Discovery of mechanisms triggering excess antibody production during chronic infection
Some autoimmune diseases and persistent infections are characterized by high levels of antibodies in the blood. But what are the causes of this hypergammaglobulinemia? A team headed by INRS's Professor Simona Stäger has successfully identified the mechanisms triggering the phenomenon. For the first time ever, she has established a link between B-cell activation by a protein–type 1 interferon–and unusually high antibody levels.
The team has also discovered that a parasite can directly activate B cells–the cells responsible for producing unusually high antibody levels. Until now, there has been no evidence that B cells can be directly stimulated by the parasite known to cause visceral leishmaniasis, a neglected and often lethal tropical disease also characterized by high levels of antibodies.
How do Leishmania donovani parasites set off this harmful immune reaction? Proteins known as endosomal TLRs (toll-like receptors) recognize the parasites as pathogens, triggering proinflammatory responses.
"In the case at hand, TLRs induce the secretion of interleukin-10 proteins that reduce immune responses and type 1 interferons that increase B-cell antibody production. The fact that type 1 interferons contribute to hypergammaglobulinemia induction was completely unknown," explains Professor Stäger.
Of particular interest is the fact that activation pathways may play a role in other diseases characterized by rising antibody levels that exacerbate conditions. This is a major lead as this poorly understood phenomenon causes immune reactions and other immune pathologies.
This research was headed by Professor Simona Stäger and her collaborators. Research was primarily conducted by Sasha Silva-Barrios, a doctoral student and the first author, with the assistance of Mélina Smans, a master's student at Centre INRS-Institut Armand-Frappier, and Claudia U. Duerr, a postdoctoral fellow at McGill University. The results were published in Cell Reports (doi:10.1016/j.celrep.2016.05.028) under the title "Innate Immune B Cell Activation by Leishmania donovani Exacerbates Disease and Mediates Hypergammaglobulinemia." The Canadian Institutes of Health Research, the Centre for Host-Parasite Interactions' New Initiatives Fund, and CRSNG funded the research.