A summary of recent research as reviewed by Eystein Husebye and Mark Anderson in Immunity (“Autoimmune Polyendocrine Syndromes: Clues to Type 1 Diabetes Pathogenesis,” )
Type 1 diabetes is a complex disease defined by an autoimmune reaction to the insulin-producing cells of the pancreas. In cases of type 1 diabetes, the body’s natural defense force, the immune system, incorrectly identifies some of the genes and proteins involved in insulin production as pathogens, or dangerous intruders into the body’s space, and therefore destroys the insulin-associated genes as if they were foreign viruses.
Why and how this autoimmune reaction occurs has proven very difficult to pin down, and the triggers that cause the body’s fight against insulin-producing cells are still unknown. Other unknowns are which proteins the body attacks, and what about those proteins labels them as intruders.
A better understanding of the precise mechanisms of the immune system is a key component to ultimately combating and reversing the autoimmune reaction to insulin-producing cells, but getting a clearer picture proves difficult because of the adaptive nature of the immune system and the heterogeneous nature of type 1 diabetes.
Recently, though, researchers have taken important steps in their understanding of type 1 diabetes by looking at a set of closely related, and even overlapping, diseases– Autoimmune Polyendocrine Syndromes. Autoimmune Polyendocrine Syndromes (APS), also referred to as Autoimmune Polyglandular Syndromes, are a family of diseases that involve several endocrine organs becoming deficient as a result of the failure of the immune system to properly distinguish between self and enemy . Patients with APS are diagnosed based on the co-occurrence of several diseases, such as Addison’s disease, thyroiditis, and Graves’ disease, which taken together indicate that there has been a large scale failure of the immune system.
There are three primary types of APS– APS type 2, APS type 1, and IPEX– each of which carries with it a high risk of developing type 1 diabetes. Because of this correlation, the specific mechanisms at play in each different type of APS can help to clarify some of the pathways of immune system malfunction that cause type 1 diabetes.
APS2: Autoimmune Polyendocrine Syndrome Type 2, What is it?
APS2 is the most common of the three types of APS, and the chances are good that within a community of type 1 diabetics, there will be at least one who exhibits APS2.
APS2 is characterized by the development of at least two of the following: type 1 diabetes, Addison’s disease (insufficient production of adrenal hormones like cortisol and aldosterone, ), and autoimmune thyroid disease (insufficient operation of the thyroid gland, as in Graves’ disease or Hashimoto thyroiditis, ). Often, patients also develop other autoimmunities, such as oophoritis (inflammation of the ovaries, ) or celiac disease (autoimmune destruction of the villi of the small intestine, ). Females are more likely than males to exhibit APS2, and type 1 diabetes occurs in about half of APS2 cases.
The exact genetic causes of APS2 have not been pinned down; APS2 tends to appear in familial clusters, but siblings or relatives do not necessarily develop the same set of autoimmune diseases or symptoms. APS2 is treated with replacement therapy– insulin for diabetes, thyroid hormone for thyroiditis, and cortisol and fludrocortisones for Addison’s disease, rather than immunosuppressive drugs.
What does APS2 tell us about type 1 diabetes?
The co-occurrence of type 1 diabetes, Addison’s disease, and thyroiditis gives researchers new clues about the genetic locus of each of the diseases, as all three have now been genetically mapped. The genes do not constitute a full picture of any of the three of the diseases, but they act as important risk identifiers in diagnosing each of the three diseases, and additionally they serve as starting points for researchers trying to tease out the exact genetic configurations of type 1 diabetes.
Furthermore, studies of APS2 patients found a particular defect in the suppressive abilities of the regulatory T cells of the immune system. Regulatory T cells, or Treg cells, are the oversight committee of the immune system. Treg cells are a specialized type of T cell that ensures that the other cells of the immune system do not attack the body’s own cells or attack any invading pathogens with so much force that the body itself is irreparably damaged . Research into Treg cells in diabetes has often focused on the number or expression patterns of Treg cells, but scientists have not found diabetics to be lacking in either regard. The peculiarities found with APS2, therefore, imply that studies should be done regarding the possibilities of defective Treg cell function in both APS2 and type 1 diabetes.
APS1: Autoimmune Polyendocrine Syndrome Type 1
What is it?
APS1 is a relatively rare syndrome caused by a mutation of a single gene that plays an important role in immune regulation– the autoimmune regulator gene, or AIRE. With an important player in immune regulation broken, patients with APS1 develop autoimmune reactions to many different parts of the body.
APS1 subjects often exhibit some combination of Addison’s disease, hypoparathyroidism (insufficient production of the parathyroid hormone, ), mucocutanous candidiasis (chronic yeast infections in the skin and nails, ), and oophoritis. Type 1 diabetes also occurs in about 20% of APS1 cases.
APS1 can often be treated with a variety of replacement therapies, depending on the exact set of diseases that manifest with each given patient– cortisol for Addison’s disease, vitamin D and calcium for hypoparathyroidism, insulin for diabetes, and so on. Immunosuppressives drugs are not widely used with APS1, but have been attempted with mixed results in a number of cases. Overall, given the complexity of symptoms and rarity of APS1, many patients have an increased risk of complications and death.
