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Contact allergy: Competitive roles of effector and suppressor cells
Clinical review Contact allergy: Competitive roles of effector and suppressor cells Rudolf L. Baer, M.D.
New York, NY First exposure to a contact allergen sets in motion two competing mechanisms, one of which leads to specific allergic hypersensitivity, mediated by effector cells, and the other to specific immunologic tolerance, mediated by suppressor cells. The immunologic stance resulting from exposure to contact allergens depends on the balance between effector and suppressor cell effects. First exposure by skin contact generally favors the induction of specific allergic contact hypersensitivity, while first exposure by parenteral injection, ingestion, and perhaps also by insertion into noncutaneous body structures generally favors a state of specific immunologic tolerance ("unresponsiveness"). However, allergen encountered by contact which is not taken up by epidermal antigen-presenting cells may also have tolerogenic effects, while allergen encountered by injection, ingestion, or insertion may reach the epidermal antigen-presenting cell system via the bloodstream and may then have sensitizing effects. (J AM ACAD DE~tV~TOL 6:921-925, 1982.)
Dermatologists in clinical practice frequently e n c o u n t e r patients suffering from allergic ecz e m a t o u s contact dermatitis, the disease resulti n g from hypersensitivity reactions due to expos u r e to contact allergens. These hypersensitivity r e a c t i o n s represent only one end of a spectrum of a v a r i e t y of states of reactivity resulting from expos u r e to contact allergens, the other end being a s t a t e of relative or absolute tolerance ("unresponsiveness"). Hypersensitivity and tolerance are the results of t w o competing phases of the immunologic res p o n s e set in motion upon initial exposure to cont a c t allergens. These two phases are modulated by
F r o m ~he Department of Dermatology, New York University School o f Medicine. Supported by NIH-Asthma and Allergic Disease Center for Immunodermatology Grant No. AI 17365. Presented at the meeting of the American Academy of Dermatology. session on Contact Dermatitis, Dec. 6, 1980. O 1 90-9622/82/050921 + 05500.50/0 © 1982 Am Acad Dermatol
different subsets of T lymphocytes, namely, effector cells, which are responsible for allergic hypersensitivity, and suppressor cells, which are responsible for specific immunologic tolerance. It appears that two distinct sets of suppressor cells are involved in contact allergy. One of these affects the induction phase, while the other affects the expression of contact hypersensitivity by effectot cells. 1 It should be noted that although other mechanisms, such as clone deletion, enhancing antibodies, and antigen-antibody complexes, also lead to tolerance, suppressor cells appear to be the major or exclusive mechanism in tolerance to contact allergens. Fig. 1 illustrates the competition between effector ceils and suppressor cells in determining the state of the skin's reactivity to any particular contact allergen. Clinical hypersensitivity of varying degrees may result when effector cells predominate. On the other hand, no clinical reaction occurs, i.e., a state of clinical tolerance will exist, 921
Journal of the American Academy of Dermatology
Baer
922
no dlnicat reaction
hypersensitivity reaction 4+3+
2+
specific immunologic un responsiveness
1 +
t ÷ ÷ ÷ ÷.--,~,~. ÷÷ ÷÷
÷
÷.l.
