Abstract
BACKGROUND: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is among the leading causes of death from an infectious agent among children worldwide. Children represent a particularly vulnerable population due to the greater challenges in diagnosis and the higher risk of progression to severe forms of the disease. However, whether different pediatric outcomes relate to distinct immunologic responses remains incompletely understood. Emerging data suggest that Mtb-specific humoral immune responses represent a correlate of protection against Mtb both following natural infection and vaccination. METHODS: To determine if immune profiles can distinguish children across the spectrum from Mtb infection to TB disease, as well as children with TB from non-TB lower respiratory tract infection, we mapped the humoral immune response across a panel of 4 dozen Mtb antigens across children presenting with symptoms of active TB (ATB), children with evidence of latent TB infection (LTBI) and children exhibiting non-TB lower respiratory tract infection (non-TB LRTI). Using a custom Luminex assay, Mtb-specific antibody subclass/isotype, Fc receptor (FcR) binding profiles, and functions were profiled across the pediatric groups. FINDINGS: A robust humoral immune response was observed in children with active TB compared to non-TB LRTI, marked by a strong IgA response, that exhibited high FcαR binding. Conversely, children with LTBI uniquely elicited Mtb-specific antibodies with enhanced opsinophagocytic FcγR2A binding, as well as a higher capacity to activate NK cells and neutrophils. INTERPRETATION: There are significant differences in humoral immune profiles across the landscape of pediatric TB, potentially contributing to differential mycobacterial control, and highlighting biomarkers that could guide both diagnostic and therapeutic approaches. FUNDING: US National Institutes of Health.