Enhanced osteoclastogenesis in patients with MSMD due to impaired response to IFN-γ

Tsumura, Miyuki; Miki, Mizuka; Mizoguchi, Yoko; Hirata, Osamu; Nishimura, Shiho; Tamaura, Moe; Kagawa, Reiko; Hayakawa, Seiichi; Kobayashi, Masao; Okada, Satoshi

doi:10.1016/j.jaci.2021.05.018

Cited by 13 publications

(14 citation statements)

References 125 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, the underlying mechanism of multifocal osteomyelitis has not yet been clarified. Recently, Tsumura et al demonstrated a relationship between impaired IFN-γ immunity and the evolution of multifocal osteomyelitis in MSMD patients [34].…”

Section: Mechanism Of Multifocal Osteomyelitis In Msmdmentioning

confidence: 99%

“…Salmonella infections are a typical manifestation in MSMD and are particularly frequently seen in patients with IL-12Rβ1 or IL-12p40 deficiency, involving defects in both IL-12 and IL-23 immunity [1,29,30]. On the other hand, the frequency of multifocal osteomyelitis is high with IFN-γR1, IFN-γR2, or STAT1 deficiency, in which IFN-γ signaling is impaired [29,[31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mendelian susceptibility to mycobacterial diseases: state of the art

Noma

Mizoguchi

Tsumura

et al. 2022

Clinical Microbiology and Infection

Self Cite

View full text Add to dashboard Cite

Section: Mechanism Of Multifocal Osteomyelitis In Msmdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mendelian susceptibility to mycobacterial diseases: state of the art

Noma

Mizoguchi

Tsumura

et al. 2022

Clinical Microbiology and Infection

Self Cite

View full text Add to dashboard Cite

“…The incidence of multifocal osteomyelitis was high, and some patients even developed osteomyelitis without other organ involvement (Dupuis et al, 2001;Hirata et al, 2013;Boudjemaa et al, 2017;Kagawa et al, 2017). It was found that this may be due to impaired IFN-g response and increased osteoclast differentiation in patients with STAT1 deficiency (Tsumura et al, 2022). Two cases of multifocal osteomyelitis had been misdiagnosed as neuroblastoma and Langerhans cell histiocytosis (Boudjemaa et al, 2017;Zhou et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Two cases of multifocal osteomyelitis had been misdiagnosed as neuroblastoma and Langerhans cell histiocytosis (Boudjemaa et al, 2017;Zhou et al, 2022). Despite histological analysis, another case of multifocal osteomyelitis was suspected sarcoidosis disease (Tsumura et al, 2022). The delay in diagnosis may be related to the low rate of positive cultures for mycobacteria.…”

Section: Discussionmentioning

confidence: 99%

A novel STAT1 loss-of-function mutation associated with Mendelian susceptibility to mycobacterial disease

Zhang

Dong

et al. 2022

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital immune deficiency characterized by susceptibility to weakly virulent mycobacteria. Loss-of-function (LOF) mutation of signal transducer and activator of transcription 1 (STAT1) is one of the common genetic causes of MSMD. In this study, we identified a patient who presented with multiple lymph node enlargements and multiple osteolytic disruptions. Mycobacterium gordonae infection was confirmed by metagenomic next-generation sequencing. Whole-exome sequencing identified a novel paternal heterozygous mutation in exon 22 of STAT1 (NM_007315.4, c.1892T>C, p.Val631Ala). This variant was confirmed pathogenic by multiple software predictions. Based on functional assays, STAT1 expression in STAT1V631A cells was not different from STAT1WT cells. But STAT1V631A mutation caused much lower activation of STAT1 when stimulated by interferon-γ (IFN-γ). Fluorescence localization analysis revealed that both STAT1V631A and STAT1WT proteins were located in the cytoplasm, and only a few STAT1V631A proteins were translocated to the nucleus in response to IFN-γ. These results suggest that STAT1V631A leads to LOF in IFN-γ-mediated mycobacterial immunity, resulting in MSMD. Treatment with antibiotics has achieved ideal disease control for this patient, and no adverse events occurred during follow-up. The STAT1 LOF deficiency is a genetic cause of MSMD, which should be considered in patients with mycobacterial disease, especially those with bone involvement.

show abstract

“…The presence of mycobacteria in the bone has been traced back to thousands of years ago (Hogan et al 2019). Mendelian susceptibility to mycobacterial disease is associated with a higher frequency of bone involvement (Tsumura et al 2022). Furthermore, previous history of mycobacterial infection, even without bone involvement, increases the risk of osteopenia and osteoporosis (Yeh et al 2016, Choi et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Serum Amyloid A proteins reduce bone mass during mycobacterial infections

Gomes

Sousa

Oliveira

et al. 2022

Preprint

View full text Add to dashboard Cite

Osteopenia has been associated to several inflammatory conditions, including mycobacterial infections. How mycobacteria cause bone loss remains elusive, but direct bone infection may not be required. Using genetically engineered mice and morphometric, transcriptomic and functional analyses, we found that infection with Mycobacterium avium impacts bone turnover by decreasing bone formation and increasing bone resorption, in a IFNg- and TNFa-dependent manner. IFNg produced during infection enhanced macrophage TNFa secretion, which in turn increased the production of serum amyloid A (SAA) 3. Saa3 expression was upregulated in the bone of both M. avium- and Mycobacterium tuberculosis-infected mice and SAA proteins were increased in the serum of patients with active tuberculosis. Furthermore, the increased SAA levels seen in active tuberculosis patients correlated with altered serum bone turnover markers. Additionally, human SAA proteins impaired bone matrix deposition and increased osteoclastogenesis in vitro. Overall, we report a novel crosstalk between the cytokine network operating in macrophages and bone homeostasis and disclose SAA proteins as potential biomarkers of bone loss during infection by mycobacteria.

show abstract

Enhanced osteoclastogenesis in patients with MSMD due to impaired response to IFN-γ

Cited by 13 publications

References 125 publications

Mendelian susceptibility to mycobacterial diseases: state of the art

Mendelian susceptibility to mycobacterial diseases: state of the art

A novel STAT1 loss-of-function mutation associated with Mendelian susceptibility to mycobacterial disease

Serum Amyloid A proteins reduce bone mass during mycobacterial infections

Contact Info

Product

Resources

About