Lymphocytes. White blood cells primarily associated with acquired immune responses are termed lymphocytes (Figure 1). There are three major types: T cells, B cells and natural killer, or NK cells.

T lymphocytes, a type of lymphocyte collectively referred to as the cellular immune system, mature in the thymus and are classified into subsets by markers on their outer surfaces and function. Most mature into CD4⁺ or CD8⁺ cells, while a smaller percentage become NK cells. T cells react to other cells in the body harboring pathogens or containing their products. For example, after a virus infects a salivary gland cell, the infected cell develops surface molecules that bind specific CD8⁺ T cells. These T cells may destroy the infected cell. In other situations, T cells stimulate the cytotoxic activities of cells containing pathogens. Finally, helper T cells present antigens to B cells, stimulating antibody production.

The B lymphocytes proliferate and differentiate after they contact and receive signals from T cells or certain microbial antigens. When initially stimulated, B cells produce immunoglobulin M antibodies, but after a complex series of gene rearrangements, a mature B cell produces a specific antibody of only one isotype. A B cell that secretes antibody is a plasma cell. Antibodies are classified by their structure into one of five classes: IgG, IgA, IgM, IgD and IgE (presented in decreasing order of abundance). Most antibodies found in serum are IgG isotypes, with lesser amounts of IgA, IgM and IgE. Secretions such as saliva contain primarily IgA and IgM classes of antibodies. These antibody isotypes come from different plasma cell populations, even though they all bind the same antigen.

In contrast to T and B cells that react specifically to one antigen, NK cells are lymphocytes that kill tumor cells and virus-infected cells nonspecifically. In healthy people, they compose 5 to 10 percent of the total T-lymphocyte population.²⁹

	INNATE IMMUNITY AND ACQUIRED IMMUNITY

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The immune system is a complex network that protects an animal from a world of potential pathogens. Frequently, the network is divided into two systems: innate and acquired.^23,26–28 The body prevents initial infection with a variety of physical barriers, antimicrobial proteins and phagocytic cells. The common characteristic of these defense mechanisms is that they are not specific for one pathogen—that is, there are not specific neutrophils that bind only to Streptococcus pneumoniae. These responses are frequently termed nonspecific or innate. In the oral cavity, the mucosal barrier and the secretions covering it prevent many pathogens from colonizing the mouth. Saliva contains many innate antimicrobial proteins such as lactoferrin, lysozyme and histatins.^30–33

If a pathogen escapes the innate system, the specific or acquired immune response provides the next line of defense.^23,26–28 We are genetically enabled to produce immune cells that react to thousands of foreign substances. These cells respond to markers, termed "antigens," on the surface of the intruder. Notably, the immune system does not construct an antibody de novo after reading the structure of the antigen. Instead, immune cells are programmed through their genes to be "specific" for one antigen. These specific immune cells must locate, physically contact and bind the antigen. After binding, division within the immune cell is triggered, which increases the number of cells that react to that antigen. While the innate immune system reacts immediately to insults from the environment, an acquired immune response takes days to weeks to develop.

It is essential that an animal distinguish self from nonself—such as a foreign bacterium.^23,26–28 Early in life, the body eliminates most T and B cells specific for self-antigens. Other regulatory mechanisms within the immune system prevent immune cells from responding to stimulation by self-antigens. Autoimmune diseases such as systemic lupus erythematosus are possibly the result of failures in the immune system to regulate responses to self-antigens.

	MUCOSAL IMMUNITY

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After production in the bone marrow, immune cells migrate to secondary lymphoid organs throughout the body.^23,26–28 These organs differ in their function. Cells populating the spleen and lymph nodes react to antigens entering the body through the blood, skin or via the lymphatic system. Antibodies produced in these sites are primarily of the IgM and IgG isotypes and circulate in the blood. In contrast, groups of immune cells populating the lamina propria and submucosal areas of the gastrointestinal, salivary, respiratory and genitourinary systems belong to the mucosal immune system.³⁴ The B cells in these sites primarily produce IgA and IgM isotypes, as these antibodies can be secreted in forms that resist degrading enzymes in mucosal secretions.³⁵ Antibodies produced in the salivary glands are actively secreted into saliva, enter the oral cavity and bind many microorganisms. The antibody-microbe complexes can then be cleared and excreted, without internalization by phagocytic cells.

