Type I Hypersensitivity (Immediate Hypersensitivity, Allergic Disorders, Anaphylaxis)

Type I hypersensitivity reactions include hay fever, allergic rhinitis, urticaria, extrinsic asthma, and anaphylactic shock. In this type of immediate hypersensitivity response, IgE, instead of IgG, is produced in response to a pathogen (allergen).

The term atopy is often used to describe IgE-mediated diseases. People with atopy have a hereditary predisposition to produce IgE antibodies against common environmental allergens and have one or more atopic diseases.

Allergens are a special class of antigens that cause an allergic response. These normally harmless substances are inhaled (e.g., mold spores, animal dander, dust mites, grasses, weeds), eaten (e.g., nuts, fruits, shellfish, eggs), or injected (e.g., venom from fire ants, wasps, bees, hornets), or they come in contact with the skin or mucous membranes (e.g., plants, cosmetics, metals, drugs, dyes, latex).

IgE resides on mast cells in connective tissue, especially the upper respiratory tract, GI tract, and dermis. When IgE meets the pathogen again, an immediate response occurs with histamine release, along with other inflammatory mediators (e.g., chemotactic factors, prostaglandins, and leukotrienes) that enhance and prolong the response initiated by histamine (Fig. 7-20).

If this response becomes systemic, widespread release of histamine (rather than just local tissue response) results in systemic vasodilation, bronchospasm, increased mucus secretion, and edema, referred to as anaphylaxis.

Classic associated signs and symptoms are wheezing, hypotension, swelling, urticaria, and rhinorrhea (clear, runny nose often accompanied by sneezing) (Fig. 7-21). Anaphylaxis is a life-threatening emergency and requires immediate intervention with injected epinephrine to restore blood pressure, strengthen the heartbeat, and open the airways. Bee stings remain the number one cause of anaphylaxis; other triggers include penicillin, foods, animal dander, children, semen, and latex.

A marked increase in the prevalence of atopic disease has occurred in the United States during the last 2 decades, indicating the importance of environmental influences. The mechanisms for this action are outlined in greater detail elsewhere.¹³⁰

Type II Hypersensitivity (Cytotoxic Reactions to Self-Antigens)

When the body’s own tissue is recognized as foreign or nonself, activation of complement occurs with subsequent agglutination (clumping together) and phagocytosis of the identified pathogens. This means the cellular membrane of normal tissues (e.g., red blood cells [RBCs], leukocytes, and platelets) is disrupted and ultimately destroyed. Self-antigen disorders include blood transfusion reactions, hemolytic disease of the newborn, autoimmune hemolytic anemia, and myasthenia gravis (Fig. 7-22).

A second type of hypersensitivity response occurs when there is a cross-reaction between exogenous pathogens and endogenous body tissues, such as in rheumatic fever. For example, group A hemolytic streptococci (the exogenous pathogen) are attacked by the immune system, but the body also misinterprets the mitral valve (endogenous body tissue) as a foreign microorganism (i.e., as streptococcus) and attacks normal, healthy tissue in the same way it attempts to destroy the true pathogenic microorganisms. Another example of this type of cross-reaction is an exogenous virus causing the immune system to attack the peripheral nervous system as nonself, such as in acute Guillain-Barré syndrome.

Type III Hypersensitivity (Immune Complex Disease)

Normally, excessive circulating antigen-antibody complexes called immune complexes are effectively cleared by the reticuloendothelial system. When circulating immune complexes (antigen-antibody complexes) successfully deposit in tissues around small blood vessels, they activate the complement cascade and cause acute inflammation and local tissue injury (Fig. 7-23).

The subsequent vasculitis most commonly affects the skin, causing urticaria (wheals); joints, causing synovitis, such as in rheumatoid arthritis; kidneys, causing nephritis; pleura, causing pleuritis; and pericardium, causing pericarditis.

Systemic lupus erythematosus (SLE) is the classic picture of vasculitis, occurring in various organ systems. The antigen is the individual’s own nucleus of cells; antinuclear antibodies (ANAs) are made, which in turn form a complex with the antigen and are deposited in the skin, joints, and kidneys, causing acute immune injury. Other examples of this hypersensitivity reaction occur in association with infections such as HBV and bacterial endocarditis, malignancies, or after drug or serum therapy.

Type IV Hypersensitivity (Cell-Mediated Immunity)

Type IV is a delayed hypersensitivity response such as the reaction that occurs in contact dermatitis after sensitization to an allergen (commonly a cosmetic, adhesive, topical medication, or plant toxin such as poison ivy), latex sensitivity, or the response to a TB skin test present 48 to 72 hours after the test.

