by selective predisposition to one or more mycobacterial and related infections, and 8 cause syndromic MSMD, which involves the combination of the mycobacterial disease infectious phenotype with additional clinical phenotypes. Among the three genetic etiologies described herein, AR IFN-γ deficiency is classified as isolated MSMD, whereas AR T-bet and ZNFX1 deficiency are classified as syndromic MSMD. Multifocal osteomyelitis is a representative symptom of MSMD, and a high frequency of multifocal osteomyelitis is reported in MSMD patients due to impaired IFN-γ responses, such as with AD IFN-γR1, AD IFN-γR2, or AD STAT1 deficiency. Impaired inhibition of osteoclast differentiation and bone resorption owing to a poor response to IFN-γ has been shown to be in association with multifocal osteomyelitis in MSMD.
Implications:
Over the past decade, genetic dissection by next-generation sequencing techniques has contributed to the understanding of the molecular bases of human immunity to mycobacteria. However, genetic etiologies are lacking for half of MSMD cases. Further studies will be needed to elucidate the pathogenesis of MSMD.
Insights
Mendelian susceptibility to mycobacterial disease (MSMD) involves genetic defects impairing IFN-γ immunity, leading to increased susceptibility to infections. Recent updates include three new genetic disorders and insights into multifocal osteomyelitis pathogenesis.
Area of Science:
- Immunology
- Genetics
- Infectious Diseases
Background:
- Mendelian susceptibility to mycobacterial disease (MSMD) is a group of genetic disorders characterized by impaired interferon-gamma (IFN-γ) immunity.
- This selective predisposition to intracellular pathogens, particularly mycobacteria, affects individuals with specific genetic mutations.
- Currently, 18 genes are known to be associated with MSMD, categorized into isolated and syndromic forms.
Purpose of the Study:
- To provide a 2020-2021 update on recent discoveries in MSMD.
- To introduce three novel genetic disorders associated with MSMD: AR IFN-γ, T-bet, and ZNFX1 complete deficiency.
- To elucidate the molecular mechanisms underlying multifocal osteomyelitis in MSMD patients.
Main Methods:
- A comprehensive literature search of PubMed databases was conducted for reports on MSMD published since January 2020.
- Relevant articles and their reference lists were screened to identify key findings and new genetic etiologies.
- The review synthesizes information on known genes, classifications, symptoms, and treatments for MSMD.
Main Results:
- Three novel genetic disorders contributing to MSMD have been identified: AR IFN-γ deficiency (isolated MSMD), and AR T-bet and ZNFX1 deficiency (syndromic MSMD).
- Multifocal osteomyelitis is a significant clinical manifestation in MSMD, particularly in patients with deficiencies in IFN-γ pathway components like IFN-γR1, IFN-γR2, or STAT1.
- Impaired IFN-γ response hinders osteoclast differentiation and bone resorption, contributing to the development of multifocal osteomyelitis.
Conclusions:
- Next-generation sequencing has significantly advanced the understanding of the genetic basis of human immunity to mycobacteria.
- Despite progress, the genetic causes for approximately half of MSMD cases remain unknown.
- Further research is crucial to fully understand the pathogenesis of MSMD and identify novel therapeutic targets.
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