Cells and antibodies from the circulation, lymphoid organs and the mucosal system protect the oral cavity. Severe alterations in any of these branches of the immune system can result in oral disease.

	THE DEVELOPMENT OF SPECIFIC IMMUNE RESPONSES

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A specific immune response to an antigen usually involves three cells: APC, T cell and B cell.^23,26–28 Frequently, these cells contact one another in lymphoid tissues, such as the lymph nodes. The APCs engulf pathogens, present them on their surfaces and migrate to lymphoid tissues. Meanwhile, T cells are continually percolating through nodes and other lymphoid sites. When a T cell specific for the antigen on the APC surface contacts it, binding occurs that stimulates the T cell and triggers cell division. Some T cells become specific cytotoxic T cells that neutralize the antigen or eliminate cells harboring the antigen. Other T cells present the processed antigen to the specific B cell, which eventually will secrete antibody of a particular isotype. The antibodies attach to the specific pathogen, which lyses it or enhances its phagocytosis by macrophages or neutrophils. These methods of microbial elimination are enhanced additionally by another group of proteins known as the complement system.

Many other inflammatory processes occur in concert with these cellular interactions.^23,26,28 Activated APCs, T cells, B cells and other nonimmune cells secrete small soluble proteins called cytokines that alter the inflammatory reaction. These proteins help regulate the immune response. Initially, certain cytokines are secreted in great concentrations by immune cells to intensify a response. Later, other anti-inflammatory cytokines are secreted by immune cells, signaling the body that an immune reaction should end. Healing processes, such as scar formation, are stimulated by specific cytokines. The exact effect that a particular cytokine has on a T cell, for example, varies according to the presence of other cytokines, the tissues surrounding the cell and the cytokine concentration.

	PRIMARY IMMUNODEFICIENCIES AND ASSOCIATED ORAL MANIFESTATIONS

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Primary disorders of the immune system are caused when defective genes controlling development or maturation of immune cells are expressed.^{19,22,23,26,29} As stated earlier, studies of specific deficiencies and their clinical manifestations have been invaluable for determining the functions of the different arms of the immune system. Generally, these diseases are categorized according to the missing or dysfunctional cell type into deficiencies of T cells, B cells or phagocytes.

Those born with T-cell defects are susceptible to infections with fungi, viruses and parasites, since T cells are central in the response to all of these pathogens (Table 1).^{19,22,23,26,29} In addition, T cells are necessary for adequate B-cell responses, so patients lacking functional T cells from birth often have decreased antibody production. In general, an inadequate number of functional B cells results in insufficient antibody production, known as hypogammaglobulinemia.²⁹ Extracellular bacteria often infect the sinuses and lungs of patients with B-cell defects, demonstrating the importance of antibodies in preventing these types of infections (Table 1).^{19,22,23,26,29} A decrease in phagocyte function or number predisposes patients to systemic fungal and bacterial infections (Table 2).

View larger version (104K): [in this window] [in a new window]   Figure 2. Severe pseudomembranous candidiasis in a young man with Job’s syndrome.

	COMBINED T- AND B-CELL DEFECTS

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Severe combined immunodeficiency. Lymphocytes develop from a common hematopoietic stem cell in the bone marrow, but do not become fully functional until they pass through other lymphoid organs.^23,26,29 Thus, failures in production of lymphocyte precursors, their maturation processes or development of lymphoid organs can cause severe immune defects.

An inability to produce the common lymphoid progenitor cell results in a disease named severe combined immunodeficiency, or SCID. Affected children have inadequate numbers of T and B cells and acquire all types of infections.^19,29 Usually, patients with SCID have a similar clinical presentation by age 3 months, with opportunistic infections such as extensive candidal infections of the mouth and skin.²⁹ Children can quickly succumb to viruses of the herpes family, such as varicella, herpes simplex and cytomegalovirus. During the first 6 to 9 months of age, circulating maternal antibodies protect the child from many bacterial infections. After these degrade, bacterial infections are much more common.

