Immune System Has Evolved To Prevent Autoimmune Disease

The findings will be published in thejournal Physical Review Letters. They are based on a new model of theimmune system that is the first to simulate the hierarchical nature ofthe body's immune response. The model predicts that chronic infectionsmay lead to autoimmune diseases, a scenario that has been proposed as acause of some rheumatic diseases like arthritis.

"There are asmany as a 100 million unique antibodies circulating through our bodiesat any given time, but just three or four of these might be effectiveagainst any particular disease," said Michael Deem, the John W. CoxProfessor in Biochemical and Genetic Engineering and professor ofphysics and astronomy. "When we get sick, the immune system identifiesthe particular antibodies that are effective, as it rapidly creates andmass produces mutant white blood cells called B cells that make onlythese antibodies."

Deem said prior research has identified anumber of alternate strategies the immune system could use to reducethe time needed to create an effective B cell. In addition, thesemethods also could produce antibodies that are more apt to bind withdisease cells. The upshot would be an immune system that respondsfaster and more effectively against disease.

"This should help usget well faster, so the question becomes, 'Why didn't we evolve thatkind of adaptive response?'" Deem said.

Deem's analysis fallswithin a branch of physics called statistical mechanics, which uses asystem's physical behavior at the molecular or atomic scale to build upa picture of the behavior at a larger level. In this case, Deem andpostdoctoral researchers Jun Sun and David J. Earl studied the physicalproperties of fragments of DNA to determine the origins, behavior, andgeneration of antibodies.

Generating antibodies is one of theprimary functions of the immune system. Antibodies are proteinmolecules that are made by B cells. Each antibody has a chemicalsignature that allows it to bind only with a particular sequence ofamino acids.

"In our study, we first sought to understand theevolutionary rules that govern the way the immune system responds to aninfection," Deem said. "With that framework in place, we identified abiologically-plausible strategy that would allow the immune system toreact more quickly and with more effective antibodies. Our analysisrevealed that such a system would be about 1,000 times more likely toproduce antibodies that attack healthy tissues."

Antibodies thatbind with something other than the antigen they evolved to attack arecalled cross-reactive, and some researchers believe cross-reactivitycauses some autoimmune diseases.

For example, some scientistshave found a correlation between chronic infection and an increasedprobability of autoimmune disease, but the strength and significance ofthe correlation is controversial. Rice's model suggests that acorrelation does exist, but that the length of the infection prior toonset of autoimmune disease is highly variable.

"People have beenlooking for a clear, significant correlation in time, but a longdistribution of onset times would lead to weaker statisticalcorrelations, particularly in those cases where the infection persistedthe longest," said Deem. "Searching for this distribution in health andmedical statistics could shed light on this immunological puzzle andsettle the scientific controversy."

The Rice analysis finds thehuman immune system evolved to minimize the risk of cross-reactivity.For example, each cell in our bodies contains about 100,000 proteinswith an average of 500 amino acids apiece. Consequently, there areabout one trillion potential docking sites, or epitopes, whereantibodies could mistakenly attach themselves to proteins in a healthycell. The mutation response method employed by our adaptive immunesystem seems keyed to this number, producing antibodies that arestatistically likely to mistakenly bond with healthy proteins slightlyless than one in a trillion times, meaning that on average, theyrecognize only invading pathogens.

The research was funded by the NIH/National Institute of Allergy and Infectious Disease.