Immunity

Margaret J. Fehrenbach and Joan A. Phelan

THE ACQUIRED IMMUNE RESPONSE

Like the inflammatory response, the acquired immune response defends the body against injury, particularly from foreign substances such as microorganisms. The immune response differs from the inflammatory response in that it has the capacity to remember past instances of injury and responds more quickly to a foreign substance that is encountered again. It works amid the background of an already activated inflammatory and innate immune response and a working repair process. The innate immune response does not involve memory. It is described along with inflammation in Chapter 2. The acquired immune response involves a complex network of white blood cells. As with inflammation, the immune response may also result in an increased level of injury and disease.

ANTIGENS

Antigens are the foreign substances against which the immune system defends the body. These substances are mainly proteins and are often microorganisms and their toxins. The immune system tolerates the normal components of the body (self) and their normal diversity. Antigens are substances that the immune system recognizes as foreign (nonself). Transformed human cells such as tumor cells or cells infected by viruses can be antigens. Human tissue, as in the case of an organ transplant, tissue graft, or incompatible blood transfusion, can also be an antigen. In diseases called autoimmune diseases, parts of an individual’s own body become antigens. Disease occurs when the immune response identifies components of self as antigen or doesn’t recognize foreign material as antigen.

CELLULAR INVOLVEMENT IN THE IMMUNE RESPONSE

Many cells are involved in the immune response. These cells can produce cell products or cytokines that are active during the immune response. The primary white blood cells involved in the immune response are lymphocytes. These cells are able to recognize and respond to an antigen when it is in contact with receptor sites on the surface of the cell. Lymphocytes, like other white blood cells, are derived from stem cells in the bone marrow. Lymphocytes constitute 20% to 25% of the white blood cell population. They are mobile antigen-sensitive cells with a long life. They have a round nucleus and only a small amount of cytoplasm. Different types of lymphocytes have different functions. The two main types of lymphocyte are called B lymphocytes (B cells) and T lymphocytes (T cells) (Figure 3-1).

A third type of lymphocyte is called the natural killer cell (NK cell). This is a large lymphocyte that is part of the body’s innate immunity and not directly involved in acquired immunity. NK cells and their activities are described in Chapter 2. NK cells have the ability to destroy foreign cells early in their appearance since they recognize them as foreign without first having to recognize them as specific antigens. They are usually located within the microcirculation and not in the outlying tissue. This cell seems to be active against viruses and cancer cells. However, in several immunodeficiency diseases, including acquired immunodeficiency syndrome, NK cell function is abnormal.

B LYMPHOCYTES

B lymphocytes develop from the stem cells in the bone marrow and then reside and mature in lymphoid tissue. Lymphoid tissue is found in lymph nodes and many other body locations, including pharyngeal and lingual tonsillar tissues. When antigen stimulates B lymphocytes, they travel to the site of injury. Two main types of B cells develop when a B cell is stimulated by an antigen: the plasma cell and the B memory cell. The B memory cell retains the memory of the antigen. In the presence of an antigen recognized by the memory B, this cell duplicates in a process called clonal selection; all of these newly formed B cells retain the capacity to recognize the previously encountered antigen.

Plasma cells have a round, pin-wheel–shaped nucleus and visible cytoplasm. Plasma cells produce proteins called antibodies. Antibodies, also called immunoglobulins (Igs), are secreted into the blood serum. Five different types of immunoglobulins exist: IgA, IgD, IgE, IgG, and IgM (Table 3-1). They all have variations of the same basic structure (Figures 3-2 and 3-3).

Specific antibodies are produced in response to specific antigens by a specific plasma cell. This specificity is a characteristic function of the immune response. The level of a specific antibody in the blood is called the antibody titer and can be measured by diagnostic laboratory tests. This is helpful in the diagnosis of some infectious diseases.

Antibodies can combine with antigen, forming an immune complex. The portion of the antibody that recognizes and binds to the antigen is called its antigenic determinate. The formation of an immune complex usually renders the antigen inactive. Immune complexes may also be involved in certain disease states.

T LYMPHOCYTES

After they develop from the bone marrow stem cell, the T lymphocytes travel to the thymus and then are processed into mature cells. The thymus is a primary lymphoid organ located high in the chest. It is quite large in infants and shrinks as an individual matures.

