Category: Diseases and conditions
Anatomy or system affected: All
Also known as: Autoimmune diseases
Definition
Normally, the immune system protects the body from infection and disease and does not trigger an immune response. If a person’s immune system goes awry, that person is said to have an autoimmune disorder (AD). ADs are characterized by the loss of what is known as immunological tolerance (the ability of the body to ignore “self” while reacting to “nonself”) and by the presence of self-reactive T cells, autoantibodies, and inflammation. In other words, a person’s immune system malfunctions by failing to differentiate between self (the body) and nonself (foreign substances, such as invading microorganisms). The immune system produces autoantibodies that mistakenly attack the body’s own healthy tissues and cells, while impaired T cells fail to protect them.
This misdirected immune response puts people at risk for infection. Additionally, many of the medications given to control the autoimmune response are powerful drugs with side effects that tend to lower the body’s ability to fight disease. This makes affected persons highly susceptible to infectious diseases.
There are more than 80 known types of ADs and more than 150 different autoimmune-related diseases, classified as either organ-specific or systemic. In organ-specific disorders, the autoimmune response is localized and directed to antigens of a single organ or tissue; the body part affected depends on what autoimmune disease a person has. Other organ systems may become affected too, because the damage these disorders cause tends to extend beyond the targeted site. In a systemic AD, the autoimmune response is widespread throughout the body, affecting multiple organs. This can be followed by complications and life-threatening events.
Causes
To understand how autoimmunity and ADs evolve requires some knowledge of how the body’s immune system works. The immune system is a complex network of specialized cells and organs that serves as the body’s defense system against attacks by antigens, those invading microorganisms or foreign substances that trigger an immune response. The components of the immune system include white blood cells (called T and B lymphocytes, or T and B cells) and chemicals and proteins in the blood, such as antibodies, complement proteins, and interferon. T cells attack antigens directly and release chemicals, known as cytokines, which control the entire immune response. B cells produce the antibody proteins that attach to a specific antigen and help immune cells destroy the antigen.
There are two types of immunity: innate and acquired (sometimes called adaptive). Innate immunity is the defense system humans have at birth. Examples of innate immunity are the cough reflex, tear and skin oil enzymes, mucus, stomach acid, and skin. The innate immune system consists of circulating white blood cells called leukocytes, two types of which are called granulocytes and monocytes. Once released from the bloodstream, they act as phagocytes to engulf and digest microorganisms, foreign substances, and cellular debris, preventing harmful substances from entering the body.
Acquired immunity develops as a person matures. The development of the components of acquired immunity takes time. As lymphocytes start to mature, they learn to tell the difference between body tissues and foreign substances. Being able to recognize a threat versus a nonthreat is the basis of immunological tolerance. Once the T and B cells are formed, the immune system utilizes the attack mechanism of the T cells and the antibodies produced by the B cells to fight invading antigens. Exposure to these various antigens enables the immune system to build a defense that is specific to each antigen.
The innate and adaptive immune systems are designed to work together in protecting the body from disease. If the innate immune system malfunctions, a person is susceptible to what are called autoinflammatory disorders. When the acquired immune system malfunctions and attacks its own tissues by mistake, the diseases that develop are called autoimmune disorders.
Autoimmunity itself is an etiology, meaning it causes disease. Exactly how or why the immune system stops recognizing the difference between healthy body tissues and antigens is unknown. It has been speculated that antibodies or T cells may attack normal cells if part of their structure resembles part of the structure of the antigen or if B cells have malfunctioned and made the wrong kind of antibody.
Despite these conjectures, ADs generally do not have a single cause; a combination of heredity and environmental factors are strongly implicated. ADs tend to run in families, and there are several genes known to put people at higher risk for developing them. However, what is inherited is a susceptibility to these disorders, not the disorder itself. Thus, ADS are hereditary, not genetic, diseases. Examples of environmental triggers that can cause a disorder to surface are viral or bacterial infections and tissue damage from exposure to sunlight or certain solvents or drugs.
