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CHANGING PATTERNS OF DISEASE AND MUCOSAL IMMUNITY
OBSERVATIONS
HAROLD C. SLAVKIN, D.D.S.
CHANGING PATTERNS OF DISEASE
AND MUCOSAL IMMUNITY There is a renewed interest
in—and greater clinical importance being placed on—the associations between oral infection and systemic diseases and the oral complications experienced by medically and immunologically compromised patients.1,2 The principles of immunology and infectious disease have become enormously important to all health professionals.3,4 Increasingly, the patterns of disease and disorders and the management of the growing subpopulation of compromised patients requires a renewal of our knowledge in immunology and our related clinical judgments and skills.5 Critical to our management of these complex diseases and disorders in the growing mature American subpopulation is an understanding of mucosal immunity. THE PRINCIPLES OF IMMUNITY
Immunity is a state of heightened resistance or accelerated reactivity toward microbes such as viruses, bacteria and yeast; transplants; or any other non-
self substance or molecule that gains access to the body. Immunity is actively acquired when it has been aroused by an exposure to an immunityprovoking stimulus: a foreign antigen, an allergen or an autoantigen. This is how most of us acquire immunity to measles and other infectious diseases, and this is the kind of immunity often generated by a vaccine. Immunity is passively acquired when it arises in a secondhand fashion, such as a newborn infant’s receiving one or more maternal antibodies transferred in the first milk, or colostrum, during initial breast-feeding. From fetal life through senescence, the oral cavity is the portal of entry for respiration, food, drink and associated external environmental antigens and allergens associated with microbes, toxins and various gases from the biosphere. The mouth is part of the mucosal linings of the body and structurally shows similarities with the same tissues in the gut, lung, conjunctiva, the oropharynx and certain other organs. The oral cavity is
bathed by fluid containing approximately 100 million bacteria per milliliter. Hundreds of microbial species constitute the oral microbial ecosystem. The oral mucosal epithelial surface is the first site of contact for the 1,000-plus pounds of food and the additional fluids consumed per person per year. In addition, the human oral mucosal lining is challenged every day with foods and beverages that are either hot or cold, sugared or sugarless, caffeinated or noncaffeinated, alcoholic or nonalcoholic—as well as with tobacco and other substances that affect the body. Oral health depends on the integrity of the oral mucosa for prevention of the penetration of microbes and macromolecules that might be infectious, allergenic or antigenic. The mucosa is protected by both specific and nonspecific immunological mechanisms. The former include mucins, lysozyme, lactoferrin, lactoperoxidase and various antimicrobial peptides.6 The latter include immune cells as well as immunoglobulins, or Igs,
JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
735
SLAVKIN particularly secretory immunoglobulin A, or sIgA.7-9 These are some of the tools of mucosal immunology. The human immune network consists of a system with cells capable of reacting with specific antigens circulating in the vascular or lymphatic system, the peripheral immune system and a system enclosed by a mucosal surface, the mucosal immune system. In the human adult, the large mucosal surface includes the oral cavity and the mucosal linings of the hollow organs and passages of the body: the respiratory, urinary and genital tracts. The gastrointestinal, or GI, tract, for example, is larger than 300 square meters. The entire mucosal surface is nearly 400 m2, or 200 times larger than the body’s total skin area.6 Unlike the skin covering the body, the mucosa of the gut and respiratory systems must protect and defend against antigens in addition to absorbing substances that are essential for life. When a foreign antigen enters the body, it can react with the mucosal surface. In the GI system (in Peyer’s patches, for example), a unique cell termed a microfolding, or an M, cell selectively binds foreign antigens and then presents the antigen to thymus-derived lymphocyte cells, or T cells, that function as antigen-presenting cells.10 These stimulated effector cells then travel through blood and/or lymph fluids to mucosal sites where bone marrow–derived lymphocytes, or B cells, are stimulated to produce Igs (primarily sIgA) that help coat the mucosal surface of the gut and destroy the foreign antigen. The mucosal immune system can produce mucosal and serum 736