In this type of reaction, the antigen is processed by macrophages and presented to T cells. The sensitized T cells then release lymphokines, which recruit other lymphocytes, monocytes, macrophages, and PMNs (Fig. 7-24). Graft-versus-host disease and transplant rejection are also examples of type IV reactions (see Chapter 21).

Definition and Overview

Autoimmune diseases fall into a category of conditions in which the cause involves immune mechanisms directed against self-antigens. More specifically, the body fails to distinguish self from nonself, causing the immune system to direct immune responses against normal (self) tissue and become self-destructive.

More than 56 autoimmune diseases have been identified, affecting everything from skin and joints to vital organs. Autoimmune diseases can be viewed as a spectrum of disorders, some of which are systemic and others of which involve a single organ. A portion of the known diseases most likely to be seen in a rehabilitation setting is listed in Table 7-5.

At one end of the continuum are organ-specific diseases, in which localized tissue damage occurs, resulting from the presence of specific autoantibodies. An example is Hashimoto’s disease of the thyroid, characterized by a specific lesion in the thyroid gland with production of antibodies with absolute specificity for certain thyroid constituents.

In the middle of the continuum are disorders in which the lesion tends to be localized in one organ, but the antibodies are not organ specific. An example is primary biliary cirrhosis, in which inflammatory cell infiltration of the small bile ductule occurs, but the serum antibodies are not specific to liver cells.

At the other end of the spectrum are non–organ-specific diseases, in which lesions and antibodies are widespread throughout the body and not limited to one target organ. SLE is an example of this type of autoimmune disease. Identification of ANAs that attack the nucleic acids (DNA and RNA) and other components of the body’s own tissues established SLE as an autoimmune disease.

In this book, with the few exceptions included in this chapter (e.g., fibromyalgia, CFS, SLE), autoimmune disorders are discussed individually in the most appropriate chapter. For example, Reiter’s syndrome, rheumatoid arthritis, and Sjögren’s syndrome are discussed in Chapter 27. Polymyositis, dermatomyositis, and progressive systemic sclerosis are discussed in Chapter 10. Giant cell arteritis is discussed in Chapter 12, sarcoidosis in Chapter 15, and so on. More information is available on autoimmune-related diseases.⁶

Etiologic and Risk Factors

Although the autoimmune disorders are regarded as acquired diseases, their causes often cannot be determined. Autoimmunity is believed to result from a combination of factors, including genetic, hormonal (women are affected more often than men by autoimmune diseases), and environmental influences (e.g., exposure to chemicals, other toxins, or sunlight and drugs that may destroy suppressor T cells).

Although no single gene has been identified as responsible for autoimmune diseases, clusters of genes seem to increase susceptibility. In most autoimmune disorders, a known or suspected genetic susceptibility is evident, and certain HLA types show increased risk, such as ankylosing spondylitis with HLA-B27 (see Table 40-20).

The influence of hormonal factors is confusing since some autoimmune diseases occur among women in their 20s and 30s, when estrogen is high, and others develop after menopause or before puberty, when estrogen levels are low. During pregnancy, many women with rheumatoid arthritis or MS experience complete remission, whereas pregnant women with SLE often experience exacerbations.

Other factors implicated in the development of immunologic abnormalities resulting in autoimmune disorders include viruses, stress, cross-reactive antibodies, and various autoimmune diseases occurring in women who have had silicone gel breast implants. This organ-specific autoimmune disease has been associated with musculoskeletal problems.

Pathogenesis

Autoimmune disorders involve disruption of the immunoregulatory mechanism, causing normal cell-mediated and humoral immune responses to turn self-destructive, resulting in tissue damage.

The exact pathologic mechanisms for this process remain unknown. The importance of the innate immune system in determining whether T cells become activated and functional in autoimmune disorders has been shown.¹⁶⁸ Researchers suspect that more than one part of the immune system must be involved for autoimmune disease to develop.

Some autoimmune diseases affect a single organ (e.g., pancreas in type 1 diabetes), whereas others affect a large system or more than one system (e.g., MS). In some cases the autoimmune process overstimulates organ function, as in Graves’ disease, in which excess thyroid hormone is produced.