The reported oral manifestations of SCID include oral candidiasis, herpes infections, recurrent oral ulcerations of the tongue and buccal mucosa, and severe necrotizing gingivostomatitis.^41,43

	T-CELL DEFECTS

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Defects in the major histocompatibility complex. Acquired immune responses develop with the recognition of molecules on immune cell surfaces. These molecules, termed the major histocompatibility complex, or MHC, are essential for the maturation of CD4⁺ T cells, presentation of foreign antigens to immune cells and distinguishing self from nonself.^23,26,29 If the genes encoding these essential molecules are mutated or deleted, antigen presentation is altered and the affected person is immunodeficient. These defects were originally called "bare lymphocyte syndrome" because the surface molecules were missing. It is now known that this syndrome includes several types of defects in the expression of MHC molecules.²⁹

MHC Class I molecules are expressed on many cells of the body. They bind and present antigenic peptides to CD8⁺ T cells, thus stimulating their cytotoxic processes. Patients with defects of these molecules are highly susceptible to recurrent bacterial and viral sinopulmonary infections.^29,44,45 Defects in the expression of MHC Class II molecules ultimately decrease the number of CD4⁺ T cells that need these molecules for maturation. Though B-cell numbers in these patients are normal, serum immunoglobulin levels are decreased because T cells do not present antigen adequately to B cells. Oral complications include infections with Candida albicans, herpes simplex viruses and other opportunistic pathogens.^41,46–49

Deficiency in CD40 ligand. Another surface molecule on T cells essential for interactions with B cells is CD40 ligand. Without this ligand, T cells cannot properly dock with B cells to stimulate further antibody isotype production. Consequently, B cells of these patients primarily produce IgM, and patients with this deficiency have hyper-IgM syndrome. Affected patients typically exhibit recurrent otitis media, respiratory infections and Pneumocystis carinii pneumonia when they are younger than two years of age.^19,29,37

Oral manifestations have not been examined extensively in these children. Given their combined T- and B-cell deficiencies, opportunistic infections, candidiasis and viral infections would be expected. Increased susceptibility to odontogenic infection and development of Ludwig’s angina can occur in these patients.^37,50

Decreases in T-cell numbers. After production in the bone marrow, progenitors of T lymphocytes migrate to the thymus for further selection and differentiation.^23,29 In DiGeorge syndrome, the thymus can be partially or completely absent due to an abnormal migration of the third and fourth branchial pouches.^24,51 Consequently, T cells fail to mature if there is no thymus, which severely decreases the T-cell population. The immunodeficiencies found in this patient group can range from slight to severe.¹⁹

Infectious complications of DiGeorge syndrome include oral candidiasis, herpetic infections, pneumonia, chronic rhinitis and susceptibility to all viral and opportunistic infections such as Pneumocystis carinii.^{19,26,29,52–54} In addition, other cardiac and craniofacial defects, including cleft palate, hypertelorism and malformed ears develop in this syndrome from disturbances in embryologic development. In some children, the parathyroids do not develop, which may contribute to enamel hypoplasia. After a common gene was identified in these patients, the name DiGeorge/velocardiofacial syndrome was suggested.²⁴

T-cells fail to mature if there is no thymus, which severely decreases the T-cell population.

NK-cell deficiency. Patients lacking one T-lymphocyte population, the NK cell, are very susceptible to herpetic infections.²⁶

	B-CELL DEFECTS

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Failures in the development or activation of B lymphocytes result in decreased circulating and secreted antibodies. In one such disease, X-linked agammaglobulinemia (Bruton’s disease), no circulating antibodies are found. These children often have respiratory and sinus infections from extracelluar, pyogenic or pus-forming bacteria, enteroviral infections and giardiasis, but they maintain some resistance to other types of pathogens. Treatment often includes infusion of gammaglobulin collected from large donor pools.^19,26,29 Oral complications of hypogammaglobulinemia include oral ulcerations and increased risk of sepsis from abscessed teeth.^19,41,55

Other B-cell defects result in an inability to produce one or more types of antibody. Sometimes these deficiencies are asymptomatic because other antibody isotypes sufficiently protect against infections.⁵⁶ Other patients will present with severe infections of the type seen in X-linked agammaglobulinemia. The most common immunodeficiency is selective IgA deficiency, occurring in one in 500 to one in 700 people.²² While some people are healthy, others have chronic respiratory infections.^19,36,56 Autoimmune diseases are more common in these patients.⁵⁷ Since secretory IgA is the major immunoglobulin of saliva, the oral health of this patient group has been studied in detail. There does not appear to be a well-established increase of dental caries or periodontal disease in this selective deficiency.^36,58–61

