Findings Explain Why DOCK8-Deficient Patients Are Susceptible to Infections
NIAID scientists have discovered a novel role for DOCK8, an immune cell protein that, when missing or mutated, results in a disorder called DOCK8 deficiency. For unclear reasons, DOCK8-deficient patients experience severe and persistent skin infections. In the latest study, researchers show that DOCK8-deficient immune cells cannot move easily in dense tissues like the skin, causing the cells to fragment and die. The study appears in the Nov. 24, 2014, online issue of The Journal of Experimental Medicine.
Background
In 2009, NIAID researchers identified DOCK8 deficiency, an immune disease that causes severe health problems, including persistent skin infections from viruses that cause cold sores (herpes simplex virus), warts (human papillomavirus), and shingles (varicella-zoster virus). Patients also have severe eczema, allergies, asthma, and a higher risk of developing cancer. At the time, researchers did not understand how DOCK8 affected the immune system.
The researchers found that bone marrow transplantation, which replaces defective immune cells with cells from a healthy donor, can be an effective treatment for DOCK8-deficient patients. However, some patients are unable to find a matching donor or are too sick to safely undergo transplantation. By understanding the role of DOCK8 in the immune system, researchers may develop better therapies in the future.
T cells from a healthy donor (left) and DOCK8-deficient patient (right) are shown moving through a gel. In this environment, DOCK8-deficient immune cells elongate, fragment, and die, a process called cytothripsis.
Results of Study
NIAID researchers noticed that DOCK8-deficient patients experienced severe skin infections disproportionate to patients with other immune deficiency diseases. The skin contains a tight network of fibers and interlocking cells. Immune cells called T and NK cells normally patrol the skin and protect against disease-causing viruses. If these cells cannot move easily, the health of the skin is compromised.
The researchers examined the ability of DOCK8-deficient immune cells to move through confined environments. They discovered that DOCK8-deficient T and NK cells cannot maintain their shape, causing the cells to elongate, fragment, and die. This type of cell death has never been reported, and the researchers named it cytothripsis, or “cell shattering.” The researchers also identified other proteins required for DOCK8 to maintain the integrity of a cell.
Significance
The study has identified a clear role for DOCK8 in the immune system. When DOCK8 is missing or mutated, T and NK cells cannot move across dense tissues like the skin, preventing immune cells from clearing viral infections. In addition, the researchers identified a new form of cell death called cytothripsis, which also may be involved in other diseases.
Next Steps
NIAID researchers are examining in greater detail how DOCK8 works with other proteins to protect immune cells as they fight off viral infections in the skin. This work promises to enable researchers to develop better treatments for people with DOCK8 deficiency as well as others who experience these infections.
Reference
Zhang Q, Dove CG, Hor JL, Murdock HM, Strauss-Albee DM, Garcia JA, Mandl JN, Grodick RA, Jing H, Chandler-Brown DB, Lenardo TE, Crawford G, Matthews HF, Freeman AF, Cornall RJ, Germain RN, Mueller SN, and Su HC. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. The Journal of Experimental Medicine (2014).