Interferon-gamma release assays in tuberculous uveitis:a comprehensive review

INTRODUCTION

T uberculosis (TB) is an infection caused by(). The global TB report 2020 revealed that a quarter of the world’s population was infected withand the incidence rate for developing the disease was 30 000 people per day. It was reportedly one of the top ten causes of death, responsible for 1.4 million fatalities worldwide in 2019. Currently, active TB and latent tuberculosis infection(LTBI) are believed to constitute a comprehensive spectrum rather than being considered as separate stages of the infection.World Health Organization guidelines define LTBI as a state of persistent immune response stimulated byantigens without evidence of clinical manifestations of active TB.LTBI has several stages that affect individuals who could be asymptomatic; they may experience a controlled infection with nonreplicating but viable organisms. LTBI is therefore considered an important reservoir of TB infection that can subsequently develop into an active disease.

UWB脈沖源經(jīng)發(fā)射天線發(fā)射無(wú)載頻單極沖激脈沖信號(hào)，接收機(jī)通過(guò)接收天線將目標(biāo)回波信號(hào)送至取樣變換電路，經(jīng)時(shí)域變換取樣得到回波信號(hào)。通過(guò)對(duì)回波信號(hào)的處理分析來(lái)提取目標(biāo)的距離方位信息。IR-UWB穿墻雷達(dá)回波信號(hào)處理流程如圖2所示，輸入數(shù)據(jù)為采樣得到的回波信號(hào)x[m,n]。首先對(duì)回波數(shù)據(jù)進(jìn)行脈沖積累，由于穿墻探測(cè)中信號(hào)經(jīng)過(guò)墻體的雙程穿透衰減，得到的目標(biāo)信息較為微弱，需要對(duì)脈沖積累后的數(shù)據(jù)作降噪處理，進(jìn)一步提高信噪比，最后輸出降噪處理后的信號(hào)。

Besides lungs, TB can affect multiple organs throughout the body, including the eyes. Ocular TB is an extrapulmonary infection that may involve any part of the ocular tissue and may occur without a history of pulmonary TB. Tuberculous uveitis (TBU) is one of the most common clinical presentations of ocular TB. The prevalence of TBU varies according to geography. While endemic areas, including India and Saudi Arabia reported a high prevalence of 5.6%-26.2%, nonendemic countries, such as the United States, Europe, and Japan, showed a lower prevalence of 0.2%-7%.

Considering the immune-related pathogenesis of TBU,immunological tests can be useful for its diagnosis. The tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are well-known immunological tests. Poor specificity of the TST for diagnosing TB in those who had been vaccinated with Bacillus Calmette-Guerin (BCG)and in residents of endemic regions, led to the subsequent development of IGRAs that enabled immunodiagnosis of LTBI. These assays performed along with or without the TST, are now increasingly used to diagnose TBU.

In this narrative review, we provide a brief description of the clinical characteristics of TBU. We further comparatively review the principles of IGRAs, including diagnostic accuracy,advantages and disadvantages, interpretation, and clinical application in adults with suspected TBU.

Some experts suggest performing TST or IGRAs for all patients with idiopathic uveitis, whereas others recommend testing patients with either suspected signs of TBU or with additional risks for TB, including birth outside the US,history of living in an endemic area, history of incarceration or homelessness, history of intravenous drug abuse, HIV positive status, failure to respond to oral corticosteroid or immunosuppressive therapy, or presence of granulomatous inflammation on presentation.

通用電氣公司在人力資源管理中堅(jiān)持以人為本的指導(dǎo)思想，高度重視人才的選拔和培養(yǎng)。公司人力資源管理的使命是培養(yǎng)企業(yè)家和企業(yè)領(lǐng)袖。“十年樹木，百年樹人”，如果用一棵大樹來(lái)比喻通用電氣公司的人力資源管理，那么可以將其概括為“苗優(yōu)土肥、根深干粗、葉茂果碩”的樹型培養(yǎng)模式。

Both ESAT-6 and CFP-10 have multiple epitopes for T lymphocytes and can, therefore, generate an intense reaction. The two remaining wells act as controls for internal test validation.The positive control well contains phytohemagglutinin(mitogen) for stimulating nonspecific T-cell response, whereas no antigen is added in the negative control (nil) well. The production of IFN-γ is then detecteda sandwich capture technique by conjugation with secondary antibodies revealing a “spot”. These spots, considered “footprints” of effector T-cells producing IFN-γ, are then enumerated.

