Beyond IgG: Novel Insights into IgA and IgM Glycosylation in Tuberculosis and Their Role in Differentiating Infection Status

Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge, particularly among the elderly. Accurate differentiation between active TB (ATB) and latent TB infection (LTBI) is essential, yet current diagnostic tools often fall short. While immunoglobulin (Ig) G glycosylation has been investigated in TB differential diagnosis, the glycosylation profiles of IgA and IgM have not been systematically studied—especially in older adults, who are more susceptible to TB reactivation. Methods: We analyzed the glycosylation patterns of IgG, IgA, and IgM in 59 elderly participants, including 22 ATB patients, 17 LTBI individuals, and 20 healthy controls. Antibody glycosylation was profiled using liquid chromatography-tandem mass spectrometry (LC-MS/MS), with a focus on distinguishing features between ATB and LTBI. Results: This study is the first to identify distinct glycosylation alterations in IgA and IgM among TB patients. Compared to LTBI and controls, ATB patients showed reduced galactosylation and increased fucosylation in IgG and IgM, indicative of an enhanced inflammatory state. Novel glycosylation changes in IgA were observed at N144/131. When combining glycosylation features across all three immunoglobulin isotypes, diagnostic performance in differentiating ATB from LTBI improved (AUC = 0.808), suggesting added value beyond IgG alone. Conclusion: Our findings demonstrate that glycosylation changes in IgA and IgM accompany active TB and are not limited to IgG. These alterations reveal broader humoral immune modulation in TB. In elderly individuals, where clinical differentiation of TB status is especially challenging, IgA and IgM glycosylation may warrant greater attention in both research and diagnostic contexts.