Distinct antibody-based signatures and functionality distinguish latent and active pediatric tuberculosis

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Background: (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.

Authors 16

1. Nadège Nziza

   Ragon Institute of MGH, MIT and Harvard · Massachusetts Institute of Technology

   Affiliation as printed

   Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA;

   Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA

2. Wonyeong Jung

   Ragon Institute of MGH, MIT and Harvard · Massachusetts Institute of Technology

   Affiliation as printed

   Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA;

   Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA

3. Tina Chen

   Ragon Institute of MGH, MIT and Harvard · Massachusetts Institute of Technology

   Affiliation as printed

   Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA;

   Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA

4. Yixiang Deng

   Ragon Institute of MGH, MIT and Harvard · Massachusetts Institute of Technology

   Affiliation as printed

   Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA;

   Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA

5. Kees L. M. C. Franken Aachen Department of Research, Leiden University Medical Center

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases (LUCID), Department of Research, Leiden University Medical Center, Leiden, Netherlands;

   Leiden University Center for Infectious Diseases (LUCID), Department of Research, Leiden University Medical Center, Leiden, Netherlands

6. Tom H. M. Ottenhoff Aachen Department of Research, Leiden University Medical Center

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center: Leids Universitair Medisch Centrum;

   Leiden University Center for Infectious Diseases (LUCID), Department of Research, Leiden University Medical Center, Leiden, Netherlands

7. Sarah Kiguli

   Makerere University

   Affiliation as printed

   Department of Pediatrics, Makerere University, Kampala, Uganda;

   Department of Pediatrics, Makerere University, Kampala, Uganda

8. Deborah Anne Lewinsohn

   Oregon Health & Science University

   Affiliation as printed

   Oregon Health & Science University;

   Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA

9. W. Henry Boom

   Case Western Reserve University

   Affiliation as printed

   Case Western Reserve University School of Medicine;

   Department. of Medicine, Case Western Reserve University, OH, USA

   Uganda-Case Western Research Collaboration, Kampala, Uganda and Cleveland, OH, USA

10. Harriet Mayanja‐Kizza
    Affiliation as printed

    Uganda-Case Western Research Collaboration, Kampala, Uganda and Cleveland, OH, USA.;

    Uganda-Case Western Research Collaboration, Kampala, Uganda and Cleveland, OH, USA

11. Mary Nsereko
    Affiliation as printed

    Uganda-Case Western Research Collaboration, Kampala, Uganda and Cleveland, OH, USA;

    Uganda-Case Western Research Collaboration, Kampala, Uganda and Cleveland, OH, USA

12. Sarah M. Fortune

    Harvard University

    Affiliation as printed

    Harvard University T H Chan School of Public Health;

    Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

13. Catherine M. Stein

    Case Western Reserve University

    Affiliation as printed

    Case Western Reserve University;

    Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, OH, USA

14. Ryan P. McNamara

    Harvard University · Ragon Institute of MGH, MIT and Harvard

    Affiliation as printed

    Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA;

    Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA

15. Galit Alter

    Ragon Institute of MGH, MIT and Harvard · Massachusetts Institute of Technology

    Affiliation as printed

    Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA;

    Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA

16. Christina Lancioni corresponding

    Oregon Health & Science University

    Affiliation as printed

    Oregon Health and Science University

    Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA