Genetic Susceptibility To Autoimmune Endocrine Disorders

Posted on February 14, 2012



Infocus, Vol. 12 No. 3, September 2004

By Yaron Tomer, MD, FACP, FACE, Associate Professor of Medicine, Division of Endocrinology, Mount Sinai School of Medicine, New York, NY, USA. Dr. Tomer is a member of AARDA Scientific Advisory Board.

Autoimmune endocrine diseases are disorders in which dysregulation of the immune system results in immune attack on endocrine glands. As a result, these endocrine glands usually are destroyed, resulting in deficiency in the hormones secreted by them. While autoimmune disorders can affect many endocrine glands, by far the most common autoimmune endocrine disorders are type 1 (juvenile) diabetes mellitus and autoimmune thyroid disease. Both juvenile diabetes and autoimmune thyroiditis are caused by infiltration of the gland by lymphocytes (a subset of white blood cells) resulting in dysfunction of the gland.

In the case of juvenile diabetes, the targets of the immune attack are structures in the pancreas called the pancreatic islets. The pancreatic islets contain specialized cells, which secrete insulin. As the disease progresses, the pancreatic islets are destroyed by lymphocytes infiltrating them, causing the production of insulin to stop. This results in elevated blood glucose that over time causes the well-known complications of diabetes (damage to the retina, kidneys, nervous system, arteries and more).

Autoimmune thyroid diseases are caused by infiltration of the thyroid by lymphocytes. Interestingly, the lymphocytic infiltration of the thyroid can result either in destruction of the thyroid, resulting in an underactive thyroid (a disease called Hashimoto?s disease), or in stimulation of the thyroid, resulting in an overactive thyroid (a disease called Graves? disease).

What causes the development of autoimmune endocrine disorders such as juvenile diabetes and autoimmune thyroiditis? The causes of these diseases are not fully understood, and it is believed that many factors contribute to their development. One central factor is genetic susceptibility. What do we mean by ?genetic susceptibility? to a disease? Genetic susceptibility to a disease means that an individual is born with a genetic makeup that makes him or her more likely to develop the disease. In classical genetic diseases (eg, cystic fibrosis), the individuals born with the mutation will develop the disease. In complex diseases, however, inheriting the susceptibility genes is not enough to develop the disease. Additional factors (eg, diet, infection, stress, etc.) are necessary for disease development.

In recent years, significant progress has been made in our understanding of the genetic susceptibility to juvenile diabetes and autoimmune thyroiditis. Indeed, some of the susceptibility genes for these diseases have been identified. The most important genes contributing to the development of juvenile diabetes are called the Human Leukocyte Antigen (HLA) genes. These genes are central to the immune response, and certain variations in these genes predispose to juvenile diabetes. Interestingly, the HLA genes also predispose to autoimmune thyroiditis. Another important immune regulatory gene contributing to both juvenile diabetes and autoimmune thyroiditis is the CTLA-4 gene. In addition, there are other genes, which are specific for each disease.

Is there a shared genetic susceptibility to juvenile diabetes and autoimmune thyroiditis? Indeed, there is a well-recognized association between juvenile diabetes and autoimmune thyroiditis. Epidemiological studies have shown that up to 30 percent of patients with juvenile diabetes have antibodies against the thyroid, and 50 percent of these patients will progress to develop clinical disease (usually Hashimoto?s disease). These observations are the basis for the current recommendation that all juvenile diabetic patients be routinely screened for thyroid autoimmunity.

The association of juvenile diabetes and autoimmune thyroiditis is also seen within families. In one study of families in which several family members had juvenile diabetes, it was found that up to 75 percent of the diabetic women had Hashimoto?s disease. These findings imply that the association between juvenile diabetes and autoimmune thyroiditis may be even stronger in cases of familial diabetes. >P>Since juvenile diabetes and autoimmune thyroiditis are strongly associated (ie, they tend to occur together within families and in the same individual), it is likely that shared genes predispose to both diseases and perhaps to other autoimmune diseases. Indeed, autoimmune diseases (eg, lupus, rheumatoid arthritis, autoimmune thyroiditis, and more) tend to aggregate in families; and it is likely that common autoimmunity genes predisposing to several autoimmune diseases exist.

In conclusion, genetic susceptibility is critical for the development of juvenile diabetes and autoimmune thyroiditis, as well as a number of other autoimmune diseases. Multiple genes, as well as environmental factors, influence these diseases most likely. Further research into the genetics of autoimmunity will enhance our understanding of the development of these diseases. Hopefully, this will help us design new treatment and prevention modalities for autoimmunity.


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