Team discovers 'missing link' in origins of allergy attacks
BY LOU BERGERON
Allergy attacks are awful, with all that sneezing and coughing, the runny nose and red eyes. But those annoying symptoms aren't driven by the invading allergen so much as by the body's defending mast cells--the sometimes overly zealous gatekeepers of a host of biological mediators normally only released in abundance to combat parasites or bacteria.
Mast cells, a critical part of the immune system, develop from hematopoietic (blood) stem cells that originate in bone marrow and journey through the blood stream to complete their maturation in peripheral tissues such as the skin, gut and respiratory tract. But until recently, the different stages of their maturation process, or differentiation, hadn't been fully deciphered.
Now, medical school researchers have identified a long-sought "missing link" in the differentiation of mast cells, opening the door to possible new approaches in treating such allergic diseases as asthma and a rare, presently incurable, disease called mast cell leukemia.
When allergens invade the body, antibodies perched on the outside of the mast cells react to the allergens and notify the mast cells to respond. The allergens injected during a bee sting, for example, prompt mast cells to release histamine, a mediator that helps the body combat the effects of the sting but also causes itching and swelling of the skin tissue at the site. If the mast cells release too much histamine, that's when an antihistamine is needed to reduce the irritation. This method of treating a mast cell overreaction can work, but each of the mediators in a mast cell requires a different medication to rein it in, resulting in a piecemeal approach to treatment.
Discovery of the new cell--called the mast cell progenitor, as it's the immediate precursor to the mature mast cell--could lead to identification of a broader and more effective treatment method.
Although the progenitor gives rise only to mast cells, it is different enough that it isn't detectable as a mast cell, which may explain a puzzling, but crucial, aspect of how mast cells respond to allergens. In healthy adults, mast cells are found in low numbers in tissues. But that changes when asthma or some other chronic disease affects such tissues.
"One of the amazing things about mast cells is that they increase [in number] very quickly," said Ching-Cheng Chen, PhD, postdoctoral scholar in pathology and first author of the paper published online July 8 in Proceedings of the National Academy of Sciences. In asthma-affected tissue, the population can double or triple, said Stephen Galli, MD, professor and chair of the Department of Pathology, one of two senior authors of the paper.
Such rapid booms in population are surprising, given the low number of mast cells usually found in tissues. The cells already present are unlikely to replicate so quickly. And since mast cells aren't present in the blood stream, there hasn't been an obvious source of new defenders.
But with mast cell progenitors around, local population explosions could occur in two ways. It may be that wherever mature mast cells reside, their progenitors are also present, but dormant until an allergen or other stimulus is detected, whereupon they finish differentiating and unleash the appropriate mediator from within. And while mature mast cells don't normally circulate in the blood, their progenitors might. Progenitors already in circulation could quickly flock to a site to finish differentiating.
Knowing how to spot mast cell progenitors may aid in developing more effective treatments for diseases like asthma. "If we can block increases in mast cell numbers, no matter if it's by blocking recruitment or blocking differentiation of the progenitors, the total number of mast cells will be low," said Chen. This in turn would keep the release of mediators low, preventing potentially dangerous reactions.
Chen and his colleagues detected the mast cell progenitors in adult mouse bone marrow. A fetal progenitor was found in a 1996 study by a group led by Hans-Reimer Rodewald (University of Ulm) and Galli, but the adult counterpart had eluded researchers. Only through a complex sorting and testing process were the Stanford researchers able to identify an adult progenitor in the bone marrow cells. Further study of adult progenitors in mice is definitely on the agenda, Galli said.
Additional co-authors of the paper include postdoctoral scholar Michele Grimbaldeston, PhD, and Mindy Tsai, DMSc, senior research scientist in pathology. Chen is supported by Galli's lab and the lab of senior co-author Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine.