Gene-mapping studies have demonstrated that allergy and autoimmunity must involve not only the recognition of antigen by T cells, but also the very important immunoregulatory effects of cytokines, inhibitory receptors, and survival factors. Linkage analysis of the human genome has revealed candidate loci for susceptibility to MS, type 1 diabetes, SLE, and Crohn’s disease. Continued genetic analysis is ongoing to identify the specific genetic link in hopes of finding a more specific treatment.¹²³

Although antibodies and T-cell receptors can accurately distinguish between closely related antigens, they sometimes cross-react with apparently unrelated antigens, either because the two antigens happen to share an identical epitope (see Fig. 7-2) or because two different epitopes have similar shapes and charges. Such cross-reactions may be the underlying pathogenesis of some autoimmune diseases.⁶¹

Many autoimmune diseases are associated with characteristic autoantibodies. In other words, the body begins to manufacture antibodies directed against the body’s own cellular components or specific organs. These antibodies are known as autoantibodies, in this case, producing autoimmune diseases.

For example, SLE is associated with anti-DNA and anti–splice sosomal (Sm) antigen, Sjögren’s syndrome is associated with anti-ribonucleoproteins (SS-A and SS-B), progressive systemic sclerosis is associated with anticentromere and anti–Scl-70 (DNA topoisomerase), psoriasis and psoriatic arthritis are associated with HLA-B13, and mixed connective tissue disease is associated with anti-ribonucleoprotein without anti-DNA.

Antibodies specific to hormone receptors on the surface of cells have been found and determined to be partially responsible for some conditions. Examples include myasthenia gravis, in which antiacetylcholine receptor antibodies are involved; Graves’ disease, in which antibodies against components of thyroid cell membranes, including the receptors for thyroid-stimulating hormone, are responsible; and certain cases of insulin-resistant diabetes mellitus, in which the antibodies affect insulin receptors on cells.

Other diseases involving autoimmune mechanisms include rheumatic fever, rheumatoid arthritis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and postviral encephalomyelitis.

Clinical Manifestations

Autoimmune disorders share certain clinical features, and differentiation among them is often difficult because of this. Common findings include synovitis, pleuritis, myocarditis, endocarditis, pericarditis, peritonitis, vasculitis, myositis, skin rash, alterations of connective tissues, and nephritis. Constitutional symptoms such as fatigue, malaise, myalgias, and arthralgias are also common.

DIAGNOSIS.

Diagnosis can be difficult because autoimmune diseases are poorly understood, mimic one another, and often consist of vague symptoms such as lethargy or migratory joint pain. Laboratory tests may reveal thrombocytopenia, leukopenia, immunoglobulin excesses or deficiencies, ANAs, rheumatoid factor, cryoglobulins, false-positive serologic tests, elevated muscle enzymes, and alterations in serum complement. The Coombs’ test is positive when hemolytic anemia is present.

Some of the laboratory alterations that occur in autoimmune diseases (e.g., false-positive serologic tests, rheumatoid factor) occur in asymptomatic people. These changes may also be demonstrated in certain asymptomatic relatives of people with connective tissue diseases, in older individuals, those taking certain medications, and people with chronic infectious diseases.

TREATMENT.

Treatment of autoimmune diseases varies with the specific disease. Treatment must maintain a delicate balance between adequate suppression of the autoimmune reaction to avoid continued damage to the body tissues and maintenance of sufficient functioning of the immune mechanism to protect the person against foreign invaders. In general, autoimmune diseases are treated by the administration of corticosteroids to produce an antiinflammatory effect and salicylates to provide symptomatic relief.

The wealth of new information gleaned from research in the last decade has been used to improve immunization strategies and hopefully will lead to new approaches to the reinduction of immune tolerance. The development of an effective vaccine is under close scrutiny,¹²³ as is the use of intense immunosuppression (immunoablation) followed by stem cell transplantation for the treatment of autoimmune diseases.

Since autoimmune disease is the result of genetic dysregulation, gene therapy may become a viable alternative in the future. Scientists have been involved in developing new drugs aimed at the mechanism of autoimmunity rather than treating its effects. Based on new information about the function of Fc receptors, which bind antibodies that are instructing the immune system in the destructive inflammation characteristic of autoimmune diseases, scientists are looking for blocking compounds to prevent this interaction.

Systemic Lupus Erythematosus

PREVENTION.

There is no known way to prevent SLE, but preventive measures can reduce the risk of flare-ups. For photosensitive people, avoidance of (excessive) sun exposure and/or the regular application of sunscreen usually prevents rashes. Regular exercise helps prevent muscle weakness and fatigue. Immunization protects against specific infections.