T cells depend on unique cell surface molecules called the major histocompatibility complex to help them recognize antigen fragments. Different types of T cells have different functions in the immune response. Some are memory cells similar to those within the B cell population; others are T-helper cells that increase the functioning of the B lymphocytes (enhancing the antibody response) and are easily identifiable by the T4 cell marker (Figure 3-4). T-suppressor cells, which usually carry the T8 marker, suppress or “turn off” the functioning of the B lymphocytes. T-cytotoxic cells, which also carry the T8 marker, are active in surveillance against virally infected cells or tumor cells by directly attacking these cells. T cells within cell-mediated immunity also orchestrate, regulate, and coordinate the overall immune response.

MACROPHAGES

Not only are macrophages present in the connective tissue during inflammation (see Chapter 2 for their role and a description of the cell), but they are also involved in the immune response to an antigen. Macrophages are active in phagocytosis of foreign substances and help both the B cells and T cells during the immune response. After phagocytosis of an antigen at the injury site, the macrophages then act as antigen-processing cells for the lymphocytes. This stimulates the lymphocytes to travel from the lymphoid tissue to the injury site.

Thus macrophages serve as a link between the inflammatory and immune responses since, in addition to phagocytosis, macrophages can also act as antigen-presenting cells. When activated, macrophages can function in many different ways, always amplifying the immune response. Unlike lymphocytes, macrophages do not remember the encountered antigen and need to be reactivated during each encounter.

CYTOKINES

Cytokines are proteins that are made by cells and are able to affect the behavior of other cells. They are produced by the cells of the immune system and play a prominent role in the activation of the immune response. Cytokines are one way that lymphocytes communicate with each other and with other immune system cells. B or T lymphocytes produce cytokines that are called lymphokines. Different cytokines have different functions (Table 3-2). They can activate macrophages and enhance the ability of macrophages to destroy foreign cells. These types of cytokines may also be involved in various other functions concerning leukocytes, fibroblasts, and endothelial cells. Macrophages produce cytokines called monokines. One of the first cytokines to be discovered was interferon. Produced by T cells and macrophages (as well as by cells outside the immune system), interferons are a family of proteins with antiviral properties. Chemokines are a family of small cytokines; their name is derived from their ability to induce directed chemotaxis in nearby responsive cells. They may be involved in controlling infection as part of the immune response such as in an infection with the human immunodeficiency virus.

MAJOR DIVISIONS OF THE IMMUNE RESPONSE

Historically the immune system has been described as two major divisions that differ in their response to an antigen. However, these divisions are interrelated, and present understanding of immune responses recognizes that these divisions are not distinctly separate mechanisms. The immune response to an antigen can take one of two forms (Figure 3-5): humoral immunity and cell-mediated immunity. Humoral (antibody-mediated) immunity involves the production of antibodies with the B lymphocytes as the primary cells. Humoral immunity is responsible for protection against many bacteria and viruses. The other division of the immune system, cell-mediated immunity or cellular immunity, involves lymphocytes, usually T cells, working alone or assisted by macrophages. The cell-mediated division regulates both major responses.

MEMORY AND IMMUNITY

Memory is a characteristic function of the acquired immune response. This contrasts with the inflammatory response, which is not capable of memory. Certain lymphocytes retain the memory of an antigen after an initial encounter. For this reason, the immune response to that antigen is much more rapid and is stronger the next time it is encountered. Immunity is this increased responsiveness that results from the retained memory of an already encountered antigen.

TYPES OF IMMUNITY

PASSIVE IMMUNITY

Two types of immunity occur: passive and active. Using antibodies produced by another person to protect an individual against infectious disease is called passive immunity. This type of immunity can occur naturally or it can be acquired. Natural passive immunity occurs when antibodies from a mother pass through the placenta to the developing fetus. These antibodies protect a newborn infant from disease while the infant’s own immune system matures.

Passive immunity can also be acquired through an injection of antibodies against a microorganism to which the person has not previously developed antibodies. This is used to confer immediate protection against the disease caused by that microorganism. These antibodies are collected from individuals who have already had the disease and have naturally produced antibodies to the disease-causing microorganism. This type of passive immunity is short-lived but can act immediately. It is used because the unprepared immune system of an individual takes longer to produce antibodies, and in the meantime the disease may develop. Acquired passive immunity, using hepatitis B immunoglobulin, may be provided to dental personnel who do not have immunity to hepatitis B after needlestick or other occupational exposure incidents.

