Circulating antibody signatures against Mycobacterium tuberculosis antigens are associated with severe and mild tuberculosis.

INTRODUCTION: Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a highly heterogeneous disease driven by the pathogen's adaptive mechanisms to subvert the host immune response. Identifying biomarkers that can stratify disease severity remains a major challenge. METHODS: In this work, we analyzed a large cohort of patients with active TB by integrating clinical, radiological, and laboratory variables. Using Factor Analysis of Mixed Data (FAMD) to define a range of severity-associated phenotypes, two principal components of variation, related to systemic and pulmonary severity were identified and combined in an overall score. Plasma circulating IgG responses against ESAT-6/CFP-10, Ag85A, HspX and Rv2626c -four key antigens with distinct behaviors during metabolic switches of Mtb- were evaluated as antibody signatures. RESULTS: Individual antibody responses showed limited associations with severity. However, specific antibody signatures presented a significantly higher effect. A signature defined by IgG responses against ESAT-6/CFP-10, Ag85A, and HspX (excluding Rv2626c) was associated with higher severity scores and features of advanced pulmonary disease. In contrast, signatures containing antibodies against Rv2626c were mainly associated with milder phenotypes. CONCLUSION: These findings demonstrate that antigen-specific IgG signatures show significant associations with specific forms of TB pathology. Additional prospective and longitudinal studies will be required to study their potential as biomarkers.