Leucine-rich alpha 2 glycoprotein is a new marker for active disease of tuberculosis

Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health problem. At present, prior exposure to Mtb can be determined by blood-based interferon-gamma release assay (IGRA), but active TB is not always detectable by blood tests such as CRP and ESR. This study was undertaken to investigate whether leucine-rich alpha-2 glycoprotein (LRG), a new inflammatory biomarker, could be used to assess active disease of TB. Cynomolgus macaques pretreated with or without Bacille Calmette-Guerin (BCG) vaccination were inoculated with Mtb to induce active TB. Blood was collected over time from these animals and levels of LRG as well as CRP and ESR were quantified. In the macaques without BCG vaccination, Mtb inoculation caused extensive TB and significantly increased plasma CRP and LRG levels, but not ESR. In the macaques with BCG vaccination, whereas Mtb challenge caused pulmonary TB, only LRG levels were significantly elevated. By immunohistochemical analysis of the lung, LRG was visualized in epithelioid cells and giant cells of the granulation tissue. In humans, serum LRG levels in TB patients were significantly higher than those in healthy controls and declined one month after anti-tubercular therapy. These findings suggest that LRG is a promising biomarker when performed following IGRA for the detection of active TB. Tuberculosis (TB) is a symptomatic disease caused by replicating Mycobacterium tuberculosis (Mtb). According to the WHO global tuberculosis report 2018 (https://www.who.int/tb/publications/global_report/en/), about 23% of the world's population is estimated to be latently infected with Mtb, Of these, up to 10% of humans develop active disease after Mtb infection 1 , which makes TB a major global health problem with the estimation of 10.4 million new cases and 1.7 million deaths in 2016 2. Importantly, 40% of estimated TB cases remain to be undiagnosed 2. Rapid detection of active TB is critical to reduce TB-related death. Recently-introduced interferon gamma release assay (IGRA) has better specificity than tuberculin skin test (TST) in TB screening and now become the standard for the identification of Mtb sensitization 1. Nevertheless, IGRA does not differentiate between active TB and resolved/latent infection 3. At present, sputum smear or culture of Mtb is still a gold standard for diagnosis of active TB. In addition, sputum culture is also a major biomarker for the evaluation of treatment 1,4,5. However, sputum test is assessable only when sputa of good quality were obtained from patients. Accordingly, sputum test is unavailable for infants with TB and patients with extrapulmonary tuberculosis. In addition, sputum test is not always available in resource-poor settings. Moreover, the sputum culture is not suitable for rapid decision making during therapy of outpatients, given that it requires long time before obtaining results 1. To detect Mtb in sputa in a rapid turnaround time, molecular diagnostics such as the GeneXpert MTB/RIF assay may be applicable 5. Nevertheless, this assay is ex...

[Retracted] The Prognostic Value of Leucine‐Rich α2 Glycoprotein 1 in Pediatric Spinal Cord Injury

“…LRG not only in peripheral blood but also in saliva can also be used as a noninvasive biomarker [25]. In humans, the serum LRG level of pulmonary tuberculosis patients is significantly increased, but decreased after anti-tuberculosis treatment [26]. These findings indicate that LRG is a promising biomarker for predicting pulmonary tuberculosis activity.…”

Inflammatory Markers in Cerebrospinal Fluid from Patients with Hydrocephalus: A Systematic Literature Review

“…LRG (leucine-rich α2-glycoprotein) is produced by various cell types including hepatocytes, astrocytes, neutrophils, and epithelial cells in the inflamed tissue. LRG levels rise in inflammatory conditions such as meningitis, tuberculosis, and rheumatoid arthritis and are therefore suggested to be a marker of inflammation similar to acute-phase proteins [25,[67][68][69][70][71][72]. LRG levels can be induced by inflammatory cytokines including IL-6 and IL-1β [67,73].…”

Tuberculosis comorbidity with rheumatoid arthritis: Gene signatures, associated biomarkers, and screening

“…62 Also, in patients with TB but no other disorders, the level of LRG was higher than healthy controls and its level was decreased after exposing to anti-TB drugs. 63 In addition, in a mice arthritis model infected by TB, the high level of LRG was the same in mice treated by an anti-IL-6R antibody as those treated by control antibody. Although this finding should also be evaluated in RA patients with TB infection, LRG represents an effective marker for detecting TB infections even in the suppression of IL-6 by biologic therapies.…”

“…Proteomic analysis of 326 proteins in RA patients with the aim of the detection of new markers of the disease activity showed an increased level of LRG compared to a healthy population and it was correlated with disease activity 62 . Also, in patients with TB but no other disorders, the level of LRG was higher than healthy controls and its level was decreased after exposing to anti‐TB drugs 63 . In addition, in a mice arthritis model infected by TB, the high level of LRG was the same in mice treated by an anti‐IL‐6R antibody as those treated by control antibody.…”