Glycosylation patterns across antibody isotypes distinguish tuberculosis states

Tuberculosis, or TB, is a lung infection caused by Mycobacterium tuberculosis and continues to pose a major global health threat, with an estimated 1.2 million deaths in 2024. TB can remain latent, or LTBI, or advance to active disease, or ATB. Although current diagnostic tests largely detect infection, they cannot efficiently define the disease state.

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The structure of an antibody of subclass IgG1. Two light chains (green and pink) and two heavy chains (blue and yellow) are shown. Glycans between the heavy chains are shown in dark gray.

Glycosylation of the antibody fragment crystallizable, or Fc, region regulates immune responses during TB by modulating immunoglobulin, or Ig, structure and effector functions. Infection-associated glycan remodeling reflects a shift toward a proinflammatory state. While IgG Fc glycosylation in TB is well characterized and shows diagnostic potential for distinguishing disease states, glycosylation of other isotypes remains largely unexplored, limiting a full understanding of humoral immunity in TB.

In a new study published in Molecular & Cellular Proteomics, Yun-Jung Yang of Taipei Medical University and an international team provide the first site-specific glycoprofiling of IgA and IgM in older adults with TB. Using targeted liquid chromatography-tandem mass spectrometry, or LC-MS/MS, they quantified Fc glycosylation patterns across IgG, IgA and IgM from 58 adult participants at Taipei Municipal Wan Fang Hospital. The findings showed that, like IgG, IgA and IgM undergo glycan remodeling during infection without major changes in antibody abundance. In addition, integration of patterns across all three isotypes provided new insight into antibody diversification and immune modulation during infection.

ATB showed a consistent proinflammatory signature: IgG exhibited lower galactosylation and higher fucosylation compared with LTBI, in line with previous studies. Importantly, similar effects were observed in other antibody isotypes: IgA1/2 at N144/131 showed reduced galactosylation from digalactosylated forms, while IgM displayed decreased galactosylation at N171, N332 and N395, increased agalactosylation at N563 and higher fucosylation and sialylation at N71. Integrating glycosylation traits across all three isotypes improved the separation of ATB from LTBI, highlighting the potential of multi-isotype Fc glycosylation profiles to improve the distinction between TB disease states.