The inductive or afferent limb of contact sensitivity begins with the topical application to the skin of a chemically reactive substance called a hapten. The hapten may be organic or inorganic and is generally of low molecular weight (<500 daltons)(1). Its ability to sensitize depends on penetrating the skin and forming covalent bonds with proteins. The degree of sensitization is directly proportional to the stability of the hapten–protein coupling. In the case of the commonly used skin sensitizer dinitrochlorobenzene, the union of the chemical hapten and the tissue protein occurs in the Malpighian layer of the epidermis, with the amino acid sites of lysine and cysteine being most reactive (2). It has been suggested that skin lipids might exert an adjuvant effect comparable with the myoside of mycobacterium tuberculosis.

There is strong evidence that Langerhans cells are of crucial importance in the induction of contact sensitivity (3). These dendritic cells in the epidermis cannot be identified on routine histologic sections of the skin by light microscopy, but they can be easily visualized using
special stains. They possess MHC class II and B7 homology receptors B7(CD80/86).

Langerhans cells are dendritic epidermal cells that possess MHC Class II antigen on their surface. The Langerhans cell ingests the hapten–protein complex, processes it, and then produces a resulting peptide that binds to the HLA-DR antigen on the surface of the cell. The peptide is then presented to a CD4⁺ helper T-cell type 1 (T_H1) with specific complementary surface receptors.

The binding of the T_H1 cell induces the Langerhans cell to release cytokines including interleukin-1(IL-1). IL-1 in turn activates the bound T_H1 cell to release interleukin-2 which leads to T-cell proliferation. The proliferating T cells magnify the response by releasing interferon-γ, which leads to increased HLA-DR display on Langerhans cells and increased cytotoxicity of T cells, macrophages, and natural killer cells. The sensitized T_H1 cells also result in an anamnestic response to subsequent exposure to the same antigen. Type IVa₁ hypersensitivity can be transferred with sensitized T_H1 cells (4).

Contact allergy involves both T effector cells leading to hypersensitivity and T suppressor cells leading to tolerance. The net effect is the balance of these two opposing inputs. Cutaneous exposure tends to induce sensitization, whereas oral or intravenous exposure is more likely to induce tolerance. Once sensitivity is acquired, it usually persists for many years; however, it occasionally may be lost after only a few years. Hardening refers to either a specific or generalized loss of hypersensitivity due to constant low-grade exposure to an antigen. This type of deliberate desensitization has been successful only in rare instances and is therefore not recommended as a therapeutic strategy.

The histologic picture in allergic contact dermatitis reveals that the dermis is infiltrated by mononuclear inflammatory cells, especially about blood vessels and sweat glands (2). The epidermis is hyperplastic with mononuclear cell invasion. Frequently, intraepidermal vesicles form, which may coalesce into large blisters. The vesicles are filled with serous fluid containing granulocytes and mononuclear cells. In Jones-Mote contact sensitivity, in addition to mononuclear phagocyte and lymphocyte accumulation, basophils are found. This is an important distinction from hypersensitivity reactions of the T_H1 type, in which basophils are completely absent.

Allergic contact dermatitis occurs most frequently in middle-aged and elderly persons, although it may appear at any age. In contrast to the classical atopic diseases, contact dermatitis is as common in the population at large as in the atopic population, and a history of personal or family atopy is not a risk factor.

The interval between exposure to the responsible agent and the occurrence of clinical manifestations in a sensitized subject is usually 12 to 96 hours, although it may be as early as 4 hours and sometimes longer than 1 week. The incubation or sensitization period between initial exposure and the development of skin sensitivity may be as short as 2 to 3 days in the case of a strong sensitizer such as poison ivy, or several years for a weak sensitizer such as chromate. The patient usually will note the development of erythema, followed by papules, and then vesicles. Pruritus follows the appearance of the dermatitis and is uniformly present in allergic contact dermatitis.

The appearance of allergic contact dermatitis depends on the stage at which the patient presents. In the acute stage, erythema, papules, and vesicles predominate, with edema and occasionally bullae (Fig. 30.1). The boundaries of the dermatitis are generally poorly marginated. Edema may be profound in areas of loose tissue such as the eyelids and genitalia. Acute allergic contact dermatitis of the face may result in a marked degree of periorbital swelling that resembles angioedema. The presence of the associated dermatitis should allow the physician to make the distinction easily. In the subacute phase, vesicles are less pronounced, and crusting, scaling, and early signs of lichenification may be present. In the chronic stage, few papulovesicular lesions are evident, and thickening, lichenification, and scaliness predominate.

