Demystifying Allergies, Inflammation, and Infections

Roberto Adachi, M.D., likens his lab’s work to learning how a car engine functions. Although in this case, he wants to make part of the engine stop working.

Adachi, a pulmonary and critical care medicine staff physician in pulmonary and critical care medicine at the Houston Veterans Affairs Medical Center, and assistant professor of pulmonary medicine at Baylor College of Medicine, is studying the inner workings of the mast cell – cells that play a role in all allergic responses and inflammation. To its credit, the mast cell also is important in the body’s defense against bacterial infection.

“We are looking for a way to retain the cell’s ability to fight infection while shutting down the parts responsible for allergy and inflammation,” Adachi said. “Like working on an engine, it is a process of first understanding each individual part, then learning how the parts work together, and finally determining how you can change the way it works.”

Mast cells play parts in skin and food allergies, asthma, and fatal allergic reactions, and have been implicated in rheumatoid arthritis, scleroderma, and forms of vasculitis. Originating in the bone marrow, they migrate to tissues all over the body.

The cells reside in the tissues until stimulated during allergic reactions or in response to injury. Each cell is packed with granules that contain many inflammatory mediators.

“Once activated, the cells have three responses,” Adachi said. “They produce lipid mediators involved in allergy and inflammation, and cytokines that call the inflammatory cells to the site. The third action is called degranulation – a dumping of the inflammatory mediators stored in the granules into the surrounding tissues.”

Adachi’s VA lab is exploring the degranulation process in hopes of shutting it down. He believes degranulation is responsible for the bad effects of mast cells.

“Since the mast cell responds in three ways simultaneously, we think if you preserve the first two, lipid mediators and cytokines, you will preserve the good part of inflammation – the defense against bacterial infection,” he said. “We believe allergies are dependent on degranulation.”

The hospital’s laboratory is looking at the final step of degranulation, when the granule membrane fuses with the cell membrane and releases its contents. So far, Adachi’s laboratory has detected nine protein components of the machinery involved in the final step of degranulation.

“We have isolated each component and studied it, and now we want to know how they work together,” he said. “Our final goal is to have a mast cell that will still defend us against bacterial infection but will be unable to hurt us.”

To learn about each specific component, the lab develops “knock-out” mice. The mice are engineered to be unable to produce one of the protein components being studied.

“We compare the knock-out mouse with a normal mouse to see what effect the missing protein component has on degranulation and ability to fight infection,” Adachi said. “We want to find a component that, when missing, disables degranulation but allows bacterial defense.”

Though initial work on the mast cell’s machinery was done studying cell lines, the mice have been critical to the research.

“A cell line doesn’t have allergies, only animals and people do,” Adachi said.

For now, Adachi and his Houston VA Medical Center colleagues continue the process of systematically learning the role each component plays in degranulation.

If his theory on degranulation holds true, Adachi hopes the research will lead to pharmacological interventions to block mast cell degranulation.

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