Risk Factors
Approximately fifty million Americans (or about 16 percent of the population of the United States) have one or more ADs. ADs usually develop in the adult years, and women are much more likely than men to be affected. This statistic would place young women at particular risk. It also has raised speculation that hormones may be involved in the autoimmune process.
People with a family history of ADs or those who have inherited certain genes are more susceptible to developing these disorders. It is not uncommon for multiple ADs to occur in one family. ADs can erupt from exposure to certain environmental triggers or from an injury to body tissue. Some ADs are more prevalent in people of certain races or ethnic backgrounds. For example, type 1 diabetes occurs more often in Caucasians, and lupus is more prevalent among African Americans and Hispanics.
ADs themselves put people at higher risk for infection because the immune system does not function normally. Tuberculosis is an especially common threat to persons who are immunocompromised, and persons with ADs are routinely screened for the disease. Most prescribed AD drugs have immunosuppressant properties, which compounds the risk of infection. Immunosuppressants have serious adverse effects that can cause bone marrow suppression, can increase the risk of infection, and can remain in the body long after the treatment has ended.
Symptoms
Rather than characterized as progressive, most ADs are characterized by flare-ups and relapses, in which triggers provoke the sudden and severe onset of symptoms, followed by a period of remission. Multiple sclerosis is a prime example. Each AD has its own set of symptoms, but there are certain symptoms that are universal, such as fatigue, dizziness, and low-grade fever. Other common symptoms include weight gain or loss, swelling, and menstrual irregularities.
Over time, the misdirected immune responses can destroy single types of cells or tissue, can cause an organ to increase in size, or can interfere with its function, resulting in damage to one or more parts of the body. The organs and tissues most frequently affected by ADs include the endocrine glands (thyroid, pancreas, and adrenal glands), components of the blood (usually red blood cells), connective tissue, the skin, muscles, and joints. Persisting symptoms that may signify damage to any of these body parts may indicate an AD and include the following: heat and cold sensitivity; changes in blood pressure or pulse; changes in mood or thinking; hair loss or excessive growth; changes in hair texture; skin rashes, ulcers, bruising, thinning, thickening, and sun sensitivity; blurred or double vision; eye pain, inflammation, or dry eyes; dry mouth, mouth sores, excessive thirst, difficulty swallowing, changes in voice quality, choking sensation, or feeling of a lump in throat; muscle, bone, and joint pain; all-over body pain and tenderness; muscle weakness and joint stiffness; deformed joints; backache; nausea or vomiting; diarrhea; constipation; bloody or foul-smelling stools; abdominal bloating and pain; gas; frequent urination; lack of coordination or balance; numbness or tingling; and tremors.
Screening and Diagnosis
The sheer number and complexity of ADs present challenges for diagnosis and generally require multiple laboratory tests to pinpoint a specific disease. Such a diagnostic battery includes basic tests, such as a complete blood count, basic and comprehensive metabolic panels, and the erythrocyte sedimentation rate, in addition to many more specialized tests specific to the diagnosis of individual ADs. Antibody blood tests include the following:
Antineutrophil cytoplasmic antibodies (ANCA). Performed when autoimmune vasculitis (Wegener’s granulomatosis) is suspected; uses indirect immunofluorescence microscopy.
Rheumatoid factor (RF). Performed when rheumatoid arthritis or Sjögren’s syndrome is suspected; detects and measures whether high levels of RF are present in the blood; test is used to diagnose rheumatoid arthritis in conjunction with X rays showing evidence of swollen joint capsules and loss of cartilage and bone.
Cyclic citrullinated peptide antibody test (CCPA). An assay used to detect the presence of citrulline antibodies in the blood. CCPA is a new test that helps to diagnose early rheumatoid arthritis when the RF test is negative.
Antinuclear antibody test(ANA). Performed to screen for ADs and when systemic lupus erythematosus (SLE)is suspected; uses enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence microscopy.
