Complement Component C1q as Serum Biomarker to Detect Active Tuberculosis.

Rosalie Lubbers,Roelof A De Paus,Frank A W Verreck,Franca Del Nonno,Simone A Joosten,Marcel Veltkamp,Ingeborg M Bajema,Linda Petrone,Leendert A Trouw,Annemieke Geluk,Kyra A Gelderman,Delia Goletti,Karin Dijkman,Tom H M Ottenhoff,Jayne S Sutherland,Geert H Groeneveld,Gerhard Walzl,Stefan M T Vestjens ,Willem Jan W Bos ,Coline H.m Van Moorsel

doi:10.3389/fimmu.2018.02427

Abstract

Background: Tuberculosis (TB) remains a major threat to global health. Currently, diagnosis of active TB is hampered by the lack of specific biomarkers that discriminate active TB disease from other (lung) diseases or latent TB infection (LTBI). Integrated human gene expression results have shown that genes encoding complement components, in particular different C1q chains, were expressed at higher levels in active TB compared to LTBI.Methods: C1q protein levels were determined using ELISA in sera from patients, from geographically distinct populations, with active TB, LTBI as well as disease controls.Results: Serum levels of C1q were increased in active TB compared to LTBI in four independent cohorts with an AUC of 0.77 [0.70; 0.83]. After 6 months of TB treatment, levels of C1q were similar to those of endemic controls, indicating an association with disease rather than individual genetic predisposition. Importantly, C1q levels in sera of TB patients were significantly higher as compared to patients with sarcoidosis or pneumonia, clinically important differential diagnoses. Moreover, exposure to other mycobacteria, such as Mycobacterium leprae (leprosy patients) or BCG (vaccinees) did not result in elevated levels of serum C1q. In agreement with the human data, in non-human primates challenged with Mycobacterium tuberculosis, increased serum C1q levels were detected in animals that developed progressive disease, not in those that controlled the infection.Conclusions: In summary, C1q levels are elevated in patients with active TB compared to LTBI in four independent cohorts. Furthermore, C1q levels from patients with TB were also elevated compared to patients with sarcoidosis, leprosy and pneumonia. Additionally, also in NHP we observed increased C1q levels in animals with active progressive TB, both in serum and in broncho-alveolar lavage. Therefore, we propose that the addition of C1q to current biomarker panels may provide added value in the diagnosis of active TB.

Highlights

Tuberculosis (TB) is a major global health threat, which is caused by infection by Mycobacterium tuberculosis (M.tb) [1]
Available microarray data from TB patients were retrieved from Gene Expression Omnibus, all data were ranked as differentially expressed between TB patients and either latent TB infection (LTBI) or other diseases [5, 7, 33,34,35,36,37]
Complement genes C1QB, SERPING1 were expressed at higher level in 8/9 (88%) of studies comparing patients with active TB to LTBI (Figure 1A)

Summary

Introduction

Tuberculosis (TB) is a major global health threat, which is caused by infection by Mycobacterium tuberculosis (M.tb) [1]. Current estimations indicate that a quarter of the global population is infected with M.tb, with a life-long risk to develop active TB disease. Particular regions, such as South-East Asia, Western-Pacific, and Africa regions account for more than 80% of infected individuals [2]. While most infected individuals remain asymptomatic latently infected (LTBI), a minority (5–10%) of these individuals progress to active TB. Diagnosis of active TB is hampered by the lack of specific biomarkers that discriminate active TB disease from other (lung) diseases or latent TB infection (LTBI). Integrated human gene expression results have shown that genes encoding complement components, in particular different C1q chains, were expressed at higher levels in active TB compared to LTBI

Methods

Results

Discussion

Conclusion