antibody responses and T cell–mediated immunity that is commonly termed “mucosally induced tolerance.”6 The B cells are produced in the bone marrow and liver. These fascinating B cells can be stimulated by T cells to produce one of the five isotypes of Ig: IgA, IgG, IgE, IgD and IgM.6 IgA is the major mucosal immune system isotype made by the B cells. Another critical component of the mucosal system is the T cells. The T cells
The eventual resolution of the foreign antigen challenge to the host mucosal immune system and the resolution of the host inflammatory response are the critical clinical issues. are identified according to markers or molecules borne on their outer cell surfaces. Most mature differentiated T cells are CD4+ and CD8+ cells, whereas a smaller percentage of these cells become natural killer cells.7 Collectively, T cells are the cellular immune system. T cells react to other cells throughout the body that might harbor microbes or pathogenic molecules. For example, after a virus infects a secretory epithelial cell, the infected epithelial cell expresses cell-surface molecules that bind specific CD8+ T cells, which in turn destroy the infected epithelial cell. In other related immune processes, T cells stimulate the killing pathways of phagocytic cells con-
taining microbes or pathogenic molecules. In addition, T cells can also serve as helper cells by providing antigen to B cells and thereby stimulating B cells to synthesize and secrete Igs. The eventual resolution of the foreign antigen challenge to the host mucosal immune system and the resolution of the host inflammatory response are the critical clinical issues. THE ORAL MUCOSAL IMMUNE SYSTEM
The architecture of the mucosal immune system is intriguing. Mucosal sites include the tonsils, adenoids and nasopharyngeal-associated lymphoreticular tissue, or NALT, found in the oral cavity. NALT serves to provide inductive sites for the upper respiratory tract and the naso-oral cavity. Mucosal inductive sites of the GI tract (Peyer’s patches and the appendix) and solitary lymph nodes collectively compose the gut-associated lymphoreticular tissue, or GALT, system. Both NALT and GALT are inductive regions where foreign antigens derived from viruses, bacteria, yeast and other molecules are encountered. The foreign antigen is then transported to an effector site. In the salivary and other exocrine glands, the cells are stimulated to produce Igs of the IgA isotype. Whole saliva from the major and minor salivary glands is produced at 750 to 1,000 mL per day (including a small contribution from the crevicular fluid).4 The concentrations of IgA, IgG and IgM isotypes found in whole saliva are 200 milligrams, 2 mg and 1 mg per 1,000 mL, respectively.4 These antibodies are the dominant isotypes found in saliva, tears, breast milk and
JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
SLAVKIN colostrum, and the GI and genitourinary tracts. Innate and adaptive immunology have served humans well over the last 50,000 years. One selective advantage of the human immune system is the organization of secondary lymphoid tissues, primarily in the upper respiratory and GI tracts. This organization facilitates antigen uptake, processing and presentation for induction of mucosal immune responses. The integration of these tissues, found in NALT and GALT as part of the mucosal immune system, is becoming better understood. The human tonsils are the secondary lymphoid tissues most accessible for the study of NALT. Although the palatine and nasopharyngeal tonsils, or adenoids, are covered with squamous epithelium and are not usually appreciated as mucosal tissue, the palatine tonsils contain deep crypts that may contain M cells, which can present antigens, and the tonsils are composed of germinal centers with 50 percent B cells capable of producing IgG and IgA isotypes.4 The tonsils exhibit not only characteristics of mucosal inductive sites but also the characteristics of effector sites, because they have high numbers of plasma cells. Further research with tonsillar cells is needed to define their functions in immunity, and to define their particular roles in mucosal immunity. PUTTING THE MUCOSAL IMMUNE SYSTEM TO WORK
Use of the mucosal immune system for establishment of a vaccine program for a number of diseases has been pursued. The
successful immunization against oral caries using antigens from Streptococcus mutans was first reported using monkeys in 1969.4,11 Salivary IgA antibodies in humans may be induced by ingestion of capsules filled with S. mutans organisms.4 However, repeated immunization may be required, as salivary antibody is short-lived. Antigens that are swallowed as a capsule, inhaled or used as a wash in the oral cavity have been tested for their ability to elicit the production of antibod-
