Mechanisms involved in allergic contact dermatitis Stephen I. Katz, MD, PhD Bethesda, Maryland Allergic contact dermatitis is a common inflammatory skin disease caused by agents such as plants, chemical compounds, and topical medications. Histologic features typically include edema within the epidermis and dermis and a lymphohistiocytic infiltrate with an admixture of basophils. Langerhans cells and keratinocytes play pivotal roles in allergic contact dermatitis reactions. Langerhans cells synthesize and express class H molecules that allow the presentation of exogenous antigens to T lymphocytes. Additionally, keratinocytes and Langerhans cells produce interleukin-1, which is thought to be a second signal that activates T cells. Mast cells and basophils also may play a proinflammatory role. Treatment primarily consists of removal of the offending agent. At times, systemic corticosteroids may be required, especially in the acute phase. In more chronic cases, topical corticosteroids may be beneficial. Antihistamines may be useful because of their soporific effects, but their usefulness is limited. (J ALLERGY CLIN 1MMUNOL 1990;86:670-2.)

Allergic contact dermatitis is a common inflammatory skin disease that represents a form of delayedtype hypersensitivity. Several factors dictate the severity and persistence of lesions, including the sensitivity of the subject, the dose of antigenic exposure, and the potency of the antigenic stimulus. The clinical lesions vary from transient redness to edematous pap: ules that become vesicular and at times even bullous. Itching is one of the hallmarks of the disease and varies in intensity. Any part of the skin that comes into contact with the sensitizing substance may be involved. Characteristically, the dermatitis is at first limited to the skin sites exposed to the antigen, although later it may spread to other areas. The histopathologic features vary according to the severity of the eruption. Perivascular infiltrates of lymphocytes and monocytes are seen in the upper dermis within 6 hours of exposure to antigen. The infiltration may be accompanied by considerable edema. Subsequently, intracellular and intercellular edema develops in the epidermis to form what is known as spongiosis. Chronic lesions of allergic contact dermatitis are characterized by hyperkeratosis, acanthosis (thickening of the epidermis), and, in the superficial dermis, a variably dense mononuclear cell infiltrate containing a considerable admixture of basophils.

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Probably the most common causes of allergic contact dermatitis are plants such as poison ivy, poison oak, and poison sumac. Plant dermatitis may occur by direct contact or indirectly from clothing or pets that have come in contact with the plant. If burned, these plants may release aerosols potent enough to cause contact dermatitis. The other most common causes of allergic contact dermatitis include nickel compounds, rubber compounds, paraphenylenediamine, and ethylenediamine. 1, 2

MECHANISMS For many years researchers and clinicians believed that the skin functioned simply as a barrier and did not play an active role in the pathogenesis of allergic contact dermatitis. Rather, it was hypothesized that an incomplete antigen or hapten would bind to a carder protein within the skin, sensitizing the T cells within the paracortical area. It is now known that the induction of contact sensitivity involves interaction between T lymphocytes and hapten-modified Ia + epidermal Langerhans cells. Langerhans cells are bone marrow derived and can, in vitro and in vivo (in animal models), replace macrophages and dendritic cells in the induction of various delayed-type hypersensitivity reactions? -5 The precise site of interaction between Langerhans cells and unsensitized T cells is unknown. However, Langerhans cells may migrate through the lymphatic system to regional lymph nodes, where they interact to generate specifically sensitized T cells. Although the precise

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roles of the afferent lymphatic vessels and regional lymph nodes are not completely clear, the necessity for an intact lymphatic drainage for sensitization to occur has been demonstrated. Exogenous antigens interacting with endogenous Ia antigen provide only one of the signals for the activation of T cells. A second signal is also required for this T-cell activation. This signal is a 15,000-dalton molecule, interleukin-1, which is secreted by macrophages and has been shown to enhance many types of immunologic responses. In addition, within the epidermis both keratinocytes and Langerhans cells are able to produce interleukin-1, which presumably provides the second signal. 6 The nature of T cell-mediated contact sensitivity is the subject of considerable study. It is generally believed that during the induction phase helper T cells proliferate and differentiate into delayed-type hypersensitivity effector cells that on challenge release lymphokines, resulting in local inflammation. There is also evidence from studies in mice that two subsets of T cells mediate delayed-type hypersensitivity reactions: a class II major histocompatibility complexrestricted helper T cell and a class 1-restricted cytotoxic T cell that responds to hapten-coupled cells. It is not known, however, whether these cytotoxic T cells actually function in vivo in contact sensitivity and contribute to the intercellular and intracellular edema seen in the epidermis. In addition to effector T cells mediating inflammation, specific suppressor T cells are also generated after sensitization with haptens. Thus the degree of immunity achieved represents a balance between sensitization and tolerance, mediated by a complex suppressor circuit acting on both the afferent and efferent pathways of the delayed hypersensitivity reaction. Whether sensitization results in net effector or net suppressor activity depends on the dose and characteristics of the infecting allergen(s) and on the integrity of the epidermal Langerhans cells. Several studies have demonstrated that the dermal infiltrate in the elicitation phase of allergic contact dermatitis in human beings consists of an admixture of helper and suppressor cytotoxic T cells, with helper cells predominating. Similar results have, however, been reported in primary irritant dermatitis, suggesting these findings are rather nonspecific. This is not surprising, because only a small percentage of T cells infiltrating a cutaneous delayed-type hypersensitivity reaction have specificity for the antigen. The vast majority (>98%) of infiltrating cells are therefore nonspecifcally recruited.