Smooth muscle antibody. Ordered with ANA to help diagnose autoimmune hepatitis or to rule out liver damage caused by viral infection.
Extractable nuclear antigen antibodies (ENA panel). Ordered when a person has symptoms of an AD and has had a positive ANA test. The four-test ENA is used to help diagnose mixed connective tissue disease, SLE, and Sjögren’s syndrome. A six-test ENA helps in diagnosing scleroderma and polymyositis.
Thyroid peroxidase antibody (TPOAb), triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone receptor antibody (TSH). TPOAb is measured when Hashimoto’s thyroiditis is suspected; T3 is used to diagnose Graves’ disease; T4 helps in evaluating thyroid gland function and helps diagnose hypothyroidism and hyperthyroidism; TSH is used to monitor the effects of Graves’ disease therapy.
Islet cell cytoplasmic autoantibodies (ICCA). Measures a group of islet cell autoantibodies targeted against several kinds of islet cell proteins. ICCA are diabetes autoantibodies and are used to distinguish type 1 diabetes from diabetes from other causes; this test is not routinely used because it is labor-intensive and requires skill to interpret results.
Antimitochondrial antibody. High levels help in diagnosing primary biliary cirrhosis; lower levels may be present in other ADs, such as autoimmune hepatitis or SLE.
Other tests include the following:
C-reactive protein. Detects the presence of inflammation and is performed when infection or certain ADs are suspected.
Complement levels (C3 and C4). Used to help diagnose the cause of recurrent microbial infections and to monitor the activity of acute or chronic autoimmune diseases.
Human leukocyte antigen B27 (HLA-B27). The presence of HLA-B27 is genetic; this test is preformed to support suspected diagnosis of ankylosing spondylitis (AS), reactive arthritis, or juvenile rheumatoid arthritis; nondiagnostic on its own.
It should be noted that most laboratory tests for autoimmune diseases are not entirely sensitive or specific and must be interpreted with care. Different techniques and assays may give different results for the same antibody test. Diagnosing can be difficult because titers of autoantibodies can be low in healthy persons and in those who are symptomatic.
Treatment and Therapy
Similar to diagnosing an AD, treatment of an AD requires multiple drugs and therapies. Also, treatment poses numerous risks. Once a diagnosis is made, the next step is to reduce the immune system response. One of the challenges in doing this is to find a balance of medications that controls the disease and maintains the body’s ability to fight disease and infection. Serious adverse reactions, some of which are life-threatening, can occur with virtually all of the drugs used to treat ADs. Increased risk of infection also can occur. The action of these drugs can damage rapidly dividing tissues, such as bone marrow, requiring that persons be monitored carefully to avoid infection. Skin reactions and rashes are also common in all AD drug therapies and in many of the ADs.
Corticosteroids have been the mainstay in the treatment of ADs, especially the systemic disorders. Corticosteroids are a group of natural and synthetic analogs of the hormones secreted by the pituitary gland and include the glucocorticoids, which are anti-inflammatory agents. Another group, called nonsteroidal anti-inflammatory drugs (NSAIDs), has been used in less severe forms of these disorders and in other ADs to relieve symptoms.
A group of antimetabolite/cytotoxic agents called disease-modifying antirheumatic drugs (DMARDs) have begun to replace the corticosteroids and NSAIDs as primary therapies for many of the systemic ADs. These powerful immunosuppressants are more steroid-sparing, yet they still induce or maintain remission. By the 1990’s, biologic DMARDs became available. Since then, they have revolutionized the treatment of many systemic ADs.
Major classes of AD drugs include the following:
Corticosteroids. Prednisone and methylprednisolone are glucocorticoid analogs that suppress inflammatory mediator production and immune effector cells and promote T lymphocyte apoptosis (death). They are used during acute periods of disease. Complications arise with high doses and prolonged therapy. Major adverse affects are bone marrow suppression, gastrointestinal complications, cataracts, and glaucoma.