÷
~÷
÷÷
÷ ÷
5: L>÷
÷
o"
• .° ,
÷
,,
Fig. 1. Competition between effeetor and suppressor cells determines the state of the skin's reactivity to a specific contact allergen. when the effects of suppressor and effector cells are in balance or when the suppressor cells predominate. [t should be emphasized that it is the immunologic events which ensue at the time of first exposure to a contact allergen which have a major impact on the outcome of this competition between effector and suppressor cells. Knowledge of the elementary features of the mechanism mediating allergic contact sensitization makes it possible to understand the factors involved in the competition between effector and suppressor cells. It is well known that under normal circumstances only small molecules (<500 daltons) in the environment enter undamaged epidermis via the horny layer and skin appendages. In order for these small molecules to become antigenic, they must combine with larger "carrier" molecules, usually proteins. According to present concepts, this occurs principally in the prickle cell layer, where contact allergens can combine with surface components of antigen-presenting cells. The surface components involved in this process have not yet been identified, but it has been suggested that it may be the immune response antigens (Ia antigens in mice and HLA-DR antigens in man) on the surface of antigen-presenting cells with which contact allergens form the fully antigenic complex, 2 Langerhans cells, mainly located in the suprabasal layers, are the antigen-presenting cells in the epidermis, and constitute 3% to 5%, perhaps even more, of the epidermal cell population. These cells, with as many as twelve dendrites, reach up
and down through the living parts of the epidermis and greatly extend their functional " r e a c h " and surface area, thus affording greater opportunities for combining contact allergen and cell surface components. Fig. 2 shows the very large number of Langerhans cells present in human epidermis obtained by suction. Fig. 3 shows greater detail of the Langerhans cells and their dendrites. These cells form an impressive system, capable of taking on agents, particularly small molecules such as contact allergens, which have penetrated the living layers of the epidermis. It should be noted that these cells do not interconnect and therefore do not form a true network in the epidernais. On the contrary, as discussed below, it is important to the production of suppressor cells that contact allergens travel between Langerhans cells to reach the dermis and dermal lymphatics. Langerhans cells are one of a group of bone marrow-derived cells, often referred to as "mononuclear phagocytes," which include, among others, the dendritic cells of spleen and thymus and the interdigitate reticulum cells of lymph nodes, a This group shares many features, one being the capacity to serve as antigen-presenting cells. Differences in ultrastructural appearance of these mononuclem" phagocytes may well be associated with differences in the functions they serve. For example, shown to have a substantial capacity to take up small molecular compounds, the epidermal Langerhans cell system has been called a reticuloepithelial trap. 4 Among the substances taken up by these cells are chromium, cobalt, formaldehyde, glutaraldehyde, gold sodium thiomalate, mercury, nickel, paraphenylenediamine, L-dopa, serotonin, and other aromatic amino acids. 4.a It is a recognized fact that some of these substances are common contact allergens. Lm~gerhans cells present contact antigen on their surfaces to T lymphocytes which circulate through the epidermis, and it can be assumed that lymphocytes frequently become apposed to Langerhans cells. However, this apposition is only transient, except when it involves lymphocytes possessing complementary surface receptors for the particular contact allergens presented by the Langerhans cells. In such an event, lymphocytes
Volume 6 Number 5 May, 1982
Contact allergy
923
Fig. 2. Langerhans cells stained for ATPase in sheet of human epidermis obtained by the suction blister method. (Courtesy Hem'y Lira, M.D., Scarsdale, NY.)
Fig. 3. Higher magnification of an area in Fig. 2. Note that the Langerhans cells do not interconnect or touch each other. (Courtesy Henry Lira, M.D., Searsdale, NY.)
become irreversibly apposed to the antigen-presenting cells, provided that they both carry identical surface HLA-DR immune response antigens. Under these circumstances, immunologic interaction between antigen-presenting cells and T lymphocytes becomes possible. As a consequence, the antigen-presenting cells become "activated" and the antigen-stimulated lymphocytes undergo blast transformation and proliferate in the thymus-dependent areas of the regional lymph nodes. Sensitized cells, i.e., effector cells gen-
erated in tile course of this proliferation, enter the blood circulation and are carried to other parts of the lymphoid system. Dissemination of effeetor cells from lymph nodes draining the original site of exposure to the entire lymphoid system explains why, in sensitized individuals, the entire skin surface almost invariably has the capacity to participate in contact allergic reactions. What are the conditions which favor development of specific immunologic tolerance, rather than specific allergic hypersensitivity? Tolerance
924
Baer
