Australian researchers say they have uncovered a strategy the immune system uses to generate effective antibodies, which could inform future vaccine design.
A team from Garvan Institute of Medical Research discovered that the immune system mutates its B cells to create antibodies more finely-tuned to foreign molecules when the targets for those antibodies, referred to as antigens, are flexible rather than rigid.
That’s important, says Deborah Burnett, co-first author of a paper in the journal Proceedings of the National Academy of Sciences, because “antibodies have to bind like glue to foreign threats, such as viruses, but avoid any of the body’s own molecules as this can lead to autoimmunity”.
The immune system constantly evolves to clear viruses from the body and to remember them so they can respond again in the future. This happens in germinal centres within the lymph nodes, where B cells multiply and mutate to produce antibodies tuned to the virus.
In their experimental models, Burnett and colleagues used an artificial pair of “foreign” and “self” molecules that were very similar, creating different versions of the same antigen but altering one connection that made it either more rigid or more flexible.
They then investigated how the immune system of mice generated antibodies to the different molecules, finding that when the foreign antigen was more flexible, the germinal centre could employ a greater number of evolution strategies to make antibodies that bound foreign but not self-molecules.
“Our results showed that the antibodies initially bonded to both the rigid self and flexible foreign antigens in the same way, unable to tell them apart,” says Burnett.
“What surprised us was that, after only a few weeks, when the foreign antigen was flexible, the antibodies were able to specifically mutate to become 67 times more selective for foreign antigens, and 19 times less selective for self.
“The antibodies generated against rigid foreign antigens were more likely to have autoimmune properties.”
The ability to produce antibodies that bind foreign but not self-molecules is a major hurdle for vaccine development, the researchers say.
And, says Garvan’s Executive Director Chris Goodnow, there is “circumstantial evidence” that antibodies against the spike molecule on the SARS-CoV-2 virus may also recognise self”.
“This may be an explanation for why antibody levels against the novel coronavirus appear to decline in patients quickly after infection,” he suggests.
“Understanding how to increase selection of antibodies that don’t bind self may illuminate a pathway to long-lived immunity against COVID-19.”
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