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Other factors, including mast cells and basophils, also have a proinflammatory effect. Studies in animals and in human beings have demonstrated that the cellular infiltrate in allergic contact dermatitis can contain up to 40% mast cells and 10% basophils. 7 The basophils are distributed throughout the infiltrate, particularly later in the reaction; at 48 to 74 hours large numbers of basophils may be observed within the blood vessels of the skin. To date, however, the exact role of the basophils in allergic contact dermatitis has not been determined.

TREATMENT Acute dermatitis is treated primarily by removing the offending agent. If the disease is widespread or entails severe facial involvement, systemic corticosteroids may be used. Less widespread disease may benefit from soaks and from the draining of blisters. In chronic dermatitis, identification and removal of the offending agent remains the primary method of management. Depending on the character of the infiltrate, topical corticosteroid creams and ointments may be helpful. In my experience antihistamines are useful only for their soporific effects. REFERENCES 1. Fisher AA. Contact dermatitis. 3rd ed. Philadelphia: Lea & Febiger, 1986. 2. Cronin E. Contact dermatitis. London: Churchill Livingstone, 1980. 3. Stingl G, Tamaki K, Katz SI. Origin and function of epidermal Langerhans ceils. Immunol Rev 1980;53:149-74. 4. Stingl G, Katz SI, Clement L, et al. Immunological functions of la-bearing epidermal Langerhans cells. J Immunol 1978; 121:2005-10. 5. Braathen LR, Thorsby E. Studies on human epidermal Langerhans cells: allo-activating and antigen-presenting capacity. Scand J Immunol 1980;11:401-10. 6. Sander DN, Dinarello CA, Morhenn VB. Langerhans cell production of intefleukin 1. J Invest Dermatol 1984;82:605-7. 7. Dvorak HF, Mihm MC Jr. Basophilic leukocytes in allergic contact dermatitis. J Exp Med 1972;135:235-54.

DISCUSSION Question. Some work from Scandinavia has suggested that allergic contact dermatitis may not in fact require cutaneous contact with the antigen. In truth, what appears to be allergic contact dermatitis may be produced by having a subject ingest a substance such as chromium, for instance. Could you comment on this observation and speculate on why the dermatitis recurs at the same site that putatively was contact sensitized? Dr. Katz. Another example is the widespread dermatitis

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caused in the past by the use of theophylline suppositories in patients allergic to ethylenediamine. Likewise, in a small percentage of patients receiving intravenous nitrogen mustard an allergic contact dermatitis will develop. The dermatitis will not necessarily recur at the same site, although it does have a predilection to do so. One explanation may be that long-lived T ceils, which are still reactive, may be present in those areas because of the previous infiltrate. Question. A wide variety of chemicals cause contact dermatitis via sensitization through the skin. Could you envision the same thing happening through the respiratory mucosa? Could some cases of what we call nonallergic rhinitis or nonallergic asthma simply be delayed hypersen-

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sitivity reactions to the same sensitizing agents that affect the skin? Dr, Katz. That is a very good question. The answer probably relates to the distribution of Langerhans cells. We know that Langerhans cells are found in the various mucosae as well as in the skin; that is, these cells have a predilection to Stratified squamous epithelia. I believe that it was Dr. Stein-Streilein (J Inununol 1983;131:1748-53) who did studies in the mid-1980s on just this point. She showed that one could induce contact dermatitis in hamsters after intratracheal inoculation with hapten. She surmised that this sensitization was due to the presence of Langerhans cells in the tracheal mucosa.

Mechanisms involved in allergic contact dermatitis.

Allergic contact dermatitis is a common inflammatory skin disease caused by agents such as plants, chemical compounds, and topical medications. Histol...
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