tends to develop when, at the time of first exposure, the contact allergen is not taken up by antigenpresenting ceils, and thus cannot be presented in an appropriate manner to T lymphocyte precursors of effeetor cells. Allergen which reaches the central compartment of the lymphoid system then can act directly on susceptible T lymphocytes and induce proliferation of clones of specific suppressor cellsY ,7 Tolerogenic effects were first reported in guinea pigs in 1929 after it was found that parenteral, particularly intravenous, administration of contact allergens tended to produce unresponsiveness to subsequent attempts to sensitize by injection into the skin, 8 and in 1946 when a similar effect was demonstrated following oral administration of contact allergen. "~Such tolerance after oral administration can be induced not only by the specific contact allergen itself but also by structurally closely related, but nonsensitizing, compounds. ~0 Experimental evidence indicates that the same phenomenon also occurs in man, t1'12 although it has been reported that attempts to utilize this phenomenon in the prevention of allergic contact sensitization have failed, la However, intradermal administration of many haptens can cause a state of allergic contact hypersensitivity, as well as other forms of delayed hypersensitivity. Modern medical and technologic developments provide increasing opportunities for exposure to contact allergens by routes other than contact. Some of the sources of exposures which should be kept in mind are: chemicals in foods, drugs, and toiletries absorbed via the oral, gastrointestinal, and genital mucous membranes; injected substances, such as drugs and chemicals used in tattoos; metals and synthetic resins used in dental fillings or prostheses; metals and synthetic resins inserted or implanted in the course of orthopedic procedures; metals in pacemakers; metaIs in intrauterine devices. Another source of tolerogenic effects is substances encountered by contact but that, during diffusion through the epidermis, bypass the antigen-presenting cells and, as a consequence', reach the dermis, dermal lymphatics, and regional lymph nodes. Even though it has been encoun-
Journal of the American Academy of Dermatology tered by contact, this fraction of the allergen may contribute to the production of suppressor cells in the central lymphoid compartment, and thereby shift the balance between effector and suppressor cells in favor of tolerance. 14 It must be emphasized that, although first encounter by parenteral injection, ingestion, or insertion generally favors a state of tolerance to contact allergens, the same encounter may in effect also contribute to the production of hypersensitivity because allergen reaches the epidermal antigen-presenting cells via the bloodstream. This explains the development of allergic contact sensitization after insertion of various metals. J~,~s Appropriate presentation of the contact allergen to T lymphocytes is a prerequisite for the induction of allergic contact hypersensitivity, and therefore one would surmise that conditions in which the antigen-presenting Langerhans cell system in the epidermis is not functioning effectively or is deficient or absent would preclude the induction of hypersensitivity. Significant support exists for this concept, but knowledge in this field is still limited. Exposures of mouse skin to ultraviolet radiation severely impair the antigen-presenting functions of Langerhans cells. 17 Contact allergen applied to such ultraviolet-irradiated skin sites tends to induce tolerance rather than hypersensitivity. Applications of sensitizing doses of the same contact allergens to these same sites 2 weeks later also fail to induce hypersensitivity, even though it has been shown that the normal functions of the Langerhans cells have been restored after that interval. Similarly, after this 2-week interval, applications of the allergen to normal, not previously in'adiated, skin sites fail to induce sensitization, lz Furthermore, application of a contact allergen to an anatomic site at which the number of Langerhans celIs is normally very small, e.g., the tail skin of mice, induces a state of tolerance rather than hypersensitivity. 18Again, subsequent applications of sensitizing doses to sites containing an adequate complement of Langerhans cells fail to induce sensitization. Thus, the state of tolerance produced for that allergen can be shown to persist. 18 It may be concluded from these findings that allergen applied to the skin at the time of first
Vnlume 6 Number 5 May, 1982
e x p o s u r e , but not appropriately presented to T l y m p h o c y t e s , tends to have the same effect as inj e c t e d or i n g e s t e d allergen. It a p p e a r s likely that future investigations will r e v e a l additional conditions which either interfere w i t h the n o r m a l functions o f epidermal Langerh a n s cells or significantly reduce their number, a n d t h e r e b y f a v o r the generation of suppressor cells after e x p o s u r e to small molecular contact allergens. F o r e x a m p l e , the topical and systemic a d m i n i s t r a t i o n o f corticosteroids in mice and g u i n e a pigs decreases the functioning epidermal L a n g e r h a n s cell population. 1~.2° It is likely that o t h e r p h a r m a c e u t i c a l and nonpharmaceutical chemicals m i g h t h a v e a similar effect. Furthermore, there m a y be u n k n o w n hereditary, congenital, or a c q u i r e d states associated with a functionally or q u a n t i t a t i v e l y inadequate epidermal Langerhans c e l l s y s t e m , w h i c h could interfere with the induction o f c o n t a c t allergy. Conversely, it appears p o s s i b l e that there m a y be as yet undiscovered states o f h y p e r t r o p h y o f the epidermal Langerhans cell s y s t e m , w h i c h would cause affected persons to h a v e i n c r e a s e d susceptibility to allergic contact sensitization. REFERENCES
1. Thomas WR, Watkins MC, Asherson GL: Differences in the ability of T cells to suppress the induction and expression of contact sensitivity. Immunology 42:53-59, 1981. 2. Thomas DW, Shevach EM: Nature of the antigenic complex recognized by T-lymphocytes. I. Analysis with an in vitro primary response to soluble protein antigens. J Exp Med 144:1253-1273, 1976. 3. Thorbecke GJ, Silberberg-Sinakin I, Flotte TJ: Langerhans cells as macrophages in skin and lymphoid organs. J Invest Dermatol 75:32-43, 1980. 4. Shelley WB, Juhlin L: Langerhans cells form a reticulnepithelial trap for external contact antigens. Nature 261:46-47, 1976. 5. Falck B, Agrup G, Jacobsson S, Rorsman H, Rosengren E, Sachner K, Ogren M: Uptake of L-dnpa and func-
Contact allergy 925
6. 7. 8. 9. 10. 11. 12. 13. 14,
15. 16. 17. 18.
