25.1: Organ-Specific Autoimmune Disorders

Learning Objectives

• Explain why autoimmune disorders develop
• Name the organ-specific autoimmune disorders and the organs that they affect
• Describe how the mechanisms of Graves disease and Hashimoto thyroiditis differ
• Name the cells that are destroyed in type 1 diabetes melitus and describe the result

In 1970, artist Walt Kelly developed a poster promoting Earth Day, featuring a character from Pogo, his daily newspaper comic strip. In the poster, Pogo looks out across a litter-strewn forest and says wryly, “We have met the enemy and he is us.” Pogo was not talking about the human immune system, but he very well could have been. Although the immune system protects the body by attacking invading “enemies” (pathogens), in some cases, the immune system can mistakenly identify the body’s own cells as the enemy, resulting in autoimmune disease.

Autoimmune diseases are those in which the body is attacked by its own specific adaptive immune response. In normal, healthy states, the immune system induces tolerance, which is a lack of an anti-self immune response. However, with autoimmunity, there is a loss of immune tolerance, and the mechanisms responsible for autoimmune diseases include type II, III, and IV hypersensitivity reactions. Autoimmune diseases can have a variety of mixed symptoms that flare up and disappear, making diagnosis difficult.

The causes of autoimmune disease are a combination of the individual's genetic makeup and the effect of environmental influences, such as sunlight, infections, medications, and environmental chemicals. However, the vagueness of this list reflects our poor understanding of the etiology of these diseases. Except in a very few specific diseases, the initiation event(s) of most autoimmune states has not been fully characterized.

There are several possible causes for the origin of autoimmune diseases and autoimmunity is likely due to several factors. Evidence now suggests that regulatory T and B cells play an essential role in the maintenance of tolerance and prevention of autoimmune responses. The regulatory T cells are especially important for inhibiting autoreactive T cells that are not eliminated during thymic selection and escape the thymus (see T Lymphocytes and Cellular Immunity). In addition, antigen mimicry between pathogen antigens and our own self antigens can lead to cross-reactivity and autoimmunity. Hidden self-antigens may become exposed because of trauma, drug interactions, or disease states, and trigger an autoimmune response. All of these factors could contribute to autoimmunity. Ultimately, damage to tissues and organs in the autoimmune disease state comes as a result of inflammatory responses that are inappropriate; therefore, treatment often includes immunosuppressive drugs and corticosteroids.

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Organ-Specific Autoimmune Diseases

Some autoimmune diseases are considered organ specific, meaning that the immune system targets specific organs or tissues. Examples of organ-specific autoimmune diseases include celiac disease, Graves disease, Hashimoto thyroiditis, type I diabetes mellitus, and Addison disease.

Celiac Disease

Celiac disease is largely a disease of the small intestine, although other organs may be affected. People in their 30s and 40s, and children are most commonly affected, but celiac disease can begin at any age. It results from a reaction to proteins, commonly called gluten, found mainly in wheat, barley, rye, and some other grains. The disease has several genetic causes (predispositions) and poorly understood environmental influences. On exposure to gluten, the body produces various autoantibodies and an inflammatory response. The inflammatory response in the small intestine leads to a reduction in the depth of the microvilli of the mucosa, which hinders absorption and can lead to weight loss and anemia. The disease is also characterized by diarrhea and abdominal pain, symptoms that are often misdiagnosed as irritable bowel syndrome.

Diagnosis of celiac disease is accomplished from serological tests for the presence of primarily IgA antibodies to components of gluten, the transglutinaminase enzyme, and autoantibodies to endomysium, a connective tissue surrounding muscle fibers. Serological tests are typically followed up with endoscopy and biopsy of the duodenal mucosa. Serological screening surveys have found about 1% of individuals in the United Kingdom are positive even though they do not all display symptoms.¹ This early recognition allows for more careful monitoring and prevention of severe disease.

Celiac disease is treated with complete removal of gluten-containing foods from the diet, which results in improved symptoms and reduced risk of complications. Other theoretical approaches include breeding grains that do not contain the immunologically reactive components or developing dietary supplements that contain enzymes that break down the protein components that cause the immune response.²

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Disorders of the Thyroid

Graves disease is the most common cause of hyperthyroidism in the United States. Symptoms of Graves disease result from the production of thyroid-stimulating immunoglobulin (TSI) also called TSH-receptor antibody. TSI targets and binds to the receptor for thyroid stimulating hormone (TSH), which is naturally produced by the pituitary gland. TSI may cause conflicting symptoms because it may stimulate the thyroid to make too much thyroid hormone or block thyroid hormone production entirely, making diagnosis more difficult. Signs and symptoms of Graves disease include heat intolerance, rapid and irregular heartbeat, weight loss, goiter (a swollen thyroid gland, protruding under the skin of the throat [Figure \(\PageIndex{1}\)]) and exophthalmia (bulging eyes) often referred to as Graves ophthalmopathy (Figure \(\PageIndex{2}\)).

Figure \(\PageIndex{1}\): Goiter, a hypertrophy of the thyroid, is a symptom of Graves disease and Hashimoto thyroiditis.