Use of the mucosal immune system for establishment of a vaccine program for a number of diseases has been pursued. ies, many with promising results.4 Mucosal immunity is significantly involved in the protection and defense against and the surveillance of microbial infections, from the earliest steps of infection with human immunodeficiency virus to the binding of a cell surface adhesion of S. mutans.4,12 The use of immunological tolerance in treatment of autoimmune diseases and allergy is another area that is being investigated using the mucosal immune system. Mucosal immunization (oral or nasal administration of antigen) can induce antigen-specific IgA and cytotoxic T-cell responses in distant mucosal-specific tissues. Induction of mucosal immune responses often results in both cell-mediated and humoral responses in the systemic lymphoid compartment. This is a rich area for the future develop-
FOR FURTHER INFORMATION National Institute of Allergy and Infectious Diseases Office of Communications National Institutes of Health Bethesda, Md. 20892 1-301-496-5717 http://www.niaid.nih.gov National Institute of Dental and Craniofacial Research Information Office National Institutes of Health Bethesda, Md. 20892 1-301-496-4261 http://www.nidr.nih.gov
ment of vaccines for oral infections. CONCLUSION
In summary, the clinical opportunities in dentistry are rapidly changing. One driver for these changes is the changing patterns of disease and the changing demographics of the United States.13,14 More people living longer and changing expectations of quality of life require each of us to effectively integrate immunology and our knowledge of infectious diseases and disorders into everyday clinical dental education, dental science and dental practice. Take some time and consider the thousands of people you serve in clinical operatories in dental or medical offices, schools or hospitals. Recall patients in your clinical experience who had diseases or disorders with oral manifestations such as delayed resorption of primary teeth, candidiasis, herpes infections, mucosal ulceration, possible septicemia resulting from tooth infections, early childhood and adult periodontitis, excessive gingival bleeding or a variety of oral mucosal lesions. In each clinical
JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
737
SLAVKIN encounter, we can learn more about each patient through our considerations and asDr. Slavkin is direcsessments of tor, National Institute his or her denof Dental and Craniofacial tal and medical Research, 31 Center histories; nuDrive, MSC 2290, Building 31, Room tritional sta2C39, Bethesda, Md. tus; use or 20892-2290. Address abuse of subreprint requests to Dr. Slavkin. stances such as alcohol, tobacco and caffeine; and individual and family behavioral issues. In such a comprehensive assessment, we then consider and analyze the patient’s immune system in terms of T- and B-cell immunodeficiencies or neutrophil defi-
738
ciencies.15,16 As health professionals, we have an important role in ensuring our patients’ health—not only in the oral cavity, but in the entire body. ■ The views expressed are those of the author and do not necessarily reflect the opinions or official policies of the American Dental Association. 1. Primer on allergic and immunologic diseases. JAMA 1997;278(special issue):18032030. 2. Kumate J. Infectious diseases in the 21st century. Arch Med Res 1997;28:155-61. 3. Fauci AS. Braunwald E, Isselbacher KJ, et al., eds. Harrison’s principles of internal medicine. 14th ed. New York: McGraw-Hill; 1997. 4. Ogra PL, Mestecky J, Lamm MF, et al., eds. Mucosal immunology. 2nd ed. San Diego: Academic Press; 1999. 5. Genco RJ. Current view of risk factors for periodontal diseases. J Periodontol 1996;67:1041-9. 6. McGhee JR, Kiyono H. In: Paul W, ed. Fundamental immunology. 4th ed. Philadelphia: Lippincott-Raven; 1999. 7. McGee DW, McMurray DN. The effect of
protein malnutrition on the IgA immune response in mice. Immunology 1988;63:25-9. 8. Fleischer TA. Immune function. Pediatr Rev 1997;18:351-6. 9. Engstrom GN, Engstrom PE, Hammarstrom L, Smith CI. Oral conditions in individuals with selective immunoglobulin A deficiency and common variable immunodeficiency. J Periodontol 1992;63:984-9. 10. Waldman TA. Immunodeficiency diseases: primary and acquired. In: Sampter M, Talmage DW, Austen KF, et al., eds. Immunological diseases. 4th ed. Boston: Little Brown; 1988:411-65. 11. Brandtzaeg P. Humoral immune response patterns of human mucosae: induction and relation to bacterial respiratory tract infections. J Infect Dis 1992;165(suppl 1):S16776. 12. Huston DP. The biology of the immune system. JAMA 1997;278:1804-14. 13. Slavkin HC. Infection and immunity. JADA 1996;127:1792-6. 14. Slavkin HC. Protecting the mouth against microbial infections. JADA 1998;129:1025-30. 15. Tolo K. Periodontal disease mechanisms in immunocompromised patients. J Clin Periodontol 1991;18:431-5. 16. Scully C, Porter SR. Orofacial manifestations in primary immunodeficiencies: common variable immunodeficiencies. J Oral Pathol Med 1993;22:157-8.
JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
HAROLD C. SLAVKIN, D.D.S.
CHANGING PATTERNS OF DISEASE
AND MUCOSAL IMMUNITY There is a renewed interest
in—and greater clinical importance being placed on—the associations between oral infection and systemic diseases and the oral complications experienced by medically and immunologically compromised patients.1,2 The principles of immunology and infectious disease have become enormously important to all health professionals.3,4 Increasingly, the patterns of disease and disorders and the management of the growing subpopulation of compromised patients requires a renewal of our knowledge in immunology and our related clinical judgments and skills.5 Critical to our management of these complex diseases and disorders in the growing mature American subpopulation is an understanding of mucosal immunity. THE PRINCIPLES OF IMMUNITY
Immunity is a state of heightened resistance or accelerated reactivity toward microbes such as viruses, bacteria and yeast; transplants; or any other non-
self substance or molecule that gains access to the body. Immunity is actively acquired when it has been aroused by an exposure to an immunityprovoking stimulus: a foreign antigen, an allergen or an autoantigen. This is how most of us acquire immunity to measles and other infectious diseases, and this is the kind of immunity often generated by a vaccine. Immunity is passively acquired when it arises in a secondhand fashion, such as a newborn infant’s receiving one or more maternal antibodies transferred in the first milk, or colostrum, during initial breast-feeding. From fetal life through senescence, the oral cavity is the portal of entry for respiration, food, drink and associated external environmental antigens and allergens associated with microbes, toxins and various gases from the biosphere. The mouth is part of the mucosal linings of the body and structurally shows similarities with the same tissues in the gut, lung, conjunctiva, the oropharynx and certain other organs. The oral cavity is
bathed by fluid containing approximately 100 million bacteria per milliliter. Hundreds of microbial species constitute the oral microbial ecosystem. The oral mucosal epithelial surface is the first site of contact for the 1,000-plus pounds of food and the additional fluids consumed per person per year. In addition, the human oral mucosal lining is challenged every day with foods and beverages that are either hot or cold, sugared or sugarless, caffeinated or noncaffeinated, alcoholic or nonalcoholic—as well as with tobacco and other substances that affect the body. Oral health depends on the integrity of the oral mucosa for prevention of the penetration of microbes and macromolecules that might be infectious, allergenic or antigenic. The mucosa is protected by both specific and nonspecific immunological mechanisms. The former include mucins, lysozyme, lactoferrin, lactoperoxidase and various antimicrobial peptides.6 The latter include immune cells as well as immunoglobulins, or Igs,
JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
735
SLAVKIN particularly secretory immunoglobulin A, or sIgA.7-9 These are some of the tools of mucosal immunology. The human immune network consists of a system with cells capable of reacting with specific antigens circulating in the vascular or lymphatic system, the peripheral immune system and a system enclosed by a mucosal surface, the mucosal immune system. In the human adult, the large mucosal surface includes the oral cavity and the mucosal linings of the hollow organs and passages of the body: the respiratory, urinary and genital tracts. The gastrointestinal, or GI, tract, for example, is larger than 300 square meters. The entire mucosal surface is nearly 400 m2, or 200 times larger than the body’s total skin area.6 Unlike the skin covering the body, the mucosa of the gut and respiratory systems must protect and defend against antigens in addition to absorbing substances that are essential for life. When a foreign antigen enters the body, it can react with the mucosal surface. In the GI system (in Peyer’s patches, for example), a unique cell termed a microfolding, or an M, cell selectively binds foreign antigens and then presents the antigen to thymus-derived lymphocyte cells, or T cells, that function as antigen-presenting cells.10 These stimulated effector cells then travel through blood and/or lymph fluids to mucosal sites where bone marrow–derived lymphocytes, or B cells, are stimulated to produce Igs (primarily sIgA) that help coat the mucosal surface of the gut and destroy the foreign antigen. The mucosal immune system can produce mucosal and serum 736
antibody responses and T cell–mediated immunity that is commonly termed “mucosally induced tolerance.”6 The B cells are produced in the bone marrow and liver. These fascinating B cells can be stimulated by T cells to produce one of the five isotypes of Ig: IgA, IgG, IgE, IgD and IgM.6 IgA is the major mucosal immune system isotype made by the B cells. Another critical component of the mucosal system is the T cells. The T cells
The eventual resolution of the foreign antigen challenge to the host mucosal immune system and the resolution of the host inflammatory response are the critical clinical issues. are identified according to markers or molecules borne on their outer cell surfaces. Most mature differentiated T cells are CD4+ and CD8+ cells, whereas a smaller percentage of these cells become natural killer cells.7 Collectively, T cells are the cellular immune system. T cells react to other cells throughout the body that might harbor microbes or pathogenic molecules. For example, after a virus infects a secretory epithelial cell, the infected epithelial cell expresses cell-surface molecules that bind specific CD8+ T cells, which in turn destroy the infected epithelial cell. In other related immune processes, T cells stimulate the killing pathways of phagocytic cells con-