19. 20.
tionally related aromatic amino acids and the Langerhans cell. J Invest Dermatol 66:265, 1976. Zembala M, Asherson GL: Depression of the T-cell phenomenon of contact sensitivity by T-cells from unresponsive mice. Nature 244:227-228, 1973. Sommer G, Parker D, Turk JL: Demonstration of suppressor cells induced by contact with 2,4-dinitrothiocyanatebenzene. Immunology 29:517-525, 1975. Sulzberger MB: Hypersensitiveness to arsphenamine in guinea pigs. I. Experiments in prevention and in desensitization. Arch Dermatol Syph 20:669-697, t929. Chase MW: Inhibition of experimental drug allergy by prior feeding of the sensitizing agent. Proc Soc Exp Biol Med 61:257-259, 1946. Baer RL, Rosenthal SA: Induction of cross-tolerancefor contact sensitivity by a non-immunogenic chemical. J Immunol 108:706-710, 1972. Lowney ED: Immunologic unresponsiveness to a contact sensitizer in man. J Invest Dermatol51:411-417, 1968. Kahn G, Phanuphak P, Claman H: Propyt gallate-contact sensitization and orally induced tolerance. Arch Dermatol 109:506-509, 1974. Leshaw S, Simon RS, Baer RL: Failure to induce tolerance to mechlorethamine hydrochloride. Arch Dermatol 113:1406-1408, 1977. Macher J, Chase MW: Studies on the sensitization of animals with simple chemical compounds. XII. The influence of the excision of allergenic depots on onset of delayed hypersensitivity and tolerance. J Exp Med 129:103-121, 1969. Tilsley DA, Rotstein DH: Sensitivity caused by internal exposure to Ni, Cr, and Co. Contact Dermatitis 6:175178, 1980. Bazex A, Parant M, Bazex J, viraben R: Manifestations cutan6es provoqu6es par le materiel metallique d'osteosynthcse. Ann Dermatol Venereol 105:9-15, 1978. Toews GB, Bergstresser PR, Streilein JW: Langerhans cells: Sentinels of skin-associated lymphoid tissue. J Invest Dermatol 75:78-82, 1980. Bergstresser PR, Toews GB, Gilliam JN, Streilein JW: Unusual numbers and distributions of Langerhans cells in skin with unique immunologic properties. J Invest Dermatol 74:312, 1980. Nordlund J], Acktes AE: A specificmethod for quantifying cells bearing Ia antigens in murine epidermis. Clin 28:577, 1980. (Abst.) Belsito DV, Flotte TJ, Lim H, Baer RL, Thorbecke J, Gigli I: Effects of topical steroids on epidermal Langerhans cells. J Invest Dermatol 76:325, 1981.
New York, NY First exposure to a contact allergen sets in motion two competing mechanisms, one of which leads to specific allergic hypersensitivity, mediated by effector cells, and the other to specific immunologic tolerance, mediated by suppressor cells. The immunologic stance resulting from exposure to contact allergens depends on the balance between effector and suppressor cell effects. First exposure by skin contact generally favors the induction of specific allergic contact hypersensitivity, while first exposure by parenteral injection, ingestion, and perhaps also by insertion into noncutaneous body structures generally favors a state of specific immunologic tolerance ("unresponsiveness"). However, allergen encountered by contact which is not taken up by epidermal antigen-presenting cells may also have tolerogenic effects, while allergen encountered by injection, ingestion, or insertion may reach the epidermal antigen-presenting cell system via the bloodstream and may then have sensitizing effects. (J AM ACAD DE~tV~TOL 6:921-925, 1982.)
