Dartmouth unDergraDuate Journal of science6

Autoimmune DiseasesA Rising Epidemic

yoo Jung Kim ‘14

meDicine

In the dawn of the twentieth cen-tury, Paul Ehrlich, an illustrious German hematologist, immunolo-

gist, and 1908 Nobel Laureate of Medi-cine, posited a biological theory of hor-ror autotoxicus, the unwillingness of the organism to endanger itself by the formation of toxic autoantibodies. In other words, an organism’s immune system could not develop an autoim-mune response. Ehrlich’s theory would remain as a widely accepted canon in the then fledgling field of immunology, despite ample evidence to the contrary published by his scientific contem-poraries and later biologists. Their findings suggested that autoimmune reactions are responsible for a wide range of disorders, including paroxys-mal cold hemoglobinuria, sympathetic ophthalmia, ocular inflammation due to lens antigens, some hemolytic ane-mias, and certain encephalitides. (1)

Ehrlich’s postulation would linger on for more than five decades, until it was finally debunked by a discovery

made by a young scientist named Noel Rose, now the Director of the Johns Hopkins Autoimmune Disease Re-search Center. Working as a part-time research assistant in the 1950s, Rose injected thyroglobulin, a major protein constituent of the thyroid gland, back into the thyroids of the rabbits from which it was originally derived, and no-ticed that the rabbits soon developed lesions in their thyroid tissue—a sign deduced to be an autoimmune response similar to that of a known condition called Hashimoto’s Thyroiditis (3). Yet, despite Rose’s discovery, over a decade passed before autoimmunity became a commonly accepted precept; the dam-age was done. The time it took the sci-entific community to fully accept the growing reality of autoimmunity has delayed the translation of its findings into medical knowledge, with grave implications in current epidemiologi-cal diagnosis of autoimmune diseases.

The Immune System and Autoimmunity

An immune system is a highly regulated biological mechanism that identifies and reacts to antigens from various foreign substances found in an organism’s body and reacts to these possible pathological threats by pro-ducing certain types of lymphocytes such as white blood cells and antibod-ies that have the ability to destroy or neutralize various germs, poisons and other foreign agents (2). Typically, the immune system is able to distinguish the foreign agents from the organism’s own healthy cells and tissues. Autoim-munity, on the other hand, describes a diseased condition in which an organ-ism fails to recognize its own cells and tissues, thereby enabling the immune system to trigger a response against its own components. (2). A low degree of autoimmunity is an integral part of an effective immune system. For exam-ple, low-level autoimmunity has been

demonstrated to be a possible factor in reducing incidence of cancer through versatile CD8+ T cells, which kill target self-cells by releasing cytokines capable of increasing the susceptibility of tar-get cells to cytotoxicity, or by secreting chemokines that attract other immune cells to the site of autoimmunity (8).

Autoimmune DiseasesAutoimmune diseases occur when

there is interruption of the usual control process, thereby allowing the system to malfunction and attack healthy cells and tissues (9). A common example of autoimmune disease is Type I Diabetes, which affects nearly a million people in the united States. It is a condition in which the pancreas does not produce enough insulin to control sugar blood levels due to the autoimmune destruc-tion of the insulin-producing pancre-atic cells (10). Some other common autoimmune disorders include rheu-matoid arthritis, systemic lupus ery-thematosus (lupus), and vasculitis (9).

Autoimmune disorders typically fall into two categories: systematic and local. Systemic autoimmune dis-eases are associated with autoanti-bodies, which are not tissue specific, and the spectrum of damage may af-fect a wide range of tissues, organs, and cells of the body. Localized auto-immune diseases are associated with organ-specific conditions that affect a single organ or tissue. However, the boundary between systematic and non-systematic disorders becomes blurred during the course of the disease as the effect and scope of localized autoim-mune disorders frequently extend be-yond the initially targeted areas (6).

