The researchers also found that the change causes these white blood cells, known as T-cells, to multiply out of control and to attack the body's own tissues.
Specifically, the study, by Connie Sommers, and her colleagues, found that the protein dubbed ‘LAT’ plays a critical role in coordinating a normal immune response.
Duane Alexander, Director of the NICHD says that the discovery not only provides an important insight into how the immune system functions, but may also lead to a better understanding of certain cancers of the immune system. This may also lead to insights into a variety of new therapies for autoimmune diseases.
The immune system is made up of cells and tissues that play a crucial role in recognising and attacking foreign substances in the body. T-cells are responsible for distinguishing between molecules foreign to the body and ‘self’ molecules, i.e. those produced by the body. When T-cells recognise a foreign substance such as a virus or bacterium, they become activated and begin the complex immune response that rids the body of the foreign invader. Before T-cells can carry out this important task, the foreign molecule must bind to a molecule known as a receptor on the T-cell's surface. This binding process is analogous to the way a key fits into a lock. In turn, the binding triggers a number of chemical reactions – called signalling pathways – within the T-cell, enabling it to react to the disease-causing substance.
Two key signalling pathways that lead to activation in all cells are the calcium pathway and the Ras pathway. The LAT (linker for activation of T-cells) protein was first identified at the NICHD in the laboratory of Lawrence E. Samelson, one of the study's co-authors. In T-cells, this protein functions by chemically linking the receptor to both the calcium and Ras downstream signalling pathways.
In the current study, the researchers mutated a specific amino acid in the LAT protein in mice. At two weeks of age, the mice with the mutated LAT protein exhibited a partial block in T-cell production. However, by four weeks of age, abnormal T-cells had rapidly expanded and the mice showed signs of autoimmune disease.
The researchers discovered that the LAT protein produced by the mutated mice, while retaining the ability to connect T-cell activating receptors to the Ras signalling pathway, could not connect the receptors to the calcium signalling pathway.
The results of the study indicate that T-cells do not develop normally if they do not receive a calcium signal, explained Paul Love, one of the study's authors and head of the Section on Cellular and Developmental Biology at NICHD's Laboratory of Mammalian Genes and Development. The results also show that coordinating the activation of the Ras and calcium signalling pathways is essential for a normal immune response.
The study raises the possibility that some autoimmune disorders in humans may result from mutations that cause unbalanced or uncoordinated signalling in T cells.
Next, researchers plan to study the effects of mutating other amino acids in the LAT protein. They also plan to determine if some human autoimmune diseases or disorders in which T-cells duplicate faster than normal, such as certain types of lymphoma and leukaemia, are caused by mutations that result in an unbalanced cell signalling response.
Bio.com
13 June 2002
