Immunologic endocrine disorders

Abstract

Autoimmunity affects multiple glands in the endocrine system. Animal models and human studies highlight the importance of alleles in HLA-like molecules determining tissue-specific targeting that, with the loss of tolerance, leads to organ-specific autoimmunity. Disorders such as type 1A diabetes, Graves disease, Hashimoto thyroiditis, Addison disease, and many others result from autoimmune-mediated tissue destruction. Each of these disorders can be divided into stages beginning with genetic susceptibility, environmental triggers, active autoimmunity, and finally metabolic derangements with overt symptoms of disease. With an increased understanding of the immunogenetics and immunopathogenesis of endocrine autoimmune disorders, immunotherapies are becoming prevalent, especially in patients with type 1A diabetes. Immunotherapies are being used more in multiple subspecialty fields to halt disease progression. Although therapies for autoimmune disorders stop the progress of an immune response, immunomodulatory therapies for cancer and chronic infections can also provoke an unwanted immune response. As a result, there are now iatrogenic autoimmune disorders arising from the treatment of chronic viral infections and malignancies.

Figure 1

Progression to diabetes of initially discordant monozygotic twin siblings of patients with type 1 diabetes, illustrating progressive conversion to diabetes. Approximately 80% become concordant for expression of anti-islet autoantibodies. From Redondo et al Concordance for Islet Autoimmunity among Monozygotic Twins, New England Journal of Medicine, December 25, 2008.

Figure 2

Summary of subsets of confirmed loci from whole genome screens associated with type 1A diabetes and their odds ratio (from Teaching Slides at www.barbaradaviscenter.org). Modified from Todd et al. Robust Association of four new chromosomes regions from genome-wide analyses of type 1 diabetes, Nature Genetics, July 6, 2007. HLA = human leukocyte antigen; INS = insulin, PTPN22 = protein tyrosine phosphatase non-receptor 22; CD 25 is also known as interleukin-2 receptor alpha chain; ERBB3e = an unidentified gene at 12q; PTPN2 = protein tyrosine phosphatase non-receptor 2; KIAA 0350 = a lectin-like gene; CTLA 4 = cytotoxic T lymphocyte associated antigen 4.

Figure 3

Hypothetical stages and loss of beta cells in an individual progressing to type 1A diabetes (from Teaching Slides at www.barbaradaviscenter.org). Reproduced with permission from Eisenbarth, GS.

Figure 4

Progression to diabetes versus number of autoantibodies (GAD, ICA5112, Insulin). From Verge, CF et al. Prediction of type 1 diabetes in first-degree relatives using a combination of insulin, GAD, ICA512bdc/IA-2 autoantibodies, Diabetes, July 1996.

Figure 5

Stages in the development of Addion's disease from Eisenbarth GS and Gottlieb PA, Autoimmune Polyendocrine Syndromes, New England Journal of Medicine, May 13, 2004. Adrenocortical function is lost over a period of years. In the first stage, genetic predisposition is conferred by a patient's HLA genotype. In the second stage, events that precipitate anti-adrenal autoimmunity occur, but are currently unknown. In the third stage, which involves presymptomatic disease, 21-hydroxylase autoantibodies predict future disease. Finally, in the fourth stage, overt Addison's disease develops. An increased plasma renin level is one of the first metabolic abnormalities to occur and is followed by the sequential development of other metabolic abnormalities (a decreased cortisol level after cosyntropin stimulation, an elevated corticotropin level, and a decreased basal cortisol level). Finally, there are severe symptoms of adrenal insufficiency, such as hypotension.