The onset of autoimmune disease is associated with a trigger, which can be pulled in numerous ways. In one possible example, certain substance in the body that is normally confined to a specific area may be released into another area due to internal trauma; the translocation may stimulate the

β

Image retrieved from http://pharmrev.aspetjournals.org/content/59/4/289/F13.large.jpg (Accessed 8 May 2011).

German hematologist and immunologist Paul Ehrlich, the 1908 Nobel Laureate of Medicine. His theory against the possibility of autoimmune response remained influential for over 50 years.

7spring 2011

immune system to recognize a natural body component as foreign and trig-ger an autoimmune response. In an-other scenario, a normal component of the body may be altered via virus, a drug, sunlight or radiation; the altered substance may then appear foreign to the immune system. Very rarely, a for-eign substance resembling a natural body component may enter the body, thereby inducing the immune system to target both the similar body sub-stance and the foreign substance (11).

Just as the triggers for autoim-mune disorders are wide and varied, so are their effects. The debilitating effects of various autoimmune disorders in-clude the destruction of a specific type of cell or tissue, stimulation into excessive growth, or interference in function. Or-gans and tissues affected by more com-mon autoimmune disorders include components of the endocrine system, such as thyroid, pancreas, and adrenal glands; components of the blood, such as red blood cells; and the connective tissues, skin, muscles, and joints (9).

Treatments for Autoimmune Diseases

Since cures are currently unavail-able for most autoimmune disorders, patients often face a lifetime of debili-tating symptoms, loss of organ and tis-sue function, and high medical costs (5). For many autoimmune disorders, the goals of treatments are to reduce chronic symptoms and lower the level of immune system activity while main-taining the immune system’s ability to fight foreign contaminants. Treatments vary widely and depend on the specific disease and the symptoms. For exam-ple, those afflicted with Type I Diabetes must replenish their insulin levels, usu-ally through injections. In autoimmune diseases like Type I Diabetes, patients may need supplements to provide a hormone or vitamin that the body is lacking. If the autoimmune disorder either directly or indirectly affects the blood or the circulatory system, such as autoimmune hemolytic anemia (AIHA), lupus, and antiphospholipi-dal antibody syndrome (AAS), patients may require blood transfusions. In autoimmune disorders that affect the bones, joints, or muscle, such as mul-

tiple sclerosis (MS) and rheumatoid ar-thritis, patients often require assistance to maintain mobility or medication to suppress pain and reduce inflamma-tion in affected areas (12). In many cases of autoimmune diseases, medi-cine is often prescribed to control or reduce the immune system’s response. Such medicine may include corticos-teroids and immunosuppressant drugs, such as azathioprine, chlorambucil, cy-clophosphamide, cyclosporine, my-cophenolate, and methotrexate (11).

Autoimmune Disorders: Women’s Disease?

Approximately one-third of the risk of developing an autoimmune disease can be attributed to heritable factors, especially gender. Women ac-count for about 75% of the estimated 23.5 million people in America afflicted by autoimmune diseases, and autoim-mune diseases constitute some of the leading causes of death and disability in women below 65 years of age (5, 13). While the relationship between sex and prevalence of autoimmune disor-ders remains unclear, researchers have noted that women have higher levels of antibodies and mount larger inflam-matory responses than men when their immune systems are triggered, possi-bly increasing the risk of autoimmunity (3, 13). Autoimmune diseases tend to fluctuate in accordance with hormonal changes, such as during pregnancy, menstrual cycle, menopause, aging and usage of birth control pills (3). Autoim-mune diseases fluctuate by racial lines as well, since two gene variants were found that are related to an increased risk of lupus among African American women (5). Despite the prevalence of female patients, autoimmunity is rarely discussed as a women’s health issue (7).

Environmental TriggersBesides genetic factors, pathologi-

cal and environmental factors play a role in initiating or exacerbating cer-tain autoimmune disorders. For ex-ample, the product of a human gene that confers susceptibility to Crohn’s disease recognizes components of cer-tain bacteria, and viral infections have long been suspected as triggers of Type

1 Diabetes. Conversely, other research suggests that the numbers of regulato-ry T cells that normally hold potentially destructive immune responses in check are reduced by viral infections (5).

