Probing the surface of white blood cells to enhance immune system medicine

White blood cells are the principle mediators of immune system function, yet efforts to influence their role in illness have been hampered due to a lack of understanding of the surface structure of these cells – until now. Dartmouth Medical School researchers characterize the structure of white blood cells and challenge assumptions about how a certain immunodeficiency disorder affects the white blood cell surface in the September 1 issue of Blood, the journal of the American Society of Hematology. Their findings could have a large 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 at Dartmouth Medical School used scanning electron microscopy to analyze the finger-like projections coating white blood cells known as microvilli. “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,” explained Higgs, who is also a member of the Immunology and Cancer Immunotherapy Research Program at Norris Cotton Cancer Center and a member of the program in immunology.

Higgs and his lab focused much of their work on lymphocytes a type of white blood cell that have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and disease. An essential feature of lymphocytes’ ability to mount an immune response is their ability to migrate from the blood into infected tissues. The process of squeezing between the cells lining blood vessel walls and into the surrounding tissue is known as ’extravasation.’ Research indicates that 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 this process 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 immune 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 these patients. Higgs and his team found no differences in the length or density of microvilli on the lymphocytes, despite expressing little to no Wiskott-Aldrich syndrome protein (WASP)Ñthe protein 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 and, in addition to characterizing their length and density, the research indicates that microvilli are dynamic structures that rapidly alternate between states of assembly and disassembly. This means that if researchers were able to biochemically dissect mechanisms by which microvilli assemble and segregate, they would be able to use this knowledge to develop immunosuppressive or anti-metastatic agents, enhancing the treatment of cancer and other diseases. Higgs and other Dartmouth medical researchers are working to investigate this promising tool through funding from a $12 million Centers of Biomedical Research and Excellence (COBRE) grant awarded by the NIH in 2003.

The researchers will continue their work in hopes of determining the proteins that assemble lymphocyte microvilli. Identification of these proteins would 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,” explained Higgs. “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 this research are the University of Toronto and Ludwig-Maximilians University in Munich, Germany. The research was supported by the American Cancer Society, the National Institutes of Health, the Pew Biomedical Scholars and the Canadian Institutes of Health Research.