taining microbes or pathogenic molecules. In addition, T cells can also serve as helper cells by providing antigen to B cells and thereby stimulating B cells to synthesize and secrete Igs. The eventual resolution of the foreign antigen challenge to the host mucosal immune system and the resolution of the host inflammatory response are the critical clinical issues. THE ORAL MUCOSAL IMMUNE SYSTEM
The architecture of the mucosal immune system is intriguing. Mucosal sites include the tonsils, adenoids and nasopharyngeal-associated lymphoreticular tissue, or NALT, found in the oral cavity. NALT serves to provide inductive sites for the upper respiratory tract and the naso-oral cavity. Mucosal inductive sites of the GI tract (Peyer’s patches and the appendix) and solitary lymph nodes collectively compose the gut-associated lymphoreticular tissue, or GALT, system. Both NALT and GALT are inductive regions where foreign antigens derived from viruses, bacteria, yeast and other molecules are encountered. The foreign antigen is then transported to an effector site. In the salivary and other exocrine glands, the cells are stimulated to produce Igs of the IgA isotype. Whole saliva from the major and minor salivary glands is produced at 750 to 1,000 mL per day (including a small contribution from the crevicular fluid).4 The concentrations of IgA, IgG and IgM isotypes found in whole saliva are 200 milligrams, 2 mg and 1 mg per 1,000 mL, respectively.4 These antibodies are the dominant isotypes found in saliva, tears, breast milk and
JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
SLAVKIN colostrum, and the GI and genitourinary tracts. Innate and adaptive immunology have served humans well over the last 50,000 years. One selective advantage of the human immune system is the organization of secondary lymphoid tissues, primarily in the upper respiratory and GI tracts. This organization facilitates antigen uptake, processing and presentation for induction of mucosal immune responses. The integration of these tissues, found in NALT and GALT as part of the mucosal immune system, is becoming better understood. The human tonsils are the secondary lymphoid tissues most accessible for the study of NALT. Although the palatine and nasopharyngeal tonsils, or adenoids, are covered with squamous epithelium and are not usually appreciated as mucosal tissue, the palatine tonsils contain deep crypts that may contain M cells, which can present antigens, and the tonsils are composed of germinal centers with 50 percent B cells capable of producing IgG and IgA isotypes.4 The tonsils exhibit not only characteristics of mucosal inductive sites but also the characteristics of effector sites, because they have high numbers of plasma cells. Further research with tonsillar cells is needed to define their functions in immunity, and to define their particular roles in mucosal immunity. PUTTING THE MUCOSAL IMMUNE SYSTEM TO WORK
Use of the mucosal immune system for establishment of a vaccine program for a number of diseases has been pursued. The
successful immunization against oral caries using antigens from Streptococcus mutans was first reported using monkeys in 1969.4,11 Salivary IgA antibodies in humans may be induced by ingestion of capsules filled with S. mutans organisms.4 However, repeated immunization may be required, as salivary antibody is short-lived. Antigens that are swallowed as a capsule, inhaled or used as a wash in the oral cavity have been tested for their ability to elicit the production of antibod-
Use of the mucosal immune system for establishment of a vaccine program for a number of diseases has been pursued. ies, many with promising results.4 Mucosal immunity is significantly involved in the protection and defense against and the surveillance of microbial infections, from the earliest steps of infection with human immunodeficiency virus to the binding of a cell surface adhesion of S. mutans.4,12 The use of immunological tolerance in treatment of autoimmune diseases and allergy is another area that is being investigated using the mucosal immune system. Mucosal immunization (oral or nasal administration of antigen) can induce antigen-specific IgA and cytotoxic T-cell responses in distant mucosal-specific tissues. Induction of mucosal immune responses often results in both cell-mediated and humoral responses in the systemic lymphoid compartment. This is a rich area for the future develop-
FOR FURTHER INFORMATION National Institute of Allergy and Infectious Diseases Office of Communications National Institutes of Health Bethesda, Md. 20892 1-301-496-5717 http://www.niaid.nih.gov National Institute of Dental and Craniofacial Research Information Office National Institutes of Health Bethesda, Md. 20892 1-301-496-4261 http://www.nidr.nih.gov
ment of vaccines for oral infections. CONCLUSION
In summary, the clinical opportunities in dentistry are rapidly changing. One driver for these changes is the changing patterns of disease and the changing demographics of the United States.13,14 More people living longer and changing expectations of quality of life require each of us to effectively integrate immunology and our knowledge of infectious diseases and disorders into everyday clinical dental education, dental science and dental practice. Take some time and consider the thousands of people you serve in clinical operatories in dental or medical offices, schools or hospitals. Recall patients in your clinical experience who had diseases or disorders with oral manifestations such as delayed resorption of primary teeth, candidiasis, herpes infections, mucosal ulceration, possible septicemia resulting from tooth infections, early childhood and adult periodontitis, excessive gingival bleeding or a variety of oral mucosal lesions. In each clinical
JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.