What does APS2 tell us about type 1 diabetes?
In APS1 patients, the AIRE gene is truncated or otherwise defective. AIRE is responsible for the transcription of the autoimmune regulator protein in the thymus (the control room of the immune system), and the autoimmune regulator protein is responsible for promoting the transcription of self-antigens like the insulin gene within the thymus. In other words, the autoimmune regulator protein is responsible for showing the immune cells in the thymus what the body’s own proteins look like. If a T cell that has been adapted to kill off one of the body’s own proteins comes back to the thymus, the autoimmune regulator helps the body to recognize that it’s trained against one of its own, and that particular autoreactive T cell is negatively selected, or marked for deletion. When the AIRE gene malfunctions, therefore, there is a failure within the immune system to kill off autoreactive T cells, and the body is more prone to develop autoimmune disorders and to propagate attacks against itself.
This functioning and malfunctioning of AIRE in APS1 patients has shed some light on the manner in which the body prevents autoimmunity under normal circumstances. Notably, when there is insufficient expression of the insulin gene in the cells of the thymus, there is a substantial increase in the risk of developing type 1 diabetes because antibodies against insulin are not properly terminated.
Looking further at the expression of insulin in the thymus will likely increase researchers’ understanding of the mechanisms by which the thymus fails to properly identify and destroy anti-insulin T cells.
IPEX: Immunodeficiency, Polyendocrinopathy, and Enteropathy, X-linked
What is it?
Immunodeficiency, Polyendocrinopathy, and Enteropathy, X-linked (IPEX) is the rarest of the three APS types. As the name suggests, IPEX results from a mutation of a single gene on the X chromosome, meaning that only males exhibit IPEX syndrome. The mutated gene, FOXP3, is important in the regulation of immune cell function, and, as a result of the mutation, patients with IPEX suffer from a number of overlapping organ insufficiencies, such as eczema (inflammation of the skin, ), chronic diarrhea due to enteropathy (a malfunction of the intestinal tract, ), autoimmune thyroid disease, anemia, and diabetes.
IPEX develops prenatally, and many of the manifestations, including diabetes, occur in infancy. Not all patients with IPEX develop the same set of autoimmune malfunctions– only 60% develop diabetes, but in most cases the group of deficiencies is sufficient to result in death before the age of two. Bone marrow transplantation and immunosuppressive therapy have recently shown some promise in treating patients with IPEX, but thus far it has proved extremely difficult to treat.
What does IPEX tell us about type 1 diabetes?
IPEX was found to be the result of a single gene mutation– the mutation of the forkhead-winged helix protein FOXP3. By studying IPEX patients, researchers have found that the FOXP3 protein plays an important role within Treg cells in the immune system. When the FOXP3 gene is mutated, and not sufficiently expressed within Treg cells, the Treg cells do not develop properly, the immune system becomes insufficiently regulated, and the severe autoimmunity of IPEX develops.
The key role of FOXP3 proteins in IPEX patients and similarly deficient mice has opened up a new avenue of study into the development and functioning of Treg cells within the immune system. Previous studies found that type 1 diabetics had the same number of Treg cells as non-diabetics in the peripheral blood stream, but research into the FOXP3 protein and has given scientists new clues as to how the Treg cells might be malfunctioning, rather than just absent. One recent study  has shown evidence that type 1 diabetes may involve malfunctions specifically in the IL-2 protein and pathway. IL-2 is thought to have an effect on the expression of the FOXP3 protein; this, then, begins to illustrate one possible route of how type 1 diabetes occurs. Much research remains to be done in this area, but by looking at evidence from type 1 diabetics in conjunction with evidence from IPEX patients, a clearer picture begins to emerge.
So what’s next?
The study of Autoimmune Polyendocrine Syndromes has helped to clarify some of the varied and overlapping pathways that regulate immunity and autoimmunity, and understanding each of these pathways– Treg expression of FOXP3, thymus regulation by AIRE, and the genetic defects possible during Treg functioning– will give researchers a much better understanding of the immune system as a whole, and specifically the endocrine autoimmunity that defines type 1 diabetes.
Each of the types of APS is rarer than type 1 diabetes alone, so collaboration between researchers in each area will be necessary to assemble enough genetic and functional data about the autoimmune conditions to propose and test treatments that directly address the immunological pathways at play. Hopefully for the research subjects, the work being done towards gaining a better understanding of the mechanisms behind APS and type 1 diabetes will better the understanding of diabetes so that we may eventually develop a cure.
1. Husebye E.S., Anderson M.S. (2010). Autoimmune Polyendocrine Syndromes: Clues to Type 1 Diabetes Pathogenesis. Immunity, 32 (4), pp. 479-487.
2. Anderson, M.S. (2008). Update in endocrine autoimmunity. J. Clin. Endocrinol. Metab. 93, 3663–3670.
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