Function crucial antibody in our blood far more complex than previously thought

Researchers at Utrecht University have discovered that a crucial antibody in human blood, known as IgA, often exists in a different form than previously assumed. The finding could have significant implications for the development of new medicines and was recently published in PNAS. The study aligns seamlessly with the work of the PHARMIGA consortium, which recently received a 5 million euro grant from PharmaNL to develop a new generation of IgA-based therapies.

Researchers at Utrecht University have discovered that a crucial antibody in human blood, known as IgA, often exists in a different form than previously assumed. The finding could have significant implications for the development of new medicines and was recently published in PNAS. The study aligns seamlessly with the work of the PHARMIGA consortium, which recently received a 5 million euro grant from PharmaNL to develop a new generation of IgA-based therapies.

Striking number of dimers            

In this study by postdoctoral researcher Amber Rolland in collaboration with Sanquin, the structure of IgA molecules in the blood was mapped in detail. The researchers found that a specific form of IgA occurs in the bloodstream far more frequently than previously assumed. This form consists of two IgA molecules linked together by a connector protein known as the J-chain, forming so-called J-chain coupled dimers. The finding is notable because circulating IgA was long thought to consist predominantly of single, monomeric molecules. In one blood donor, these dimers accounted for nearly 30 per cent of all IgA present.

Fundamentally different

The researchers also found it remarkable that antibody-producing B cells generate both monomeric and dimeric IgA simultaneously. Until now, it was widely assumed that these different forms were produced in separate locations by distinct cells. By investigating the origin of IgA molecules in the bloodstream, the team discovered that both the monomeric and dimeric forms could be traced back to the same B cells using innovative mass spectrometry techniques.

“These findings point to a much broader and more complex role for IgA in the blood than previously recognised,” said Albert Heck, who led the study. “It is fundamentally different from the picture commonly described in the literature.”

It is fundamentally different from the picture commonly described in the literature

Diverging strategies

According to the researchers, the discovery that a single population of IgA clones can consist of both monomeric and dimeric forms may have important implications for how these antibodies function in the immune system. The structure of an IgA molecule determines how it binds to an antigen, meaning that different forms can target the same pathogen in different ways. Monomeric IgA, for example, is known to more readily trigger inflammatory immune responses to combat infection, whereas dimeric IgA appears to be more effective at neutralising pathogens directly.

“Although further research is needed, for example into the mechanisms that determine the balance between these different forms, these findings have important implications for our understanding of human IgA,” said Heck.

Strengthened potential

These findings also have important implications for the development of IgA-based medicines, particularly for the treatment of cancer, infectious diseases and autoimmune disorders. Researchers already knew that IgA may offer advantages over IgG, the antibody type on which many current therapies are based. However, the discovery that IgA exists in multiple forms, each with distinct stability, functional properties and pathogen-clearing capabilities, further strengthens its potential as a therapeutic platform, according to Heck. Advancing that potential is a central goal of the PHARMIGA consortium within PharmaNL.