ACTIVE IMMUNITY

Active immunity can occur naturally or be acquired. It occurs naturally when a microorganism causes the disease. Protection against further attack by that microorganism is conferred to the individual if the body recovers from the disease. A less risky way of achieving active immunity is by an acquired or artificial means. A person is injected with or ingests either altered pathogenic microorganisms or products of those microorganisms. The altered microorganism or product cannot produce infection but is able to act as an antigen. This is called a vaccine, and the process is called vaccination. When the pathogenic microorganism is encountered after vaccination, the immune system produces a stronger, faster response and prevents development of the disease. This production of acquired immunity is called immunization.

Immunization lowers the risk of a microorganism causing disease because it safely prepares the immune system to fight future attacks by the disease-causing microorganism. In some cases more than one exposure to the antigen is needed to ensure adequate immunity. A repeated exposure by way of a vaccination is called a booster. Immunization by vaccination is used to protect children and adults against many diseases. Dental personnel should be vaccinated against the hepatitis B virus because of their high risk of occupational exposure to that virus.

IMMUNOPATHOLOGY

Immunopathology is the study of immune reactions involved in disease. The immune response helps defend the body against disease-producing antigens, but it can also malfunction and cause tissue damage. Immunopathology includes diseases caused by malfunctioning of the immune system. Hypersensitivity reactions and autoimmune diseases are examples of conditions in which damage is caused by the immune response.

HYPERSENSITIVITY

Hypersensitivity reactions are also called allergic reactions (allergy) and comprise the same types of reactions that occur when the immune response is fighting microorganisms and protecting the body against disease. However, hypersensitivity reactions are exaggerated immunopathologic responses; tissue destruction occurs as a result of the immune response. Four main types of hypersensitivity reactions occur; they are classified by the nature of the immune response that causes the disease (Table 3-3).

AUTOIMMUNE DISEASES

The immune system learns to differentiate between the body’s own cells and tissues and foreign substances early in embryologic development. This recognition and the nonresponsiveness of the immune system to the body’s own cells and tissues are called immunologic tolerance. In autoimmune diseases, also called connective tissue diseases, the recognition mechanism breaks down, and certain body cells are no longer tolerated. The immune system treats body cells as antigens. An autoimmune disease may involve a single cell type or a single organ or may be even more extensive, involving multiple organs. Tissues and even entire organs may be damaged. An example is the T cells that attack pancreatic cells contributing to diabetes mellitus. Genetic factors may play a role in the predisposition of an individual to autoimmune disease, and viral infection may also be involved. Several autoimmune diseases have oral manifestations. These are described later in this chapter.

IMMUNODEFICIENCY

Immunodeficiency is a type of immunopathologic condition that involves a deficiency in number, function, or interrelationships of the involved white blood cells and their products. This condition may be congenital (present at birth) or acquired (developed after birth). Immunodeficiency may be inherited genetically, or it can be caused by numerous other factors. When a person’s immune system is not functioning adequately, infections and tumors may develop. Studies have shown that stress and depression may be associated with decreased levels of immune function. Acquired immunodeficiency syndrome, which is discussed in Chapter 4, is an example of an immunodeficiency that has numerous oral manifestations.

ORAL DISEASES WITH IMMUNOLOGIC PATHOGENESIS

APHTHOUS ULCERS

Aphthous ulcers, also known as canker sores or aphthous stomatitis, are painful oral ulcers for which the cause remains unclear. They frequently recur in episodes. Three forms of recurrent aphthous ulceration exist: (1) minor, (2) major, and (3) herpetiform. The three forms differ in the size and duration of the ulcers. Aphthous ulcers are common ulcers in the oral cavity, occurring in about 20% of the general population. However, a dramatic variation in occurrence takes place, from as high as 57% of a professional school population to 5% of patients studied in a large inner city hospital. The first episode of these ulcers usually occurs in adolescence, and they are somewhat more common in females than in males. The clinical appearance and location are important in establishing the diagnosis.

Trauma is the most commonly reported precipitating factor in the development of aphthous ulcers. They are often reported to occur after trauma to the oral mucosa during dental procedures (e.g., in the area of film placement or at the site of injection of local anesthetics). Some patients may experience aphthous ulcers as a result of manipulation of oral tissues during dental hygiene treatment. Emotional stress has also been suggested as a contributing factor. Some patients associate the initiation of aphthous ulcers with eating certain foods such as citrus fruits. However, it is possible that patients perceive these foods as causative because of the sensitivity of the ulcers to foods with a high acid content. The recurrence of aphthous ulcers has been associated with menstruation, whereas pregnancy has been found to produce a decrease in the episodes. These ulcers occur in association with certain systemic diseases such as:

Substantial evidence indicates that aphthous ulcers have an immunologic pathogenesis. Patients in whom aphthous ulcers develop have slightly elevated levels of antibodies to oral mucous membranes. Histologically an infiltrate of lymphocytes is present in the lesion, suggesting that cell-mediated immunity may be important in development of the ulcers. The infiltrate contains primarily T-helper cells in the prodromal stage, T-cytotoxic cells in the ulcerative phase, and T-helper cells again in the healing stage. The T-cytotoxic cells are probably responsible for the ulceration. However, the specific antigen to which they are responding has not yet been identified.