	NEUTROPHIL DEFECTS

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Recurrent infections with staphylococci, Pseudomonas, Candida and other fungi can occur if the phagocyte population is decreased or functionally unable to kill phagocytized pathogens. Recurrent pyogenic infections with extracellular bacteria classically occur in these deficiencies (Table 2).^19,26,62 While patients with T-cell or neutrophil deficiencies are susceptible to mucosal candidiasis, Candida also can cause septicemia in those with inadequate neutrophil function.

Serious periodontal changes have been documented in both quantitative and qualitative neutrophil diseases. More than 50 years ago, severe, rapidly progressing periodontitis was noted in patients with pronounced drug-induced agranulocytosis.⁶³ Other disorders characterized by low neutrophil counts are associated with severe periodontitis, such as cyclic neutropenia and prolonged neutropenias during cancer treatment.^{36,39,64–66}

There are several types of qualitative neutrophil deficiencies in which neutrophils lack sufficient migration or killing processes. Rapidly progressing periodontal disease is a feature of some variants, such as leukocyte adhesion deficiency or Chédiak-Higashi syndrome (Table 2). However, it is not found uniformly.

Chronic granulomatous disease. Although rare, chronic granulomatous disease, or CGD, is the most common inherited disorder of phagocyte function.^67–69 The incidence is reported to be six per million and has a 6:1 male predilection. Usually it is inherited in an X-linked mode (66 percent), but autosomal recessive transmission occurs. Patients with CGD have phagocytes that engulf particles normally, but fail to generate superoxide anion, hydrogen peroxide and hydroxyl radicals via nicotinamide-adenine dinucleotide phosphate, or NADPH, oxidase. The result is ineffective intracellular killing of catalase-positive bacteria and fungi. A mutation in any of the four genes for the structural units of NADPH results in CGD. CGD patients have normal B- and T-cell functions, serum IgG levels and neutrophil chemotaxis.⁷⁰

When infected, a patient with CGD will have fever, leukocytosis and a localized inflammatory response. However, the inflammatory response does not resolve, and granulomas form in a number of tissues such as the liver. Skin, lungs and mucous membranes of the oral and perianal regions are involved most often, since these sites are portals of entry for many microorganisms. Catalase-positive microorganisms such as Staphylococcus aureus and species of Serratia, Candida and Pseudomonas cause most persistent infections. Prophylaxis with trimethoprimsulfamethoxazole is routine for these patients,⁷¹ and recombinant interferon gamma is used to reduce the frequency and severity of infections.^72,73 Other treatments include bone marrow transplantation and allogenic granulocyte transfusions.⁷⁴

Oral lesions and ulcerations have been reported consistently in both patients with CGD and the heterozygous female carriers. The ulcers are similar clinically to aphthae, recur frequently at multiple sites and last seven to 10 days. They heal without scarring.^75,76 Unlike aphthae, ulcers in CGD often involve the attached gingiva (Figure 3). Intraoral ulcerations consistent with discoid lupus lesions have been reported in carriers of the CGD defect.^77–79 Oral candidiasis also occurs and is treated aggressively. Though gingivitis is reported,^69,75 there appears to be no greater risk of destructive periodontal disease in these patients.⁷⁶ This is possibly because other pathways in CGD neutrophils kill periodontal pathogens.³⁶

View larger version (80K): [in this window] [in a new window]   Figure 3. Ulceration on the attached gingiva of a child with chronic granulomatous disease. The ulcer healed without scarring.

Patients with LAD have recurrent life-threatening bacterial infections, with impaired pus formation and wound healing.⁶² Similar to CGD, the primary sites of involvement are the skin, mucous membrane of the mouth and the GI tract. Recurrent oral ulcerations are a common feature, but the ulcers heal slowly with scarring (Figure 4). Rapidly progressing, juvenile periodontal disease is prevalent, despite aggressive preventive therapy (Figure 5).^66,81,82 Many young adults with LAD are edentulous. Linear gingival erythema inconsistent with local factors also occurs (Figure 6). Oral candidiasis occurs frequently and must be treated aggressively.

