Research Highlights

B cells: Siglecs stop self-attack

B cells release antibodies directed against foreign antigens. For decades it was thought that B cells remain tolerant to an antigen unless they receive a second signal, either from T cells or some other inflammatory marker. However, it is known that some antigens can actually stimulate a B cell response without help. Thus, B cells must have an alternative method for distinguishing between 'self' proteins that should not provoke a reaction, and 'non-self' antigens that require immediate action. Without this, antibodies generated against an individual's own molecules can cause autoimmune diseases including Crohn's disease and Lupus. To determine how B cells can independently distinguish whether an antigen requires activation or tolerance, David Nemazee and colleagues explored the role of sialic acid-binding Ig-like lectins (siglecs) in T cell-independent B cell responses.

As previously described in Molecular mimicry: Sugar coating bacterial infection, very few microbes express sialic acid, so proteins that are decorated with these sugars are ideal indicators of 'self'. Siglecs bind sialic acids and are expressed on the surface of B cells. These lectins contain intracellular motifs that trigger inhibitory cell signaling pathways, so the authors hypothesized that they might play a part in B cell tolerance to self antigens. To test this possibility, they used carbohydrate compounds acquired from the Consortium for Functional Glycomics to design polymers containing sialic acids. These polymers mimic large self antigens that a B cell might encounter and develop tolerance to, such as other cells.

Mice injected with the polymer backbone alone developed a robust antibody response, whereas mice inoculated with polymers containing sialic acid did not, despite the observation that these were better at binding to B cells. Further investigation showed that, rather than masking the polymer antigen, sialic acids prevented B cell activation by sending inhibitory signals through siglecs. When exposed to these same polymers, knockout mice deficient in just one of nine siglecs in the murine repertoire did not develop tolerance to sialylated polymers. The authors concluded that B cell siglecs are responsible for recognizing sialic acids as self and consequently shutting down antibody responses.

This study explains how tolerance to some B cell antigens can arise in the absence of secondary signals. The results also demonstrate that artificial sialic acid polymers could be used to therapeutically induce tolerance for the treatment of autoimmune disorders.

Author: Heather Buschman