URTICARIA AND ANGIOEDEMA

Urticaria and angioedema are similar lesions. Urticaria, also called hives (Figure 3-9), appears as multiple areas of well-demarcated swelling of the skin, usually accompanied by itching (pruritus). The lesions are caused by localized areas of vascular permeability in the superficial connective tissue beneath the epithelium. Angioedema (Figure 3-10) is a similar lesion that appears as a diffuse swelling of tissue caused by permeability of deeper blood vessels. The skin covering the swelling appears normal, and angioedema is usually not accompanied by itching. Urticaria and angioedema both may occur in acute self-limited episodes. Occasionally chronic or recurrent forms may occur.

In many cases of urticaria and angioedema the cause cannot be identified. Infection, trauma, emotional stress, and certain systemic diseases have been reported to cause these lesions. Ingested allergens are frequent causes of urticaria.

Several mechanisms are capable of causing the increased vascular permeability that results in urticaria and angioedema, including the release of the chemical mediator histamine from mast cells stimulated by IgE antibodies (type I hypersensitivity) and the activation of IgG or IgM antibodies along with trauma, causing vascular permeability. Acetylsalicylic acid (aspirin) and nonsteroidal antiinflammatory drugs such as ibuprofen can produce a nonspecific effect that can cause vascular permeability. A rare hereditary form of angioedema exists in which uncontrolled activation of the complement cascade occurs, resulting in prolonged vascular permeability.

The diagnoses of urticaria and angioedema are based on the clinical appearance of the lesions and the patient’s history. Avoidance of the causative agent, if identified, is important in managing patients with recurring urticaria and angioedema. Immediate treatment is essential. Antihistaminic drugs are the principal method of treatment. Angioedema involving the larynx and pharynx can cause asphyxiation and therefore may be fatal.

CONTACT MUCOSITIS AND DERMATITIS

Contact mucositis and contact dermatitis are lesions that result from the direct contact of an allergen with the skin or mucosa. The development of these conditions involves a T cell–mediated immune response and is an example of type IV hypersensitivity. The exact underlying immunologic basis is not always clear.

In contact mucositis the mucosa becomes erythematous and edematous, often accompanied by burning and pruritus (Figure 3-11, A). The mucositis occurs at the point at which the offending agent has contacted the mucosa, giving it a smooth, shiny appearance that is firm to palpation. Small vesicles and ulcers may appear in the affected areas. In contact dermatitis the initial lesion may be erythematous, with swelling and vesicles. Later the area becomes encrusted with a scaly, white epidermis.

Topical antibiotics, antihistamines, preservatives in local anesthetics, and components of topical medication are common causes of allergic reactions. Acrylics, metal-based alloys, epoxy resins, and the flavoring agents in chewing gum and dentifrices all have been reported to cause contact mucositis.

Contact dermatitis, particularly that affecting the hands, may occur in response to the materials used in dentistry. The routine use of gloves in dental care has decreased the incidence of this type of dermatitis, but latex gloves and glove powder have also been responsible for contact dermatitis in some individuals (Figure 3-11, B).

Skin testing for sensitivity to a particular substance can help confirm the agent that caused the lesion. However, first the substance has to be identified. Topical and systemic corticosteroids may be used in the management of these lesions in some patients.

FIXED DRUG ERUPTIONS

Fixed drug eruptions are lesions that appear in the same site each time a drug is introduced. The lesions generally appear suddenly after a latent period of several days and subside when the drug is discontinued. They appear again when the drug is reintroduced, usually with greater intensity. Clinically there may be single or multiple slightly raised, reddish patches or clusters of macules on the skin or rarely the mucous membranes. Pain and pruritus may be associated with these lesions.

