Researchers led by HMS Associate Professor of Medicine Julia Wang offer a new, unifying theory on the origins of autoimmune diseases. In two related papers in the May 2011 issue of the American Journal of Pathology, the team outlines a process by which a carbohydrate abundant in skin and connective tissue called dermatan sulfate turns traitorous. The resulting disease may be systemic, as in lupus or rheumatoid arthritis, or localized, as in Type 1 diabetes or Graves’ disease.
Only a tiny subset of molecules in the body are known to have the potential to become autoantigens, targets of an immune system that mistakes “self” as foreign. Immune B cells play a key role by producing autoantibodies to these autoantigens.
In mice, Wang, along with current and former research fellows Jongmin Lee, Ming Yan, Jung-hyun Rho and Michael Roehrl, demonstrate that dermatan sulfate plays a pivotal role in regulating a type of B cell called B-1a. Levels of both dermatan sulfate and B-1a cells are elevated when cell turnover is high, as in wound healing.
The researchers suggest that, when dead cells pile up, dermatan sulfate may help speed the clearing of these cells by the immune system. Dermatan sulfate has a downside, however. When cells with a high affinity for the molecule die, the resulting complexes can become unrecognizable as self. These complexes stimulate the proliferation of B-1a cells and the production of autoantibodies, which in turn mark healthy tissues for destruction. When autoantibodies bind to autoantigens on healthy cells, other autoimmune B cells infiltrate the tissue, and damage ensues.
In an accompanying patient study, Wang and colleagues Rho, Roehrl, Wei Zhang and Mandakolathur Murali found that the full complement of autoantigens in humans—more than 200—could be classified by their affinity for dermatan sulfate. “It is those molecules that can associate with dermatan sulfate which have a propensity to become autoantigens,” Wang said.
Wang and her coauthors came to their conclusion by an unconventional route. “We did not investigate this in the traditional immunological way, using genetic approaches,” Wang explained, referring to the strategy of tinkering with genes to heighten or dial back certain proteins in B cells or other autoimmune-response components.
Instead, Wang said, “we used immunological, biochemical and proteomic tactics to isolate a common denominator among autoantigens” in cell cultures, in a mouse model, and in humans. With most research focused on proteins, she said, dermatan sulfate has not been an obvious target for study.
Autoimmune diseases “are ripe for a real breakthrough,” said Wang, who with colleagues has begun developing personalized molecular serum testing for patients to help diagnose autoimmune diseases at a more precise molecular level.
“Many therapies target over-reactive B cells,” Wang said. “Now, with a new mechanism for B-1a cell activation in mind, scientists have a chance to disrupt the start of that dangerous process.”
To learn more, students may contact Julia Wang at julia_wang@rics.bwh.harvard.edu
