AI Article Synopsis

  • * The study investigated how impaired IFN-γ responses in specific deficiencies (AD IFN-γR1 and AD STAT1) lead to increased osteoclast differentiation and activity, using various laboratory techniques.
  • * Results indicated that individuals with AD IFN-γR1 and AD STAT1 deficiencies have heightened osteoclast numbers due to reduced inhibition from IFN-γ, which may contribute to excessive bone resorption in areas of infection.

Article Abstract

Background: Patients with Mendelian susceptibility to mycobacterial disease (MSMD) experience recurrent and/or persistent infectious diseases associated with poorly virulent mycobacteria. Multifocal osteomyelitis is among the representative manifestations of MSMD. The frequency of multifocal osteomyelitis is especially high in patients with MSMD etiologies that impair cellular response to IFN-γ, such as IFN-γR1, IFN-γR2, or STAT1 deficiency.

Objectives: This study sought to characterize the mechanism underlying multifocal osteomyelitis in MSMD.

Methods: GM colonies prepared from bone marrow mononuclear cells from patients with autosomal dominant (AD) IFN-γR1 deficiency, AD STAT1 deficiency, or STAT1 gain of function (GOF) and from healthy controls were differentiated into osteoclasts in the presence or absence of IFN-γ. The inhibitory effect of IFN-γ on osteoclastogenesis was investigated by quantitative PCR, immunoblotting, tartrate-resistant acid phosphatase staining, and pit formation assays.

Results: Increased osteoclast numbers were identified by examining the histopathology of osteomyelitis in patients with AD IFN-γR1 deficiency or AD STAT1 deficiency. In the presence of receptor activator of nuclear factor kappa-B ligand and M-CSF, GM colonies from patients with AD IFN-γR1 deficiency, AD STAT1 deficiency, or STAT1 GOF differentiated into osteoclasts, similar to GM colonies from healthy volunteers. IFN-γ concentration-dependent inhibition of osteoclast formation was impaired in GM colonies from patients with AD IFN-γR1 deficiency or AD STAT1 deficiency, whereas it was enhanced in GM colonies from patients with STAT1 GOF.

Conclusions: Osteoclast differentiation is increased in AD IFN-γR1 deficiency and AD STAT1 deficiency due to an impaired response to IFN-γ, leading to excessive osteoclast proliferation and, by inference, increased bone resorption in infected foci, which may underlie multifocal osteomyelitis.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2021.05.018DOI Listing

Publication Analysis

Top Keywords

deficiency stat1
28
ifn-γr1 deficiency
20
stat1 deficiency
20
multifocal osteomyelitis
16
response ifn-γ
12
patients ifn-γr1
12
colonies patients
12
deficiency
10
stat1
9
patients
8

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!