Complement Component C1q as Serum Biomarker to Detect Active Tuberculosis

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.

An Inflammatory Story: Antibodies in Tuberculosis Comorbidities

“…IgG1 and IgG3 subclasses are also the main antibodies capable of activating complement (119). Consistent with these associations, complement C1q levels are higher in active TB compared to latent TB, and complement cascade molecules are upregulated 18 months before progression from Mtb infection to TB disease (120)(121)(122). Moreover, some monoclonal Mtb IgG1 can enhance bacterial replication in vitro, demonstrating the potential to exacerbate disease (27).…”

Inverse correlation between serum complement component C1q levels and whole blood type‐1 interferon signature in active tuberculosis and QuantiFERON‐positive uveitis: implications for diagnosis

“…22 Furthermore, increased expression of mRNA for complement component C1q has been described in peripheral blood cells from active TB patients. [23][24][25] More recently, Lubbers et al reported elevated serum C1q levels in APTB as compared to LTBI, healthy controls, and disease controls. 23 Consequently, serum C1q was proposed as biomarker to detect active TB disease.…”

“…[23][24][25] More recently, Lubbers et al reported elevated serum C1q levels in APTB as compared to LTBI, healthy controls, and disease controls. 23 Consequently, serum C1q was proposed as biomarker to detect active TB disease. 23 However, Lubbers et al did not explore serum C1q levels in relation to TB-associated uveitis.…”

“…23 Consequently, serum C1q was proposed as biomarker to detect active TB disease. 23 However, Lubbers et al did not explore serum C1q levels in relation to TB-associated uveitis. Also, no correlations with peripheral blood type-1 IFN signatures were determined.…”

Identification of reduced host transcriptomic signatures for tuberculosis and digital PCR-based validation and quantification

“…C1QB encodes a component of the complement 1 (C1Q) complex, part of the complement immune system. Expression of genes encoding components of C1Q have been shown to correlate with the progression of active TB compared to HC and LTBI cohorts [42] and a recent study showed that, in four independent cohorts, components of the C1Q complex are elevated in patients with active TB compared to those with LTBI [43]. ZNF296 encodes a member of the C2H2 zinc-finger protein family, which contain DNA binding motifs often found in transcription factors.…”