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.