Support groups; counseling; and reliance on family members, friends, and health care professionals can help alleviate the effects of stress. Lifestyle choices and personal behavior are very important for people with SLE. These include smoking, excessive consumption of alcohol, too much or too little of prescribed medication, or postponing regular medical checkups.¹⁴⁴

DIAGNOSIS.

Diagnosis of SLE is difficult because it often mimics other diseases and the symptoms are often vague, varying greatly from individual to individual. The American Rheumatism Association has issued a list of criteria for classifying SLE to be used primarily for consistency in epidemiologic surveys. Usually four or more of these signs are present at some time during the course of the disease (see Box 7-7).

In addition to the routine history and physical examination, laboratory findings are an important part of the diagnosis of SLE and subsequent monitoring of clinical disease activity. Specific test procedures and their significance are available.¹⁴³ ANAs are present in all cases of SLE, but their presence does not make a definitive diagnosis. However, if ANAs are absent, SLE is probably not present. Lupus anticoagulant testing and immunologic antiphospholipid establish the presence of antiphospholipid syndrome.

Magnetic resonance imaging scans of the head are usually ordered for all people experiencing new episodes of focal neurologic deficits, seizures, altered consciousness, or psychosis. Neuropsychologic assessment may be helpful for identifying subtle, clinically latent sequelae of CNS events, such as stroke, and in monitoring the response to drug treatment.⁶²

TREATMENT.

The objectives of medical intervention are to reverse the autoimmune and inflammatory processes and prevent exacerbations and complications. At the present time, pharmacologic interventions are the primary means of accomplishing these goals.

Mild symptoms can be managed with NSAIDs to relieve muscle and joint pain while reducing tissue inflammation. Corticosteroid-sparing agents (e.g., methotrexate) used earlier preserve bone and offer protection from premature cardiovascular disease. Anticoagulants for individuals who have antiphospholipid antibody syndrome and coagulopathies ensure a more favorable outcome.

Antimalarial agents (e.g., chloroquine [Aralen], hydroxychloroquine [Plaquenil]) are useful against the dermatologic, arthritic, and renal symptoms of this disease. Immunomodulating drugs (e.g., azathioprine [Imuran], cyclophosphamide [Cytoxan]) are immunosuppressive drugs used to suppress inflammation and subsequently the immune system. These are used only with active disease, especially with severe kidney involvement. Corticosteroids and cytotoxic drugs are given in more severe disease that has not responded to these other types of drug therapy.

Treatment in the future may be more specific as knowledge of genes that participate in the predisposition, pathogenesis, pharmacogenetics of, and protection against this disease come to light. Better understanding of the role of sex hormones has allowed trials of weak androgens or prolactin inhibitors.

New immunomodulators or immunosuppressants, immune ablation with subsequent stem cell transplantation, and more precise immunoregulation (e.g., tolerance-induction strategies; intervention at the level of T-cell costimulation; targeting of cytokines, complement, and FcγR) may become standard intervention tools.^23,134

PROGNOSIS.

The prognosis improves with early detection and intervention that prevents organ damage and improves life expectancy. The overall reduction in the use of large doses of corticosteroids over the past 2 decades has significantly reduced morbidity and mortality rates.

People with SLE have an increased prevalence of valvular and atherosclerotic heart disease, apparently because of factors related to the disease itself and to drug therapy necessary in severe cases. Symptomatic large-vessel occlusive disease in SLE, occurring several years after the diagnosis of the disease, is associated with a relatively poor short-term outcome. There is an increased risk of certain cancers in SLE; the risk appears to be most heightened for lymphoma.¹⁹

Prognosis is less favorable for those who develop cardiovascular, renal, or neurologic complications or severe bacterial infections. High stress, poor social support, and psychologic distress are modifiable factors associated with health outcomes for people with SLE.^66,261

Fibromyalgia

DIAGNOSIS.

No definitive test is currently available to determine the presence of fibromyalgia, and usually the organs involved are not the cause but merely the messenger of a problem originating elsewhere in the body.

According to the American College of Rheumatology (ACR), two criteria must be met before a medical diagnosis of FMS can be made: (1) widespread (four-quadrant) pain both above and below the waist present for at least 3 months and (2) subjective report of pain when pressure is applied to 11 of the 18 common FMS tender points on the body (see Fig. 7-28).

Subjective assessment of tender points can be elicited by the use of an instrument called a dolorimeter, which distributes pressure equally over a discrete point. With a dolorimeter, the pressure required to produce pain in a given area can be recorded.

