An Fc receptor and IgA functional signature identifies TB disease in children living with HIV

BACKGROUND: Tuberculosis (TB) is a leading cause of morbidity and mortality among children living with HIV (CLHIV). TB disease is difficult to detect with current clinical microbiological, immunological, and radiographic tools. Serological assays that determine levels of Mycobacterium tuberculosis reactive antibodies inconsistently identify TB but antibody Fc receptor engagement and effector functions are promising biomarkers of TB disease. The objectives of this study are to identify antigen specific antibody signatures in CLHIV with TB disease that both 1) respond to treatment and 2) distinguish CLHIV with TB disease from those without TB disease. METHODS: This study evaluated serum antibody properties from a well-characterized cohort of Kenyan CLHIV via two orthogonal approaches: 1) longitudinal assessment following individuals over the course of treatment and 2) cross-sectional examination of individuals with and without clinical TB disease. For each individual sample, 13 antibody functional properties against 8 Mtb and 4 non-Mtb microbial antigens were measured and analyzed via univariate and multivariate machine-learning approaches. RESULTS: FcαR/CD89 immune complex formation with antibodies reactive to four Mtb antigens including ESAT-6 & CFP-10, FcγRI/CD64 associated with one Mtb antigen, and HIV gp120 IgA1 distinguished CLHIV with from those without TB disease and decreased over the course of treatment. INTERPRETATION: An Mtb and HIV reactive peripheral blood antibody functional signature of FcαR/CD89, FcγRI/CD64, and IgA1 are potential correlates of TB disease in CHLIV.