Exposure to various synthetic chemicals and metals in the initiation of autoimmune disease may also in-crease susceptibility to autoimmune disorders. Generally, metals inhibit immune cell proliferation and acti-vation; mercury, gold, and silver, for example, can induce lymphocyte pro-liferation and subsequent autoim-munity. A broad range of synthetic chemicals, including hormone supple-mentation, hormone blockers, pesti-cides, insecticides, fungicides, and food and herbal products, may elicit estro-genic or anti-estrogenic activity (5).

A Rising Epidemic and Challenges in Combating Autoimmune Disorders

In 2005, in a report to the uS Congress, the National Institutes of Health (NIH) released Progress in Au-toimmune Disease Research, which reported that more than eighty known autoimmune diseases, such as multiple sclerosis, Type 1 Diabetes, rheumatoid arthritis, Crohn’s disease and myasthe-nia gravis, affect anywhere from 14.7 to 23.5 million people in America (4, 5).

While a significant portion of Americans suffer from autoimmunity disorders, according to a 2001 survey by the Autoimmune Diseases Associa-tion, over 45 percent of patients with autoimmune diseases have been la-beled chronic complainers in the earli-est stages of their illness. Diagnosis is difficult because a patient’s symptoms are likely to be vague with a tendency to fluctuate in the beginning. Thus, a typi-cal patient usually undergoes a series of tests before a correct diagnosis is made, which can sometimes take years. (7)

ConclusionsConsidering the prevalence of au-

toimmune disorders in America, both the scientific community and the pub-lic must recognize the urgency of the autoimmune epidemic. Today’s prac-ticing physicians must be aware of the

Dartmouth unDergraDuate Journal of science8

rising epidemic of autoimmune disease and be able to diagnose their symptoms properly and accurately before irrevers-ible damage occurs. In addition, since the patients afflicted with autoimmune disorders are predominantly women, these disorders should be discussed as an issue relevant to women’s health.

Due to the vast number of auto-immune diseases, further research is unlikely to pinpoint a single cause for autoimmunity. Rather, research should be focused on defining varied common triggers, including environmental pol-lution and specific pathological agents.

References

1. A. Silverstein, Nat. Immunol. 2, 279-281 (2001). 2. Multiple Sclerosis Glossary (2010). Available at http://www.ucsfhealth.org/education/multiple_sclerosis_glossary/index.html (April 2011).3. D. J. Nakazawa, The Autoimmune Epidemic (Touchstone, New York, ed. 1, 2008).4. Progress in Autoimmune Disease Research (2005). Available athttp://www.niaid.nih.gov/topics/autoimmune/Documents/adccfinal.pdf (April 2011).5. Autoimmune Disease (2011). Available athttp://www.nlm.nih.gov/medlineplus/autoimmunediseases.html (April 2011).6. Autoimmune Disorders (2007). Available at http://www.labtestsonline.org/understanding/conditions/autoimmune.html (April 2011).7. Autoimmune Disease in Women (2011). Available at http://www.aarda.org/women_and_autoimmunity.php (April 2011).8. U. Walter, P. Santamaria, Curr. Opin. Immmunol. 6, 624-631 (2005).9. Questions & Answers (2011). Available at http://www.aarda.org/q_and_a.php (April 2011).10. A. B. Notkins, A. Lernmark, J. Clin. Invest. 9, 1247-1252 (2001).11. P. L. Cohen, Merck Manual of Medical Information (2007). Available at http://www.merckmanuals.com/home/print/sec16/ch186/ch186a.html (April 2011).12. Autoimmune Disorders (2007). Available at http://health.nytimes.com/health/guides/disease/autoimmune-disorders/overview.html#Treatment (April 2011). 13. K. McCoy, Women and Autoimmune Disorders, Every Day Health (2009). Available at http://www.everydayhealth.com/autoimmune-disorders/understanding/women-and-autoimmune-diseases.aspx (April 2011).