Controversy also exists regarding current use of the ACR’s criteria for tender point count in clinical diagnosis of FMS. In fact, the original author of the ACR criteria has suggested that counting the tender points was “perhaps a mistake” and has advised against using it in clinical practice as the only means of diagnosis.²⁶⁶ A proposed survey method that does not require physical examination may be more accurate.¹²⁹

Often, the diagnosis is determined as a process of elimination by ruling out other conditions based on clinical presentation and past medical history (Box 7-8). In addition to the presence of tender points, skin fold tenderness, increased reactive skin hyperemia, and low tissue compliance (in the trapezius and paraspinal regions) provide further diagnostic information.

No special laboratory or radiologic testing is necessary for making a diagnosis of FMS; routine testing for rheumatoid factor or ANAs is not recommended. While routine inexpensive tests, including complete blood count, basic chemistry (blood urea nitrogen, creatinine, hepatic enzymes, serum calcium), and thyroid function, should be undertaken (if not done in the past year); any other test to rule out other conditions, unless clinically indicated (by both symptoms and physical examination), is a waste of time and resources.

A routine complete blood count test may demonstrate anemia caused by medications or another disease, which may contribute to fatigue, and cytopenia; a baseline chemistry test is useful in monitoring various medication side effects. Because spinal pain in FMS and pain caused by pathologic changes in the spine (e.g., osteoarthritis and osteopenia with vertebral compression fracture) cannot always be distinguished clinically, a spinal x-ray may be necessary for a middle-aged or older adult, especially considering other risk factors for these conditions. It is important not to miss these diagnoses, because the management approach is likely to be different from FMS alone. A sleep study should be considered only when history suggests a primary sleep disorder.²⁷³

TREATMENT.

Despite the chronicity and complexity of FMS, there are pharmacological and nonpharmacological interventions available that have clinical benefit. Helping clients with fibromyalgia must be holistic and multidisciplinary, including education and support, stress management, nutrition and lifestyle training (e.g., coping strategies, applying work simplification and ergonomic principles, and psychotherapy), medications (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, muscle relaxants, analgesics, and anticonvulsants), local modalities and techniques for muscle pain (e.g., relaxation techniques, biofeedback, Physiologic Quieting, or soft tissue techniques), and conditioning and aerobic exercise.

Cognitive behavioral therapy aimed at altering sensory, affective, cognitive, and behavioral aspects of chronic pain (e.g., pain severity, emotional distress, depression, anxiety, pain behavior) has been shown to be effective over a long period, even when the disease process cannot be controlled and symptoms worsen. Based on current evidence, a stepwise program emphasizing education, certain medications, exercise, cognitive therapy, or all four should be recommended.⁹²

Alternative and complementary intervention (e.g., acupuncture, herbal or vitamin supplements, chiropractic, hypnotherapy, and others) is available and often provides palliative relief from symptoms for periods. Like most interventions (medical or unconventional), no single intervention is effective all the time, and the person with FMS may cycle through various modalities over time.

PROGNOSIS.

Many people with mild symptoms are managed without a specialist and have an expected good long-term outcome, but most people experience persistent symptoms of fibromyalgia for many years or a lifetime. Good therapy must be instituted early in the client’s course if there is to be any chance of achieving substantial improvement or a remission.

Organ and Tissue Transplantation

With recent advances in technology and immunology, organ and tissue transplantation is becoming commonplace. In fact, transplantation of almost any tissue is feasible, but the clinical use of transplantation to remedy disease is still limited for many organ systems because of the rejection reaction. Transplant rejection, an isoimmune phenomenon, occurs in response to transplantation because the body usually recognizes the donor tissue as nonself and attempts to destroy the tissue shortly after transplantation.

In all cases of graft rejection, the cause is incompatibility of cell surface antigens. The rejection of foreign or transplanted tissue occurs because the recipient’s immune system recognizes that the surface HLA proteins of the donor’s tissue are different from the recipient’s.

For this reason, HLA matching of donor and recipient greatly enhances the probability of graft acceptance. Certain antigens are more important than others for a successful transplant, including ABO and Rh antigens present on RBCs and histocompatibility antigens, most importantly the HLA. As expected, a better chance of graft acceptance is evident with syngeneic or autologous transplants because the cell surface antigens are identical.

For a complete discussion of histocompatibility, graft rejection (acute versus chronic), graft-versus-host disease, and immunosuppression, see Chapter 21.

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