737
SLAVKIN encounter, we can learn more about each patient through our considerations and asDr. Slavkin is direcsessments of tor, National Institute his or her denof Dental and Craniofacial tal and medical Research, 31 Center histories; nuDrive, MSC 2290, Building 31, Room tritional sta2C39, Bethesda, Md. tus; use or 20892-2290. Address abuse of subreprint requests to Dr. Slavkin. stances such as alcohol, tobacco and caffeine; and individual and family behavioral issues. In such a comprehensive assessment, we then consider and analyze the patient’s immune system in terms of T- and B-cell immunodeficiencies or neutrophil defi-
738
ciencies.15,16 As health professionals, we have an important role in ensuring our patients’ health—not only in the oral cavity, but in the entire body. ■ The views expressed are those of the author and do not necessarily reflect the opinions or official policies of the American Dental Association. 1. Primer on allergic and immunologic diseases. JAMA 1997;278(special issue):18032030. 2. Kumate J. Infectious diseases in the 21st century. Arch Med Res 1997;28:155-61. 3. Fauci AS. Braunwald E, Isselbacher KJ, et al., eds. Harrison’s principles of internal medicine. 14th ed. New York: McGraw-Hill; 1997. 4. Ogra PL, Mestecky J, Lamm MF, et al., eds. Mucosal immunology. 2nd ed. San Diego: Academic Press; 1999. 5. Genco RJ. Current view of risk factors for periodontal diseases. J Periodontol 1996;67:1041-9. 6. McGhee JR, Kiyono H. In: Paul W, ed. Fundamental immunology. 4th ed. Philadelphia: Lippincott-Raven; 1999. 7. McGee DW, McMurray DN. The effect of
protein malnutrition on the IgA immune response in mice. Immunology 1988;63:25-9. 8. Fleischer TA. Immune function. Pediatr Rev 1997;18:351-6. 9. Engstrom GN, Engstrom PE, Hammarstrom L, Smith CI. Oral conditions in individuals with selective immunoglobulin A deficiency and common variable immunodeficiency. J Periodontol 1992;63:984-9. 10. Waldman TA. Immunodeficiency diseases: primary and acquired. In: Sampter M, Talmage DW, Austen KF, et al., eds. Immunological diseases. 4th ed. Boston: Little Brown; 1988:411-65. 11. Brandtzaeg P. Humoral immune response patterns of human mucosae: induction and relation to bacterial respiratory tract infections. J Infect Dis 1992;165(suppl 1):S16776. 12. Huston DP. The biology of the immune system. JAMA 1997;278:1804-14. 13. Slavkin HC. Infection and immunity. JADA 1996;127:1792-6. 14. Slavkin HC. Protecting the mouth against microbial infections. JADA 1998;129:1025-30. 15. Tolo K. Periodontal disease mechanisms in immunocompromised patients. J Clin Periodontol 1991;18:431-5. 16. Scully C, Porter SR. Orofacial manifestations in primary immunodeficiencies: common variable immunodeficiencies. J Oral Pathol Med 1993;22:157-8.
JADA, Vol. 130, May 1999 Copyright ©1998-2001 American Dental Association. All rights reserved.