The fixed drug eruption is a type of allergic reaction (type III hypersensitivity) in which immune complexes are deposited along the endothelial wall of blood vessels. The ensuing inflammatory reaction causes vasculitis and subsequent damage to the vessel wall, giving rise to erythema and edema of the superficial layers of the skin or mucosa. If possible, the drug causing the reaction should be identified, and its use discontinued.

ERYTHEMA MULTIFORME

Erythema multiforme is an acute, self-limited disease that affects the skin and mucous membranes. The cause is not clear, but some evidence exists that it is a hypersensitivity reaction.

Erythema multiforme most commonly occurs in young adults and affects men more commonly than women. The characteristic skin lesion is called a target, iris, or bull’s eye lesion and consists of concentric rings of erythema alternating with normal skin color. The color is darkest at the center of the lesion (Figure 3-12). The term erythema multiforme refers to the variety of skin lesions that can occur, which range from macules to plaques to bullae. Erythema multiforme can affect the oral mucosa either alone or in association with skin lesions. Skin lesions can occur without oral lesions. The oral lesions are usually ulcers (Figure 3-13, A&B). However, erythematous areas may also occur. The ulcers frequently form on the lateral borders of the tongue. Crusted and bleeding lips are frequently seen in erythema multiforme, and gingival involvement is rare. The disease usually has an explosive onset, and systemic symptoms are mild or lacking. It may be chronic on occasion, or there may be recurrent acute episodes. The most severe form of erythema multiforme is called Stevens-Johnson syndrome (Figure 3-13, C). Mucosal lesions are more extensive and painful, genital mucosa and the mucosa of the eyes may be involved, and lips are generally encrusted and bloody.

Although the cause of erythema multiforme is not clear, in some cases triggering factors can be identified. Infections such as herpes simplex, tuberculosis, and histoplasmosis have been associated with episodes of erythema multiforme, as have malignant tumors and drugs such as barbiturates and sulfonamides.

LICHEN PLANUS

Lichen planus is a benign, chronic disease affecting the skin and oral mucosa. In some patients this disease may affect both the skin and the oral mucosa. In others either oral mucosa or skin alone may be affected. The lesions have a characteristic pattern of interconnecting lines called striae, resembling the pattern of the plant lichen as it grows on rocks and trees.

The classic appearance of lichen planus affecting the oral mucosa is an arrangement of interconnecting white lines and circles (Figure 3-14). The slender white lines are called Wickham’s striae. The fundamental lesion is a small, papular, pinhead-sized, domed or hemispheric, glistening white nodule on the mucosa. The clinical appearance depends on the arrangement of these minute papules and striae. The most common location is the buccal mucosa. However, lichen planus also occurs on the tongue, lips, floor of the mouth, and gingiva. Lesions of lichen planus are frequently distributed symmetrically in the oral cavity.

The prevalence of lichen planus in the general population of the United States has been reported to be about 1%. In one study of 100 cases, the age of individuals affected ranged from 13 to 78 years. However, the disease is most common in middle age. A slight female predominance has been suggested. In another reported study of 200 cases, most were found to be asymptomatic and were discovered on routine oral examination.

Many factors have been implicated in lichen planus; however, the cause remains unknown. Erosive lesions do tend to worsen with emotional stress. Many drugs and chemicals have been shown to produce lichenoid lesions, but these have a different histologic appearance from true lichen planus.

REACTIVE ARTHRITIS (REITER SYNDROME)

Reactive arthritis (Reiter syndrome) classically comprises the triad of arthritis, urethritis, and conjunctivitis. However, all the components of the syndrome may not be present. Polyarteritis is generally the most prominent component of this syndrome. (A syndrome is a group of signs and symptoms that occur together. Other syndromes are described elsewhere in this text.) The cause of this syndrome is not clear. An antigenic marker called HLA-B27 is present in most patients with reactive arthritis suggesting a genetic influence. An abnormal immune response to a microbial antigen is considered the most likely mechanism of occurrence. Reactive arthritis is far more prevalent in men (10:1) than in women (15:1). Reactive arthritis characteristically develops 1 to 4 weeks after venereal or gastrointestinal infection and is usually benign and self-limited.

The arthritis of this condition usually involves the joints of the lower extremities (knees and ankles). It may be asymmetric and migratory, chronic and recurrent.

Radiographically a periosteal proliferation can be detected on the heels, ankles, metatarsals, phalanges, knees, and elbows. Fever, malaise, and weight loss may be associated with the arthritis. The urethritis usually precedes the other lesions. No infectious organisms can be identified. The conjunctivitis is usually mild, but some individuals experience iritis (inflammation of the iris).