Dermatologists in clinical practice frequently e n c o u n t e r patients suffering from allergic ecz e m a t o u s contact dermatitis, the disease resulti n g from hypersensitivity reactions due to expos u r e to contact allergens. These hypersensitivity r e a c t i o n s represent only one end of a spectrum of a v a r i e t y of states of reactivity resulting from expos u r e to contact allergens, the other end being a s t a t e of relative or absolute tolerance ("unresponsiveness"). Hypersensitivity and tolerance are the results of t w o competing phases of the immunologic res p o n s e set in motion upon initial exposure to cont a c t allergens. These two phases are modulated by
F r o m ~he Department of Dermatology, New York University School o f Medicine. Supported by NIH-Asthma and Allergic Disease Center for Immunodermatology Grant No. AI 17365. Presented at the meeting of the American Academy of Dermatology. session on Contact Dermatitis, Dec. 6, 1980. O 1 90-9622/82/050921 + 05500.50/0 © 1982 Am Acad Dermatol
different subsets of T lymphocytes, namely, effector cells, which are responsible for allergic hypersensitivity, and suppressor cells, which are responsible for specific immunologic tolerance. It appears that two distinct sets of suppressor cells are involved in contact allergy. One of these affects the induction phase, while the other affects the expression of contact hypersensitivity by effectot cells. 1 It should be noted that although other mechanisms, such as clone deletion, enhancing antibodies, and antigen-antibody complexes, also lead to tolerance, suppressor cells appear to be the major or exclusive mechanism in tolerance to contact allergens. Fig. 1 illustrates the competition between effector ceils and suppressor cells in determining the state of the skin's reactivity to any particular contact allergen. Clinical hypersensitivity of varying degrees may result when effector cells predominate. On the other hand, no clinical reaction occurs, i.e., a state of clinical tolerance will exist, 921
Journal of the American Academy of Dermatology
Baer
922
no dlnicat reaction
hypersensitivity reaction 4+3+
2+
specific immunologic un responsiveness
1 +
t ÷ ÷ ÷ ÷.--,~,~. ÷÷ ÷÷
÷
÷.l.
÷
~÷
÷÷
÷ ÷
5: L>÷
÷
o"
• .° ,
÷
,,
Fig. 1. Competition between effeetor and suppressor cells determines the state of the skin's reactivity to a specific contact allergen. when the effects of suppressor and effector cells are in balance or when the suppressor cells predominate. [t should be emphasized that it is the immunologic events which ensue at the time of first exposure to a contact allergen which have a major impact on the outcome of this competition between effector and suppressor cells. Knowledge of the elementary features of the mechanism mediating allergic contact sensitization makes it possible to understand the factors involved in the competition between effector and suppressor cells. It is well known that under normal circumstances only small molecules (<500 daltons) in the environment enter undamaged epidermis via the horny layer and skin appendages. In order for these small molecules to become antigenic, they must combine with larger "carrier" molecules, usually proteins. According to present concepts, this occurs principally in the prickle cell layer, where contact allergens can combine with surface components of antigen-presenting cells. The surface components involved in this process have not yet been identified, but it has been suggested that it may be the immune response antigens (Ia antigens in mice and HLA-DR antigens in man) on the surface of antigen-presenting cells with which contact allergens form the fully antigenic complex, 2 Langerhans cells, mainly located in the suprabasal layers, are the antigen-presenting cells in the epidermis, and constitute 3% to 5%, perhaps even more, of the epidermal cell population. These cells, with as many as twelve dendrites, reach up
and down through the living parts of the epidermis and greatly extend their functional " r e a c h " and surface area, thus affording greater opportunities for combining contact allergen and cell surface components. Fig. 2 shows the very large number of Langerhans cells present in human epidermis obtained by suction. Fig. 3 shows greater detail of the Langerhans cells and their dendrites. These cells form an impressive system, capable of taking on agents, particularly small molecules such as contact allergens, which have penetrated the living layers of the epidermis. It should be noted that these cells do not interconnect and therefore do not form a true network in the epidernais. On the contrary, as discussed below, it is important to the production of suppressor cells that contact allergens travel between Langerhans cells to reach the dermis and dermal lymphatics. Langerhans