Research

Taking Aim at Defective Immune Systems

A T cell carries the protein WASp (green) both in the cytoplasm and the nucleus (blue) outside the nucleolus (red). The discovery of WASp in the nucleus of blood cells is a significant new step in the study of autoimmune diseases.

The study of the rare disease Wiskott-Aldrich syndrome has provided researchers at Children’s Hospital of Pittsburgh of UPMC with extraordinary new insight into blood cells’ production of specialized proteins that underlie the body’s ability to prevent conditions ranging from asthma to cancer.

Armed with this information, scientists have a new target in the pursuit of cures for a range of diseases rooted in immune system deficiencies according to the study’s director, Dr. Yatin Vyas, MD, a hematologist / oncologist and scientist from Children’s Hospital.

Wiskott-Aldrich syndrome is a genetic disease linked to the X chromosome that occurs in approximately 1 in 200,000 births. Children with the syndrome, nearly all male, have a defective immune system resulting in severe, life-threatening infections, autoimmune diseases and cancers.

Previous research has shown that syndrome sufferers experience a loss of function of a particular protein, named the Wiskott-Aldrich syndrome protein (WASp), which was known to be present in the cytoplasm of white blood cells and platelets. The new findings revealed that WASp also exists in blood cell nuclei, where it performs a significant function in maintaining gene activation.

Impaired Immunity

Many boys who suffer from Wiskott-Aldrich syndrome develop conditions such as hemolytic anemia, low platelets, neutropenia, eczema, arthritis, vasculitis, inflammatory bowel disease and kidney disease. They also are prone to blood cancers such as leukemia and lymphoma.

Through the discovery that WASp is present in the cell nucleus, the research team determined that nuclear WASp plays a role in the activation of genes that control development of T-helper type 1 (Th1) cells, a subset of lymphocytes crucial to a healthy immune system.

“Without enough WASp present in the nucleus, Th1 immunity is impaired, and this type of immunity is required to combat most infections and many cancers,” said Dr. Vyas, who is also an assistant professor of pediatrics at the University of Pittsburgh School of Medicine.

If Th1 immune cells are deficient, another group of immune cells known as T-helper type 2 (Th2) dominates the immune system. Overexpression of Th2 cells leads to autoimmune conditions such as asthma and colitis.

“This finding significantly expands our understanding of the importance of WASp in the biology of the immune cell and its potential as a therapeutic target in certain immune disorders.”

An Exquisite Model

With Wiskott-Aldrich syndrome, “nature has given us an exquisite model to understand the immune system,” Dr. Vyas said, adding that WASp appears to both participate in the T cell’s gene activation and play an important role in the balance of the two arms of the immune responses, Th1 and Th2.

Dr. Vyas noted that one of the challenges in the study was working with miniscule blood samples that are taken from children, as opposed to larger samples generally obtained from adults. In the laboratory, researchers used elaborate techniques capable of isolating DNA from as few as 1,000 blood cells per sample. “That’s a major innovation here,” Dr. Vyas said.

“Our discovery could have far-reaching implications to the development of diseases caused by the imbalance of Th1 and Th2 responses. Now that we have identified that WASp is present in the nucleus, we are interested in exploring the details of how this protein might function in gene activation and the overall integrity of chromosomes in the immune cells.”

The findings of Dr. Vyas’ study, which was funded by the National Institutes of Health, were published in the journal Science Translational Medicine.

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Last Update
July 29, 2010

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