Researchers have known for many years that autoimmune diseases such as rheumatic fever (when the body makes antibodies that attack the heart) or Guillain-Barré syndrome (body makes antibodies that attack peripheral nerves) can occur after the body mounts immune responses against certain infectious pathogens.
But until now nobody understood exactly how these infection-produced types of autoimmunity occur; or why the body seems unable to prevent them.
A team led by Drs. Tyani Chan and Robert Brink at the Garvan Institute of Medical Research in Sydney, Australia have confirmed a ‘weak link’ in the immune system – and “the exact conditions under which an infection can trigger an autoantibody response.”
Specifically, the researchers, who specialize in the study of how immune B cells produce self-attacking ‘rogue antibodies,’ say their finding “explains a lot about how autoimmune conditions that target particular organs such as the heart or nervous system could develop after an infection.”
As they lay it out in a fee-based paper published Nov 8 by the journal Immunity:
• Our immune cells go through processes when they are first formed that ensure they are able to identify our own bodies (self), and therefore avoid self-attack. These processes are generally reliable as they take place in a steady, regulated way.
• But the antibody-creating B cells go through a second and much more chaotic phase of development when the body is engaged in trying to fend off disease or infection.
• In order to cope with the immeasurable range of microbes in our environment, B cells have evolved the ability to mutate their antibody genes randomly until they produce one that sticks strongly to the invader.
• At that point, the ‘successful’ B cells proliferate and flood the system with these new antibodies.
• This ‘high affinity antibody’ generation process occurs very rapidly within specialized environments in the lymph system known as ‘germinal centers’. [See video.]
• Most of the time, germinal centers serve us well, helping us fight disease and build up a protective armory for the future.
• Unfortunately, the urgency and speed at which B cells mutate within the germinal center, as well as the random nature of the process, creates a unique problem. Sometimes the antibody created to fight the invader, or ‘antigen’, also happens to match ‘self’ and has the potential to cause attack on the self (autoimmune activity).
Chan and Brink developed sophisticated mouse models to investigate when and how this happens.
Focused Infection Far from the Germinal Center Can Spell Trouble
They demonstrated that:
• When the invading antigen is abundant and generally present throughout the body, rogue autoantibody-generating B cells are deleted and autoimmunity is avoided.
• In contrast, when the target antigen is located only in a tissue or organ remote from the germinal center, B cells capable of reacting against both antigen and ‘self’ are able to escape the germinal center and produce autoantibodies.
“Essentially we’ve shown there’s a big hole in self-tolerance when it comes to cross-reactive autoantibodies that can attack organ-specific targets,” says Brink. “Our finding explains a lot about how autoimmune conditions that target particular organs such as the heart or nervous system could develop after an infection.
Importantly, she adds, “It also suggests that if you know enough about the disease and the molecular messaging systems involved, it may be possible in future to modulate the germinal center response.”
The team says they’ll continue to use their new mouse model to study the various molecular reactions involved in the progression of an autoimmune response.
Source: Based on Garvan Institute media release, Nov 9, 2012