Researchers at Boston Children's Hospital and Harvard Medical School shed light on the “runaway train” aspect of autoimmune disease in a recently published article in Cell. Two seminal discoveries were reported: The role of rogue B cells and the cause of epitope spreading.
To understand what leads to epitope spreading, Michael Carroll, Ph.D., of Boston Children's Hospital and Harvard Medical School, and his team used a "confetti" technique in a mouse model of lupus.
When the body senses an antigen, B cells aggregate in germinal centers. In these germinal centers, B cells make competing antibodies in response to the detected antigen, battling each other to create the best antibody for the job of neutralizing the invading threat. Eventually, the best B cell clone with the most effective antibody wins out, and, in concert with other immune cells, activates an attack. However, this highly effective process can wreak havoc if the body incorrectly senses an "autoantigen" on one of its own tissue types.
By using fluorescent colors to differentiate between B cell clones, Carroll's team watched the same germinal center activity happen during an autoimmune response. The B cell "colors" battled to create an autoantibody in a model of lupus.
Once the autoimmune response is triggered, Carroll, senior author on the paper, says the "runaway train pulls out of the station, so to speak," and the immune system begins to go after other similar autoantigens elsewhere in the body.
"Over time, the B cells that initially produce the 'winning' autoantibodies begin to recruit other B cells to produce additional damaging autoantibodies.
"This finding was such a surprise," says Carroll. "It not only tells us that autoreactive B cells are competing inside germinal centers to design an autoantibody, but then we also see that the immune response broadens to attack other tissues in the body, leading to epitope spreading at the speed of wildfire."
Now, with their confetti mouse model that allows them to observe loss of self tolerance and autoreactive epitope spreading, the team will further interrogate how the complex dance between inflammation, natural cell death/removal by the immune system and antigens inside cell nuclei might exacerbate B cell production of autoantibodies.
For now, the team says, understanding how B cell activity in germinal centers relates to epitope spreading is a big leap in the right direction. They speculate that a therapy that "blocks" germinal centers might one day be used to halt the vicious cycle of autoimmune diseases.
Caption: Natural selection on a small scale: Immune cells called B cells battle each other to produce the best antibody. Here, green represents the B cells that are producing the "winning" antibody, which stamp out competing B cells (other colors). Credit: Carroll lab/Boston Children's Hospital