The most common cause of hypothyroidism in the United States is Hashimoto thyroiditis, also called chronic lymphocytic thyroiditis. Patients with Hashimoto thyroiditis often develop a spectrum of different diseases because they are more likely to develop additional autoimmune diseases such as Addison disease (discussed later in this section), type 1 diabetes, rheumatoid arthritis, and celiac disease. Hashimoto thyroiditis is a T_H1 cell-mediated disease that occurs when the thyroid gland is attacked by cytotoxic lymphocytes, macrophages, and autoantibodies. This autoimmune response leads to numerous symptoms that include goiter (Figure \(\PageIndex{1}\)), cold intolerance, muscle weakness, painful and stiff joints, depression, and memory loss.

Figure \(\PageIndex{2}\): Exophthalmia, or Graves ophthalmopathy, is a sign of Graves disease. (credit: modification of work by Jonathan Trobe, University of Michigan Kellogg Eye Center)

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Type 1 Diabetes

Juvenile diabetes, or type 1 diabetes mellitus, is usually diagnosed in children and young adults. It is a T-cell-dependent autoimmune disease characterized by the selective destruction of the β cells of the islets of Langerhans in the pancreas by CD4 T_H1-mediated CD8 T cells, anti-β-cell antibodies, and macrophage activity. There is also evidence that viral infections can have either a potentiating or inhibitory role in the development of type 1 diabetes (T1D) mellitus. The destruction of the β cells causes a lack of insulin production by the pancreas. In T1D, β-cell destruction may take place over several years, but symptoms of hyperglycemia, extreme increase in thirst and urination, weight loss, and extreme fatigue usually have a sudden onset, and diagnosis usually does not occur until most β cells have already been destroyed.

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Autoimmune Addison Disease

Destruction of the adrenal glands (the glands lying above the kidneys that produce glucocorticoids, mineralocorticoids, and sex steroids) is the cause of Addison disease, also called primary adrenal insufficiency (PAI). Today, up to 80% of Addison disease cases are diagnosed as autoimmune Addison disease (AAD), which is caused by an autoimmune response to adrenal tissues disrupting adrenal function. Disruption of adrenal function causes impaired metabolic processes that require normal steroid hormone levels, causing signs and symptoms throughout the body. There is evidence that both humoral and CD4 T_H1-driven CD8 T-cell–mediated immune mechanisms are directed at the adrenal cortex in AAD. There is also evidence that the autoimmune response is associated with autoimmune destruction of other endocrine glands as well, such as the pancreas and thyroid, conditions collectively referred to as autoimmune polyendocrine syndromes (APS). In up to 80% of patients with AAD, antibodies are produced to three enzymes involved in steroid synthesis: 21-hydroxylase (21-OH), 17α-hydroxylase, and cholesterol side-chain–cleaving enzyme.³The most common autoantibody found in AAD is to 21-OH, and antibodies to any of the key enzymes for steroid production are diagnostic for AAD. The adrenal cortex cells are targeted, destroyed, and replaced with fibrous tissue by immune-mediated inflammation. In some patients, at least 90% of the adrenal cortex is destroyed before symptoms become diagnostic.

Symptoms of AAD include weakness, nausea, decreased appetite, weight loss, hyperpigmentation (Figure \(\PageIndex{3}\)), hyperkalemia (elevated blood potassium levels), hyponatremia (decreased blood sodium levels), hypoglycemia(decreased levels of blood sugar), hypotension (decreased blood pressure), anemia, lymphocytosis (decreased levels of white blood cells), and fatigue. Under extreme stress, such as surgery, accidental trauma, or infection, patients with AAD may experience an adrenal crisis that causes the patient to vomit, experience abdominal pain, back or leg cramps, and even severe hypotension leading to shock.

Figure \(\PageIndex{3}\): Hyperpigmentation is a sign of Addison disease. (credit: modification of work by Petros Perros)

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Interactive Element

Case Study Preview: “Sun-Kissed and Misdiagnosed: Kerry’s Autoimmune Awakening”

Kerry, a 40-year-old pilot, notices a strange rash that flares up after sun exposure - not quite a sunburn, but red, raised, and persistent. Initially puzzled, her doctor orders lab tests that uncover protein and hemoglobin in her urine, along with signs of hemolytic anemia. Before she can follow up with a specialist, Kerry has a seizure, leading to urgent testing for autoantibodies. The diagnosis: systemic lupus erythematosus (SLE), an autoimmune disease that affects multiple organs through type III hypersensitivity reactions.

This case explores the challenges of diagnosing autoimmune disorders like SLE, the role of antinuclear and anti-Sm antibodies, and why symptoms like photosensitivity, butterfly rash, and seizures are classic red flags. You'll also learn how treatments like corticosteroids and hydroxychloroquine help control flare-ups and reduce inflammation - even though there’s no cure.

When the immune system turns on the self, how do you read the signs? And why doesn’t sunscreen help when it’s lupus, not sunburn?

Chapter 19 Case Study - Sun-Kissed and Misdiagnosed: Kerry’s Autoimmune Awakening

 

Key Concepts and Summary

• Autoimmune diseases result from a breakdown in immunological tolerance. The actual induction event(s) for autoimmune states are largely unknown.
• Some autoimmune diseases attack specific organs, whereas others are more systemic.
• Organ-specific autoimmune diseases include celiac disease, Graves disease, Hashimoto thyroiditis, type I diabetes mellitus, and Addison disease.

Footnotes

1. 1 D.A. Van Heel, J. West. “Recent Advances in Coeliac Disease.” Gut 55 no. 7 (2006):1037—1046.
2. 2 ibid.
3. 3 P. Martorell et al. “Autoimmunity in Addison’s Disease.” Netherlands Journal of Medicine 60 no. 7 (2002):269—275.