Skin and mucous membrane lesions are seen in many patients with reactive arthritis. Oral lesions occur almost anywhere in the oral cavity (Figure 3-19). Aphthouslike ulcers, erythematous lesions, and areas of depapillation of the tongue that mimic geographic tongue have been described in patients with reactive arthritis.

LANGERHANS CELL DISEASE

Langerhans cell disease was formerly called histiocytosis X. Traditionally three entities were grouped under the category of histiocytosis X: (1) Letterer-Siwe disease, (2) Hand-Schüller-Christian disease, and (3) solitary eosinophilic granuloma. Histologically all are characterized by a combination of Langerhans cells and eosinophils (Figure 3-20). Langerhans cells were originally called histiocytes and were responsible for the name histiocytosis X. In all three diseases the proliferating cell is the Langerhans cell. The presence of eosinophils is thought to result from the production of an eosinophilic chemotactic factor produced by the macrophage.

The Langerhans cell (a type of macrophage) is an immunologically competent cell of the mononuclear phagocyte series and participates in cell-mediated immunity. The cause and pathogenesis of Langerhans cell disease remains unclear. A reactive process, a primary immunodeficiency disease, and a neoplastic process have all been suggested.

Letterer-Siwe disease (acute disseminated form) is an acute fulminating disorder that usually affects children younger than 3 years of age. The course of the disease is usually so rapid that significant oral involvement does not often occur. The disease resembles a lymphoma in that it generally has a rapidly fatal course that sometimes responds to chemotherapy.

The chronic disseminated or multifocal form of Langerhans cell disease has been called Hand-Schüller-Christian disease. This form occurs in children, usually younger than 5 years of age. A classic triad is seen in about 25% of patients. All changes are caused by localized collections of Langerhans cells. The triad includes single-to-multiple, well-defined or “punched-out” radiolucent areas in the skull (may also occur in the jawbones); unilateral or bilateral exophthalmos; and diabetes insipidus that is caused by collections of macrophages in the sella turcica area, affecting the pituitary gland.

Oral manifestations of the chronic disseminated form of the disease include sore mouth with or without ulcerative lesions, halitosis, gingivitis, unpleasant taste, loose and sore teeth, early exfoliation of teeth, and nonhealing extraction sites. A characteristic loss of supporting alveolar bone occurs, mimicking advanced periodontal disease (Figure 3-21).

A solitary or chronic localized form has been called eosinophilic granuloma of bone. This form primarily affects older children and young adults. Males are affected twice as commonly as females. The skull and mandible are commonly involved with eosinophilic granuloma. The radiographic appearance varies, and the lesion may resemble periodontal disease or periapical inflammatory disease; or it may appear as a well-circumscribed radiolucency with or without a sclerotic border (Figure 3-22). Cases of multifocal eosinophilic granuloma have also been reported.

AUTOIMMUNE DISEASES THAT AFFECT THE ORAL CAVITY

Several autoimmune diseases affect the oral cavity (Table 3-5). In this type of disease tissue damage occurs because the immune system treats the person’s own cells and tissues as antigens. An individual with one autoimmune disease has an increased risk of developing another. Although these are systemic diseases, they are included in this chapter because of their relationship to immunity.

SJÖGREN SYNDROME

Sjögren syndrome is an autoimmune disease that affects the salivary and lacrimal glands, resulting in a decrease in saliva and tears. This combination of dry mouth and dry eyes is sometimes called sicca (dry) syndrome. Decreased salivary flow (hyposalivation) results in dry mouth (xerostomia); decreased lacrimal flow results in dry eyes (xerophthalmia). The eye damage that occurs in Sjögren syndrome is called keratoconjunctivitis sicca. Other secretory glands such as sweat glands and glands that lubricate the vagina can also be affected. The specific cause of Sjögren syndrome is not known. Both cellular and humoral immunity are involved.

In some patients only the mouth and eyes are involved. In others the autoimmune process can be more extensive. Many patients (about 50%) with Sjögren syndrome have another autoimmune disease such as rheumatoid arthritis or systemic lupus erythematosus. Lacrimal and salivary gland involvement without the presence of another autoimmune disease is called primary Sjögren syndrome. When another autoimmune disease accompanies salivary and lacrimal gland involvement, the combination is called secondary Sjögren syndrome.

