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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:149

Article

Tsumura, Miyuki¹  Miki, Mizuka^1,2,3  Mizoguchi, Yoko¹  Hirata, Osamu^1,4  Nishimura, Shiho^1,5  Tamaura, Moe^1,6  Kagawa, Reiko¹  Hayakawa, Seiichi¹  Kobayashi, Masao^1,7  Okada, Satoshi¹ 

[1] Hiroshima Univ, Dept Pediat, Grad Sch Biomed Sci, Hiroshima, Japan

[2] Hiroshima Red Cross Hosp, Dept Pediat, Hiroshima, Japan

[3] Atom Bomb Survivors Hosp, Hiroshima, Japan

[4] Hiroshima City Hiroshima Citizens Hosp, Hidamari Children Clin, Hiroshima, Japan

[5] Hiroshima City Hiroshima Citizens Hosp, Dept Pediat, Hiroshima, Japan

[6] Hiroshima Nishi Med Ctr, Dept Pediat, Hiroshima, Japan

[7] Chugoku Shikoku Block Blood Ctr, Japanese Red Cross, Hiroshima, Japan

关键词: Mendelian susceptibility to mycobacterial diseases;    MSMD;    STAT1;    IFN-gR1;    mycobacteria;    osteomyelitis;    osteoclastogenesis;   

DOI  :  10.1016/j.jaci.2021.05.018

来源: Elsevier

【 摘 要 】

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-y, such as IFN-yR1, IFN-yR2, 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-yR1 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-y. The inhibitory effect of IFN-y 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-yR1 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-yR1 deficiency, AD STAT1 deficiency, or STAT1 GOF differentiated into osteoclasts, similar to GM colonies from healthy volunteers. IFN-y concentration-dependent inhibition of osteoclast formation was impaired in GM colonies from patients with AD IFN-yR1 deficiency or AD STAT1 deficiency, whereas it was enhanced in GM colonies from patients with STAT1 GOF. Conclusions: Osteoclast differentiation is increased in AD IFNyR1 deficiency and AD STAT1 deficiency due to an impaired response to IFN-y, leading to excessive osteoclast proliferation and, by inference, increased bone resorption in infected foci, which may underlie multifocal osteomyelitis. (J Allergy Clin Immunol 2022; 149:252-61.)

【 授权许可】

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