DMARDs. Azathioprine (AZA) is a purine analog (6-mercaptopurine) that inhibits synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins and interferes with purine metabolism and mitosis, suppressing delayed hypersensitivity responses and cell-mediated cytotoxicity. Common adverse effects include leukopenia, pancreatitis, hepatitis, bone marrow suppression, potential malignancies, and pulmonary disease.
Cyclophosphamide is a nitrogen-derived alkylating agent/cytotoxic immunosuppressant that cross-links DNA and RNA strands, inhibiting cell functions and protein synthesis. It has a dose-dependent effect on the immune system, and at high doses, it can induce an aberrant anti-inflammatory immune effect on lymphocyte activity, can affect regulatory T cells, and can cause a state of serious immunosuppression that includes major bone-marrow suppression, leukopenia, anemia, and thrombocytopenia. There also can be adverse effects on the gastrointestinal or renal-genitourinary tracts and the cardiovascular system, and there can be increased risk of malignancy and pulmonary toxicity.
Methotrexate(MTX). A dihydrofolate reductase inhibitor and antimetabolite approved for treatment of rheumatoid arthritis and psoriasis. Despite its efficacy, MTX has major toxic effects with prolonged use, including liver damage, cytopenias, and several pulmonary diseases, the most frequently reported of which is hypersensitivity pneumonitis.
Hydroxychloroquine. An antimalarial agent with immunosuppressant properties. The drug has cardiovascular effects that can cause toxic myopathy, cardiomyopathy, and peripheral neuropathy.
Biological DMARDs. Adalimumab is a monoclonal antibody and tumor necrosis factor (TNF) inhibitor that binds TNF-alpha and blocks its interaction with cell surface receptors. Adverse events include renal-genitourinary effects and dyslipidemia.
Infliximab is a chimeric (part human/part synthetic) monoclonal antibody and anti-TNF agent that binds TNF-alpha and blocks its interaction with cell surface receptors. A twofold risk of infection is the most common adverse event, and the risk of developing tuberculosis may be greater than with other anti-TNF agents. Skin and subcutaneous tissue infectionsand apoptosis-inducing activity (cell death) can occur.
Etanercept is a TNF receptor antagonist that inhibits binding of TNF-alpha and TNF-beta to cell surface receptors, preventing its interaction with TNF receptors and rendering it biologically inactive. Its use can cause infections of the respiratory tract, skin, or subcutaneous tissue. All three biological DMARDs are approved for the treatment of rheumatoid arthritis, psoriasis, ankylosing spondylitis, ulcerative colitis, and Crohn’s disease.
Prevention and Outcomes
ADs are lifelong, chronic diseases that cannot be prevented or cured, but they can be managed. Being compliant with therapy, knowing the triggers, living a healthy lifestyle, and reducing stress can help to alleviate symptoms and reduce the damaging effects of these complicated diseases.
Further Reading
Firestein, Gary S. “The Inflammatory Response.” In Cecil Medicine, edited by Lee Goldman and Dennis Ausiello. 23d ed. Philadelphia: Saunders/Elsevier, 2008. Explains the immune response and how the immune system protects the body from foreign substances and from infection by bacteria and viruses. Describes antigens and antibodies and how they function.
Goronzy, J. J., and C. M. Weyand. “The Innate and Adaptive Immune Systems.” In Cecil Medicine, edited by Lee Goldman and Dennis Ausiello. 23d ed. Philadelphia: Saunders/Elsevier, 2008. Explains the two types of immunity, describes the components of both types, and shows how they work together.
Shlomchik, Mark J. “Immunologic Basis of Hematology: Tolerance and Autoimmunity.” In Hematology: Basic Principles and Practice, edited by Ronald Hoffman et al. 5th ed. Philadelphia: Churchill Livingstone/Elsevier, 2009. Explains self-reactive lymphocytes and the origin, control, and breakdown of self-tolerance in autoimmune diseases. Also discusses implications and therapy.