The oral manifestation of Sjögren syndrome is xerostomia (dry mouth), which occurs as a result of decreased salivary flow and causes the mucosa to become erythematous. Patients complain of oral discomfort. Lack of saliva causes the mouth to feel sticky. Lips are cracked and dry, and a generalized loss of filiform and fungiform papillae occurs on the dorsum of the tongue (Figure 3-23). Patients with xerostomia are at high risk for the development of caries, periodontal disease, and oral candidiasis.

Both major and minor salivary glands are affected. Parotid gland enlargement, usually bilateral and symmetric, occurs in about 50% of patients (Figure 3-24). The characteristic histologic appearance of these enlarged glands consists of replacement of the glands by lymphocytes and the presence of islands of epithelium called epimyoepithelial islands. Biopsy of the minor salivary glands is often performed to confirm a diagnosis of Sjögren syndrome. The minor glands show aggregates of lymphocytes surrounding the salivary gland ducts (Figure 3-25).

In addition to the oral findings, patients with decreased lacrimal flow that results in xerophthalmia complain of burning and itching of the eyes and photophobia (abnormal visual intolerance to light). Severe eye involvement may lead to ulceration and opacification of the cornea. Twenty percent of patients with Sjögren syndrome also have Raynaud phenomenon, which is a disorder affecting the fingers and toes. Cold and emotional stress trigger the reaction, which is characterized by an initial pallor of the skin that results from vasoconstriction and reduced blood flow. The initial pallor is followed by cyanosis, which occurs because of the decreased blood flow. When the skin is rewarmed, the blood vessels dilate, and the hyperemia results in a reddening of the skin. Finally, in minutes to hours the color returns to normal. Raynaud phenomenon can occur alone or in association with other autoimmune diseases, as well as in Sjögren syndrome. Patients with Sjögren syndrome might also complain of myalgia, arthralgia, and chronic fatigue.

Laboratory abnormalities are commonly found in patients with this syndrome. Ninety percent of patients with Sjögren syndrome have a positive reaction to rheumatoid factor, which is an antibody to IgG that is present in serum. It is an antibody to an antibody. Patients with other autoimmune diseases such as rheumatoid arthritis also react positively to rheumatoid factor. Other autoantibodies, called anti-Sjögren syndrome A and anti-Sjögren syndrome B, are also found in patients with Sjögren syndrome. Other laboratory abnormalities include mild anemia, a decreased white blood cell count, an elevated erythrocyte sedimentation rate, and a diffuse elevation of serum immunoglobulins.

SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE) is an acute and chronic inflammatory autoimmune disease of unknown cause. The disorder affects women eight times more frequently than men, predominantly during the childbearing years. It occurs three times more frequently in black women than in white women. SLE is a syndrome rather than a specific disease entity and includes a wide spectrum of disease activity and signs and symptoms that range from lesions confined to the skin such as discoid lupus erythematosus to a widespread, debilitating, life-threatening disease with multiple-organ involvement. SLE is usually chronic and progressive, with periods of remission and exacerbation.

Both cellular and humoral immunity are impaired in SLE. It has been suggested that cellular immunity is primarily affected, resulting in deregulation of the humoral response. Antigen and antibody complexes are deposited in various organs and stimulate an inflammatory response, which may be responsible for the tissue damage that occurs in SLE. Autoantibodies to the patient’s deoxyribonucleic acid (DNA) (antinuclear antibodies) are present in serum. These circulating antibodies are responsible for the positive antinuclear antibody and lupus erythematosus laboratory test results. Production of these antibodies is enhanced by estrogen. Antibodies to lymphocytes are present in some patients. Evidence exists for a genetic component in the pathogenesis of SLE.

PEMPHIGUS VULGARIS

Pemphigus vulgaris is a severe, progressive autoimmune disease that affects the skin and mucous membranes. It is characterized by intraepithelial blister formation that results from breakdown of the cellular adhesion between epithelial cells. This type of epithelial cell separation is called acantholysis. The patient with pemphigus vulgaris has circulating autoantibodies that are reactive against components of the epithelial cell attachment mechanism. The higher the titer of circulating antibodies, the greater the epithelial destruction. These autoantibodies are also found in surrounding epithelial cells. Pemphigus vulgaris is the type of pemphigus seen most frequently. Three other forms of pemphigus are (1) pemphigus vegetans, (2) pemphigus foliaceus, and (3) pemphigus erythematosus. These are much rarer conditions, but all are characterized by epithelial acantholysis. No sex predilection exists. A broad age range has been reported, including both children and elderly individuals. Most cases occur in the fourth and fifth decades of life. Genetic and ethnic factors have been reported. Although it is a relatively rare condition, pemphigus vulgaris is often seen in Ashkenazi Jews.