View larger version (82K): [in this window] [in a new window]   Figure 4. Mucosal ulceration that healed with scarring on the lower lip of this child who has leukocyte adhesion deficiency.

View larger version (82K): [in this window] [in a new window]   Figure 5. Rapidly progressing juvenile periodontal disease in a 5-year-old girl who has leukocyte adhesion deficiency. All primary teeth exhibited more than 50 percent bone loss at the time of examination.

View larger version (85K): [in this window] [in a new window]   Figure 6. Marked linear gingival erythema in a child with leukocyte adhesion deficiency.

Nonimmunological abnormalities⁸⁵ include facial, skeletal and connective-tissue disorders. These patients have characteristic facial features with broad nasal bridges, prominent foreheads and rough skin texture. Recurrent bone fractures, hyperextensible joints, scoliosis and craniosynostosis also occur in Hyper IgE syndrome. Recently, we reported that 72 percent of patients with Hyper IgE syndrome who were studied at the National Institutes of Health had failures or delays in the resorption of primary teeth.⁸⁴ This interferes with the eruption of permanent successors, and extraction of the retained primary teeth promotes the normal process of tooth eruption. The causes of delayed or absent resorptive processes remain unknown, but they may involve cytokine activation of osteoclasts, macrophages or both.

	TREATING PRIMARY IMMUNODEFICIENCIES

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Many primary immunodeficiencies are fatal in the first or second decade of life. Some children can be made immunocompetent with bone marrow transplantation, or BMT, sparing them a life of continuous infections and hospitalizations.^74,86–88 The complications of BMT and the patient’s ability to withstand further immunosuppression, however, must be considered before this therapy is considered. Without BMT, patients are treated by early and aggressive infection therapy and maintenance with prophylactic antibiotic regimens.^{19,47,71,89,90}

The dental team caring for immunodeficient patients must safeguard the health of the oral cavity. Aggressive preventive dental care including oral hygiene instructions, nutritional counseling and fluoride gel applications can mintain oral health and circumvent involved dental procedures. It is important to maintain a current medical history that contains information about recent hospitalizations, infections and medications. Also, a complete blood cell count with white cell differential and platelet count is needed before complicated dental procedures are performed. It is essential that the dentist or hygienist consult frequently with the physicians managing the immunodeficient patient. Additional antibiotic prophylaxis often is warranted before invasive dental treatment since bacteremias from dental procedures could be fatal to these patients. Since many patients are maintained on continuous antibiotic therapy that permits the outgrowth of penicillin-resistant oral organisms, prophylaxis with another class of antibiotics may be necessary. Consultation with infectious disease specialists can help dental clinicians choose alternative antibiotics.

The causes of delayed or absent resorptive processes remain unknown, but they may involve cytokine activation of osteoclasts, macrophages or both.

Appropriate diagnosis and treatment of oral soft-tissue infections also are necessary for this special population. Empirical treatments should be avoided, if possible. Frequently, viral, fungal and bacterial cultures are needed to establish the causative agent of oral ulcerations and lesions. For example, different concentrations of the antiviral agent acyclovir are needed to effectively treat herpes zoster and herpes simplex. Herpetic infections of oral soft tissues in an immunocompromised host can resemble major aphthous stomatitis. Therefore, cultures are needed to determine the best treatments.

Immunologists who evaluate children who have recurrent, persistent infections start by taking a good health history. Children with normal immune functions have an average of six to eight respiratory infections per year for the first 10 years of life, and up to six cases of otitis and two cases of gastroenteritis per year for the first two to three years.¹⁹ They may have more if they stay in child care centers or have older siblings.

Children with impaired defenses have more severe and persistent infections and fail to thrive. Oral complications that might signal abnormal immune functions in children include prepubertal periodontitis,⁶⁰ persistent candidiasis and herpetic infections, as well as prolonged or unusual dental infections. These oral infections may indicate an underlying immune problem and should prompt the dentist to contact the patient’s physician. This information will help the physician decide whether further referrals are necessary.