卡介苗性骨髓炎幸存者中依赖γ干扰素的免疫

Interferon-gamma-dependent Immunity in Bacillus Calmette-Guérin Vaccine Osteitis Survivors.

作者信息

Pöyhönen Laura, Kröger Liisa, Huhtala Heini, Mäkinen Johanna, Mertsola Jussi, Martinez-Barricarte Ruben, Casanova Jean-Laurent, Bustamante Jacinta, He Qiushui, Korppi Matti

机构信息

From the *Center for Child Health Research, University of Tampere and University Hospital and †School of Health Sciences, University of Tampere, Tampere, Finland; ‡Department of Pediatrics, University Hospital, Kuopio, Finland; §Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, ¶Department of Pediatrics, University of Turku and University Hospital, and ‖Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland; **St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University and ††Howard Hughes Medical Institute, New York, NY; and ‡‡Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, §§Paris Descartes University, Imagine Institute, ¶¶Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, and ‖‖Center for the Study of Primary Immunodeficiencies, Paris AP-HP, Necker-Enfants Malades Hospital, Paris, France, EU.

出版信息

Pediatr Infect Dis J. 2016 Jun;35(6):690-4. doi: 10.1097/INF.0000000000001127.

DOI:10.1097/INF.0000000000001127

PMID:26954602

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4865404/

Abstract

BACKGROUND

Inborn errors of interferon-gamma (IFN-γ)-mediated immunity underlie disseminated disease caused by Mycobacterium bovis Bacillus Calmette-Guérin (BCG) live vaccines. We hypothesized that some patients with osteitis after BCG vaccination may have an impaired IFN-γ immunity. Our aim was to investigate interleukin (IL)-12 and IFN-γ ex vivo production stimulated with BCG and BCG + IFN-γ or BCG + IL-12, respectively, in BCG osteitis survivors.

METHODS

Fresh blood samples were collected from 132 former BCG osteitis Finnish patients now aged 21-49 years, and IL-12 and IFN-γ were measured in cell cultures with and without stimulation with BCG and with BCG + IFN-γ or BCG + IL-12, respectively. As a pilot study, known disease-causing genes controlling IFN-γ immunity (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, NEMO and CYBB) were investigated in 20 selected patients by whole exome sequencing.

RESULTS

By the limit of <5th percentile, ex vivo IL-12 concentration and increase in concentration was low in 5 and ex vivo IFN-γ concentration and increase in concentration was low in 6 patients (including 2 samples with both IL-12 and IFN-γ findings). By the limit of <10th percentile, an additional 6 and 4 patients were, respectively, detected (including 2 samples with both findings). With 2 exceptions, low concentrations and low increases in concentrations picked-up the same cases. Mutations in known disease-causing IFN-γ-related genes were not found in any of these patients.

CONCLUSION

These findings call for searching of mutations in new genes governing IFN-γ-dependent immunity to live BCG vaccine.

摘要

背景

干扰素-γ（IFN-γ）介导的免疫先天性缺陷是卡介苗（BCG）活疫苗所致播散性疾病的基础。我们推测，部分接种BCG后发生骨炎的患者可能存在IFN-γ免疫受损。我们的目的是分别研究BCG骨炎幸存者体内经BCG以及BCG + IFN-γ或BCG + IL-12刺激后白细胞介素（IL）-12和IFN-γ的体外产生情况。

方法

采集了132名曾患BCG骨炎、现年龄在21至49岁之间的芬兰患者的新鲜血液样本，分别在有或无BCG以及BCG + IFN-γ或BCG + IL-12刺激的细胞培养物中检测IL-12和IFN-γ。作为一项初步研究，通过全外显子组测序对20名选定患者中控制IFN-γ免疫的已知致病基因（IFNGR1、IFNGR2、STAT1、IL12B、IL12RB1、ISG15、IRF8、NEMO和CYBB）进行了研究。

结果

以低于第5百分位数为界值，5名患者的体外IL-12浓度及浓度增加值较低，6名患者的体外IFN-γ浓度及浓度增加值较低（包括2份同时有IL-12和IFN-γ检测结果的样本）。以低于第10百分位数为界值，又分别检测出另外6名和4名患者（包括2份同时有两种检测结果的样本）。除2例例外情况外，浓度低和浓度增加值低所检出的是相同病例。在这些患者中均未发现已知的与IFN-γ相关致病基因的突变。