In more than 50% of cases of pemphigus vulgaris the first signs of disease occur in the oral cavity. Oral lesions can precede cutaneous lesions by many months. The appearance of oral lesions ranges from shallow ulcers to fragile vesicles or bullae.

Because the bullae are so fragile, they rupture soon after they form; the detached epithelium remains as a gray membrane (Figure 3-29). Ulcers are painful and range in size from small to very large. Gentle finger pressure with movement on clinically normal mucosa can produce a cleavage in the epithelium and result in the formation of a bulla. This is called Nikolsky’s sign.

Skin lesions in pemphigus vulgaris include erythema, vesicles, bullae, erosions, and ulcers. Microscopic examination of tissue shows an intact basal layer of epithelium attached to the underlying connective tissue (Figure 3-30). The loss of attachment between the epithelial cells results in detached cells that appear rounded. These rounded cells are called acantholytic cells or Tzanck cells and are present in the area of separation. Tzanck cells may also be seen on cytologic smear, but the diagnosis must be confirmed by biopsy.

MUCOUS MEMBRANE PEMPHIGOID

Mucous membrane pemphigoid is also known as cicatricial pemphigoid and benign mucous membrane pemphigoid. It is a chronic autoimmune disease that affects the oral mucosa, conjunctiva, genital mucosa, and skin. It is not as severe as pemphigus vulgaris. Lesions may heal with scarring. The name cicatricial pemphigoid refers to this healing with scarring. Autoantibodies and complement components have been identified at the basement membrane of the epithelium. Lesions occur as a result of cleavage of the epithelium from the underlying connective tissue in this area.

The most common site for mucous membrane pemphigoid lesions is the gingiva. The gingival lesions have been called desquamative gingivitis (Figure 3-31). The appearance ranges from erythema to ulceration and involves both the free and the attached gingiva. However, desquamative gingivitis is a clinical and descriptive term, and similar lesions can be seen in lichen planus and pemphigus vulgaris. In this disease as in pemphigus vulgaris, a Nikolsky’s sign can be produced on normal-appearing tissue by gentle friction. Bullae, erosions, and ulcers can also occur in other locations in the oral cavity. Bullae are thick walled and much less fragile than those of pemphigus vulgaris, and they may persist for 24 to 48 hours.

BULLOUS PEMPHIGOID

Some investigators have suggested that bullous and mucous membrane pemphigoid are variants of a single disease. However, differences exist between the two diseases that make this questionable. Eighty percent of patients with bullous pemphigoid are older than 60 years of age, and no sex predilection exists. Unlike mucous membrane pemphigoid, in bullous pemphigoid circulating autoantibodies are usually detectable; and unlike pemphigus vulgaris, the circulating autoantibodies do not correlate with disease activity. Oral lesions are less common in bullous pemphigoid than in mucous membrane pemphigoid, occurring in only about one third of patients. When they occur, the gingival lesions are very similar to those of mucous membrane pemphigoid, and other mucosal lesions are more extensive and painful. As in mucous membrane pemphigoid, the microscopic appearance of bullous pemphigoid shows a cleavage of the epithelium from the connective tissue at the basement membrane.

High doses of systemic corticosteroids and nonsteroidal antiinflammatory drugs are used in the management of bullous pemphigoid. The disease is chronic with periods of remission and is usually not life threatening.

BEHÇET SYNDROME

Behçet syndrome is a chronic, recurrent autoimmune disease consisting primarily of oral ulcers, genital ulcers, and ocular inflammation. No sex predilection exists, and the mean age of onset is 30 years. There is an increased prevalence of this syndrome in individuals from the Mediterranean region and Asia. Evidence for an immunologic pathogenesis includes the identification of antibodies to human mucosa in patients with Behçet syndrome and the association between Behçet syndrome HLA B5 and HLA B51.

The oral ulcers that occur in Behçet syndrome are very similar in appearance to aphthous ulcers (Figure 3-33). They are painful and recurrent. The lesions range in size from a few millimeters to several centimeters. The genital ulcers are usually small and located on the scrotum or base of the penis and the labia majora. The ocular lesions usually begin with photophobia and can develop into conjunctivitis and uveitis. The skin lesions show a papular pattern of pustules and are most common on the trunk and limbs.

Selected References