cells are one of a group of bone marrow-derived cells, often referred to as "mononuclear phagocytes," which include, among others, the dendritic cells of spleen and thymus and the interdigitate reticulum cells of lymph nodes, a This group shares many features, one being the capacity to serve as antigen-presenting cells. Differences in ultrastructural appearance of these mononuclem" phagocytes may well be associated with differences in the functions they serve. For example, shown to have a substantial capacity to take up small molecular compounds, the epidermal Langerhans cell system has been called a reticuloepithelial trap. 4 Among the substances taken up by these cells are chromium, cobalt, formaldehyde, glutaraldehyde, gold sodium thiomalate, mercury, nickel, paraphenylenediamine, L-dopa, serotonin, and other aromatic amino acids. 4.a It is a recognized fact that some of these substances are common contact allergens. Lm~gerhans cells present contact antigen on their surfaces to T lymphocytes which circulate through the epidermis, and it can be assumed that lymphocytes frequently become apposed to Langerhans cells. However, this apposition is only transient, except when it involves lymphocytes possessing complementary surface receptors for the particular contact allergens presented by the Langerhans cells. In such an event, lymphocytes
Volume 6 Number 5 May, 1982
Contact allergy
923
Fig. 2. Langerhans cells stained for ATPase in sheet of human epidermis obtained by the suction blister method. (Courtesy Hem'y Lira, M.D., Scarsdale, NY.)
Fig. 3. Higher magnification of an area in Fig. 2. Note that the Langerhans cells do not interconnect or touch each other. (Courtesy Henry Lira, M.D., Searsdale, NY.)
become irreversibly apposed to the antigen-presenting cells, provided that they both carry identical surface HLA-DR immune response antigens. Under these circumstances, immunologic interaction between antigen-presenting cells and T lymphocytes becomes possible. As a consequence, the antigen-presenting cells become "activated" and the antigen-stimulated lymphocytes undergo blast transformation and proliferate in the thymus-dependent areas of the regional lymph nodes. Sensitized cells, i.e., effector cells gen-
erated in tile course of this proliferation, enter the blood circulation and are carried to other parts of the lymphoid system. Dissemination of effeetor cells from lymph nodes draining the original site of exposure to the entire lymphoid system explains why, in sensitized individuals, the entire skin surface almost invariably has the capacity to participate in contact allergic reactions. What are the conditions which favor development of specific immunologic tolerance, rather than specific allergic hypersensitivity? Tolerance
924
Baer
tends to develop when, at the time of first exposure, the contact allergen is not taken up by antigenpresenting ceils, and thus cannot be presented in an appropriate manner to T lymphocyte precursors of effeetor cells. Allergen which reaches the central compartment of the lymphoid system then can act directly on susceptible T lymphocytes and induce proliferation of clones of specific suppressor cellsY ,7 Tolerogenic effects were first reported in guinea pigs in 1929 after it was found that parenteral, particularly intravenous, administration of contact allergens tended to produce unresponsiveness to subsequent attempts to sensitize by injection into the skin, 8 and in 1946 when a similar effect was demonstrated following oral administration of contact allergen. "~Such tolerance after oral administration can be induced not only by the specific contact allergen itself but also by structurally closely related, but nonsensitizing, compounds. ~0 Experimental evidence indicates that the same phenomenon also occurs in man, t1'12 although it has been reported that attempts to utilize this phenomenon in the prevention of allergic contact sensitization have failed, la However, intradermal administration of many haptens can cause a state of allergic contact hypersensitivity, as well as other forms of delayed hypersensitivity. Modern medical and technologic developments provide increasing opportunities for exposure to contact allergens by routes other than contact. Some of the sources of exposures which should be kept in mind are: chemicals in foods, drugs, and toiletries absorbed via the oral, gastrointestinal, and genital mucous membranes; injected substances, such as drugs and chemicals used in tattoos; metals and synthetic resins used in dental fillings or prostheses; metals and synthetic resins inserted or implanted in the course of orthopedic procedures; metals in pacemakers; metaIs in intrauterine devices. Another source of tolerogenic effects is substances encountered by contact but that, during diffusion through the epidermis, bypass the antigen-presenting cells and, as a consequence', reach the dermis, dermal lymphatics, and regional lymph nodes. Even though it has been encoun-
