White blood cells are principal players in immune system function. Yet efforts to influence their role in illness have been hampered by a lack of understanding of the surface structure of these mediator cells - until now.
Dartmouth Medical School (DMS) researchers have characterized the structure of white blood cells, and their report, in the Sept. 1 issue of Blood, challenges assumptions about how an inherited immune disorder in males affects the white blood cell surface. Their finding could have an impact on treatments for autoimmune diseases such as diabetes, rheumatoid arthritis and lupus, as well as AIDS and cancer metastasis.
The researchers, led by Henry N. Higgs, Assistant Professor of Biochemistry, used scanning electron microscopy to analyze the finger-like projections known as microvilli that coat white blood cells.
"If you asked most medical scientists what a white blood cell looked like they would say a smooth sphere that floats around in the blood, but, in fact, they are not smooth at all - they have these wonderful invaginations and protrusions coming off of them," said Higgs, who is also a member of the immunology and cancer immunotherapy research program at Norris Cotton Cancer Center and a member of the DMS program in immunology.
Higgs and his lab focused on lymphocytes, white blood cells with multiple roles in the immune system, including the production of antibodies and other substances that fight infection and disease. An essential feature of lymphocytes is their ability to migrate from the blood into infected tissues to mount an immune response. The process of squeezing between the cells lining blood vessel walls and into the surrounding tissue is known as extravasation. Microvilli may play a key role in this process. They allow white blood cells hurtling through the bloodstream at speeds analogous to a car traveling at 500 miles per hour to attach to the vessel wall and roll to a stop.
Disruption of the putative receptors on microvilli tips that mediate extravasation could have significant therapeutic benefits. Drugs that eliminate lymphocyte microvilli could lead to a less toxic form of immune suppression for transplant recipients. Since many cancer cells share the same mechanism of extravasation as lymphocytes, ablating microvilli could also prevent metastasis of cancer cells to distant parts of the body. Similarly, by thwarting lymphocyte migration to deposits of cholesterol in coronary arteries, drugs could prevent the atherosclerosis that leads to heart attacks.
Higgs extended this work to compare lymphocytes in patients with Wiskott-Aldrich syndrome, a hereditary immunodeficiency disorder that affects males and manifests itself through low platelets and recurrent bacterial infections. These conditions can eventually cause a fatal hemorrhage or infection in patients. Higgs and his team found no differences in the length or density of microvilli on the lymphocytes, despite expressing little to none of the Wiskott-Aldrich syndrome protein (WASP) whose deficiency leads to the syndrome. This challenges the long-held view that an absence of WASP led to the inability to form microvilli on lymphocytes.
The study represents the first quantitative characterization of lymphocyte microvilli, according to Higgs, and indicates that microvilli are dynamic structures that rapidly alternate between states of assembly and disassembly. This means that if researchers could biochemically dissect mechanisms by which microvilli assemble and segregate, they would be able to develop immunosuppressive or anti-metastatic agents to enhance treatment of cancer and other diseases.
Higgs and other Dartmouth medical researchers are exploring this promising tool through funding from a $12 million Centers of Biomedical Research and Excellence (COBRE) grant the National Institutes of Health awarded to DMS in 2003. The researchers hope to identify the proteins that assemble lymphocyte microvilli to provide a specific target for drug therapy.
"If there is one key protein involved in this process then there is the potential to basically figure out what chemical you could jam into a site on this protein - sort of like wedging a door open so it doesn't shut," Higgs said. "And we want to make sure that wedge doesn't prop any other doors open that should stay closed."
Other institutions that took part in the research are the University of Toronto and Ludwig-Maximilians University in Munich, Germany. The work was supported by the American Cancer Society, the National Institutes of Health, the Pew Biomedical Scholars and the Canadian Institutes of Health Research.
By THADDEUS SHATTUCK DMS '04
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Last Updated: 12/17/08