Generally,may not be isolated from the ocular tissue in all TBU patients. Ocular TB may be classified as such, based on an affected patient’s clinical findings meeting diagnostic criteria or a clinical definition. Figueiraproposed that investigations for TB should be performed in any of the following situations: 1) Uveitis of unknown etiology, either recurrent or unresponsive to conventional therapy; 2) Ocular findings highly suggestive of ocular TB; 3) Before initiating immunosuppressive therapy, particularly that with biologic agents.

CD4 T lymphocytes were believed to play a significant role in the immune response to TB until recent studies provided evidence to support the additive role played by CD8 T lymphocytes. RD-1-specific CD8 Tlymphocytes are also more frequently detected in recent or active TB infections than in LTBI. These findings led to the development of the fourth generation of IGRAs, QFT-Plus. This test package contains two tubes with TB-specific antigens, TB1 and TB2.The TB1 tube containing long peptides derived from ESAT-6 and CFP-10, was designed to induce a specific CD4 T-cell response. The TB2 tube also contains the same long peptides as TB1 along with shorter peptides that can stimulate the CD8 T-cell response. The ability to elicit both CD4 and CD8 T-cell responses is believed to improve the sensitivity of this generation of IGRAs.

取已知含量的藥材樣品（編號(hào)：11）細(xì)粉適量，每份0.1 g，共6份，分別加入一定質(zhì)量濃度的單一對(duì)照品溶液各適量，按“2.2.2”項(xiàng)下方法制備供試品溶液，再按“2.1”項(xiàng)下試驗(yàn)條件進(jìn)樣測(cè)定，記錄離子信號(hào)強(qiáng)度并計(jì)算加樣回收率，結(jié)果見(jiàn)表5。

A definitive diagnosis of TBU requires isolation offrom intraocular tissue specimens obtained through invasive procedures such as aqueous paracentesis, vitreous aspiration,or retinal biopsy.culture remains the gold standard for a definitive diagnosis of ocular TB. Other methods include detection of acid-fast bacilli on smear examination,amplification ofnucleic acids, and histopathological examination of ocular tissues. However, there are limitations in identifying the organism in the eye. Usually,only a limited amount of ocular tissue sample can be extracted,and associated procedural complications may potentially damage vision. The Collaborative Ocular Tuberculosis Study showed that patients with presumed TBU demonstrated low positive yield offrom intraocular fluid samples on polymerase chain reaction. Given the limitations of ocular sampling and associated low positivity yield, TBU was rarely diagnosed using this method. This may contribute to delays in diagnosis and treatment, resulting in poor visual outcomes.Consequently, a finding of uveitis with intraocular features characteristic of TBU in conjunction with positive results of indirect tests, is considered sufficient evidence for a diagnosis.Two indirect investigations, including the TST and IGRAs,evaluate the intensity of the host immunological reaction to TB antigens, which may manifest as a T lymphocyte-mediated immune response or as a delayed hypersensitivity reaction.The TST is antest performed using a purified protein derivative consisting of ＞200 protein precipitates derived from a heat-inactivated. The diagnostic feature of a positive TST is the development of skin induration, interpreted within 48-72h after an intradermal injection of the purified protein derivative. The American Thoracic Society and Centers for Disease Control and Prevention have provided guidelines for the interpretation of positive TST findings, as shown in Table 1.Notably, a technique that helped identify different mycobacterial antigens, including early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10), was developed into a test for blood-basedevaluation of the immune response to TB. In the absence of cross-reactivity due to prior BCGvaccination, measurement of interferon-gamma (IFN-γ)produced by T lymphocytes in response to these antigens,forms the basis of IGRAs performed for the diagnosis of TB.

現(xiàn)如今的小學(xué)生，雖然在心智與身體都處在發(fā)育階段，但是很多小學(xué)生都有著很強(qiáng)的自我意識(shí)，在組織集體活動(dòng)或是展開(kāi)課堂管理時(shí)，常常會(huì)出現(xiàn)叛逆的情緒。老師常常面臨著來(lái)自學(xué)校管理和課堂管理能力不夠的雙重壓力，在如此狀況下，老師和學(xué)生很難實(shí)現(xiàn)友好互動(dòng)，矛盾甚至?xí)蝗患ぐl(fā)。……