Journal of the American Academy of Dermatology tered by contact, this fraction of the allergen may contribute to the production of suppressor cells in the central lymphoid compartment, and thereby shift the balance between effector and suppressor cells in favor of tolerance. 14 It must be emphasized that, although first encounter by parenteral injection, ingestion, or insertion generally favors a state of tolerance to contact allergens, the same encounter may in effect also contribute to the production of hypersensitivity because allergen reaches the epidermal antigen-presenting cells via the bloodstream. This explains the development of allergic contact sensitization after insertion of various metals. J~,~s Appropriate presentation of the contact allergen to T lymphocytes is a prerequisite for the induction of allergic contact hypersensitivity, and therefore one would surmise that conditions in which the antigen-presenting Langerhans cell system in the epidermis is not functioning effectively or is deficient or absent would preclude the induction of hypersensitivity. Significant support exists for this concept, but knowledge in this field is still limited. Exposures of mouse skin to ultraviolet radiation severely impair the antigen-presenting functions of Langerhans cells. 17 Contact allergen applied to such ultraviolet-irradiated skin sites tends to induce tolerance rather than hypersensitivity. Applications of sensitizing doses of the same contact allergens to these same sites 2 weeks later also fail to induce hypersensitivity, even though it has been shown that the normal functions of the Langerhans cells have been restored after that interval. Similarly, after this 2-week interval, applications of the allergen to normal, not previously in'adiated, skin sites fail to induce sensitization, lz Furthermore, application of a contact allergen to an anatomic site at which the number of Langerhans celIs is normally very small, e.g., the tail skin of mice, induces a state of tolerance rather than hypersensitivity. 18Again, subsequent applications of sensitizing doses to sites containing an adequate complement of Langerhans cells fail to induce sensitization. Thus, the state of tolerance produced for that allergen can be shown to persist. 18 It may be concluded from these findings that allergen applied to the skin at the time of first
Vnlume 6 Number 5 May, 1982
e x p o s u r e , but not appropriately presented to T l y m p h o c y t e s , tends to have the same effect as inj e c t e d or i n g e s t e d allergen. It a p p e a r s likely that future investigations will r e v e a l additional conditions which either interfere w i t h the n o r m a l functions o f epidermal Langerh a n s cells or significantly reduce their number, a n d t h e r e b y f a v o r the generation of suppressor cells after e x p o s u r e to small molecular contact allergens. F o r e x a m p l e , the topical and systemic a d m i n i s t r a t i o n o f corticosteroids in mice and g u i n e a pigs decreases the functioning epidermal L a n g e r h a n s cell population. 1~.2° It is likely that o t h e r p h a r m a c e u t i c a l and nonpharmaceutical chemicals m i g h t h a v e a similar effect. Furthermore, there m a y be u n k n o w n hereditary, congenital, or a c q u i r e d states associated with a functionally or q u a n t i t a t i v e l y inadequate epidermal Langerhans c e l l s y s t e m , w h i c h could interfere with the induction o f c o n t a c t allergy. Conversely, it appears p o s s i b l e that there m a y be as yet undiscovered states o f h y p e r t r o p h y o f the epidermal Langerhans cell s y s t e m , w h i c h would cause affected persons to h a v e i n c r e a s e d susceptibility to allergic contact sensitization. REFERENCES
1. Thomas WR, Watkins MC, Asherson GL: Differences in the ability of T cells to suppress the induction and expression of contact sensitivity. Immunology 42:53-59, 1981. 2. Thomas DW, Shevach EM: Nature of the antigenic complex recognized by T-lymphocytes. I. Analysis with an in vitro primary response to soluble protein antigens. J Exp Med 144:1253-1273, 1976. 3. Thorbecke GJ, Silberberg-Sinakin I, Flotte TJ: Langerhans cells as macrophages in skin and lymphoid organs. J Invest Dermatol 75:32-43, 1980. 4. Shelley WB, Juhlin L: Langerhans cells form a reticulnepithelial trap for external contact antigens. Nature 261:46-47, 1976. 5. Falck B, Agrup G, Jacobsson S, Rorsman H, Rosengren E, Sachner K, Ogren M: Uptake of L-dnpa and func-
Contact allergy 925
6. 7. 8. 9. 10. 11. 12. 13. 14,
15. 16. 17. 18.
19. 20.
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