Sjogren’s Sydrome is an autoimmune disease, a disease in which a host own immune system attacks the host, where the victim of attack is a host’s salivary and lachrymal glands. Rapid deterioration of these the salivary glands and lachrymal glands by lympocytes – white bloods cells from the lymph nodes, induces poor tear production and saliva production, respectively. Continuation of these symptoms often leads to xerostomia, dry mouth, and keratoconjunctivitis sicca (dry eye). As you can imagine, these are very uncomfortable symptoms for individuals to live with chronically. Effects of these symptoms include trouble swallowing, hoarseness, and loss of sense of taste. We’ve seen mice that have contracted Sjogren’s syndrome scratch out the hair of the surrounding area of the eyes in attempts to relieve the symptoms of chronic dry eye. In humans, the symptoms are the same, however, for unknown reason, there is a strong female bias, with around 90% of those contracting the disease being women. There is no cure for the disease, but continual study of the disease illuminates further knowledge of the disease’s origins and potential area for greater treatment.
It has been shown that knocking out the gene for ID3 for mice causes mice to contract Sjogren’s Syndrome. ID3 is an inhibitory protein which dimerizes (bonds) competitively to E-Proteins. These E-Proteins are absolutely crucial to the proliferation and maturation of one of the 3 lymphocytes in the body, T-Cells, more specifically CD4+ T-Cells, also known as Helper T-cells. When ID3 is not present for competitive binding to E-proteins, the cycle for proliferation and maturation of T-cells.
One of the most important consequences of ID3 absence is selection. Selection is the process by which a T-cells receptors bind to antigens, any signal protein that may provoke an immune response. If the T-cell responds to a foreign antigen, it is positively selected and continues its life cycle. It a T-cell responds to its host’s own antigens, it is negatively selected and dies. It is by this mechanism that the body kills autoimmune cells that will react and respond to the body rather than foreign threat. Without Id3 this selection is disturbed, and the consequences are apparent.
Furthermore, the the T-cells of ID3KO mice, produce larger numbers of the ligand IL-13 which sends a signal to produce more white blood cells called mast cells. The significant increase in the number of mast cells is involved in gland deterioration.
At this point, Ian, my secondary mentor, and I, have been attempting to see if particular T-Cell Receptors are more likely to produce IL-13 or not. If we noticed a trend, we may be able to single out the major culprit for Sjogrens. To single the main factor, we have looked at millions of cells from mice thymi – thymus being the location T-cells mature and reside – using Antibodies dies and a Flow Cytometer to look at the different colored stain cells.
This attempt has yielded results, but has also shown that through staining and dying alone, there are just too few cells to notice.
Due to this drawback, we have determined that using a transgene to completely alter all of a T-cell receptor would be the best next step. If all the receptors act alike, we can determine exactly which T-cell receptor causes the increase in mast cell stimulation that ultimately leads to the destruction of the glands.
This will be the focus if Ian and I and relates to Yuan’s goal of identifying functional portions of the T-cell receptor and using genetic techniques in his lab.