Different areas of the skin vary in their ease of sensitization. Pressure, friction, and perspiration are factors that seem to enhance sensitization. The eyelids, neck, and genitalia are among the most readily sensitized areas, whereas the palms, soles, and scalp are more
resistant. Tissue that is irritated, inflamed, or infected is more susceptible to allergic contact dermatitis. A clinical example is the common occurrence of contact dermatitis in an area of stasis dermatitis that has been treated with topical medications or sensitizing chemicals.

The skin conditions most frequently confused with allergic contact dermatitis are seborrheic dermatitis, atopic dermatitis, psoriasis, and primary irritant dermatitis. In seborrheic dermatitis, there is a general tendency toward oiliness of the skin, and a predilection of the lesions for the scalp, the T-zone of the face, midchest, and inguinal folds.

Atopic dermatitis (Chapter 29) often has its onset in infancy or early childhood. The skin is dry, although pruritus is a prominent feature, it appears before the lesions and not after them, as in the case of allergic contact dermatitis. The areas most frequently involved are the flexural surfaces. The margins of the dermatitis are indefinite, and the progression from erythema to papules to vesicles is not seen.

Psoriasis is characterized by well demarcated erythematous plaques with white to silvery scales; pruritus is often mild or absent. Lesions are often distributed symmetrically over extensor surfaces such as the knee or elbow.

The dermatitis caused by a primary irritant is a simple chemical or physical insult to the skin. For example, what is commonly called dishpan hands is a dermatitis caused by household detergents. A prior sensitizing exposure to the primary irritant is not necessary, and the dermatitis develops in a large number of normal persons. The dermatitis begins shortly after exposure to the irritant, in contrast to the 12 to 96 hours after exposure in allergic contact dermatitis. Primary irritant dermatitis may be virtually indistinguishable in its physical appearance from allergic contact dermatitis. It should be emphasized that skin conditions may coexist. It is not unusual to see allergic contact dermatitis caused by topical medications applied for the treatment of atopic dermatitis and other dermatoses.

A variant of contact allergy is contact urticaria (CU). There are three categories of CU: immunologic contact urticaria (ICU), protein contact dermatitis (PCD), and nonimmunologic contact urticaria (NCU). ICU is an immediate wheal-and-flare response generated by a wide variety of contactants. The immunopathogenesis of both ICU and PCD appears to be mediated at least in part by antigen-specific IgE and type I hypersensitivity. The immunopathologic mechanisms in PCD other than type I are unclear. Several authors have reported Type IV cutaneous reactions corroborated by positive patch tests (5). NCU is caused by some allergens such as fragrances and benzyl alcohol known to cause immunologic reaction; however, in the case of NCU, the etiology is unclear.

Once the diagnosis of allergic contact dermatitis is made, vigorous efforts should be directed toward determining the cause. A careful, thorough history is absolutely mandatory. The temporal relationship between exposure and clinical manifestations must be kept in mind as an exhaustive search is made for exposure to a sensitizing allergen in the patient’s occupational, home, or recreational environment. The location of the dermatitis most often relates closely to direct contact with a particular allergen. At times this is rather straightforward, such as dermatitis of the feet, caused by contact sensitivity to shoe materials or dermatitis from jewelry appearing on the wrist, the ear lobes, or the neck. The relationship of the dermatitis to the direct contact allergen may not be as obvious at other times, and being able to associate certain areas of involvement with particular types of exposure is extremely helpful. Contact dermatitis of the face, for example, is often due to cosmetics directly applied to the area. One must keep in mind other possibilities, however, such as hair dye, shampoo, and hair-styling preparations. Contact dermatitis of the eyelid, although often caused by eye shadow, mascara, and eye liner, also may be caused by nail polish. Involvement of the thighs may be caused by keys or coins in pants pockets. Therefore, it is vital that the physician be familiar with various distribution patterns of contact dermatitis that may occur in association with particular allergens.

Frequently, the distribution of the skin lesions may suggest a number of possible sensitizing agents, and patch testing is of special value. Certain allergens may be airborne, and exposure may occur by this route. Dermatitis among farmers caused by ragweed oil sensitivity occurs occasionally. Smoke from burning the poison ivy plant may contain the oleoresin as particulate matter, and thus expose the sensitive individual. Forest fire fighters develop generalize allergic contact dermatitis from smoke from the burning branches and leaves containing urushiol. Another route of acquiring poison ivy contact dermatitis without touching the plant is by indirect contact with clothing or animal fur containing the oleoresin. It should be remembered also that systemic administration of a drug or a related drug that has been previously used topically and to which the patient has been sensitized can elicit a localized or generalized eruption. An example is sensitivity to ethylenediamine. A patient may have developed localized contact dermatitis to topically applied ethylenediamine hydrochloride previously used as a stabilizer in such compounds as Mycolog cream. After being sensitized, a localized or
generalized eruption may then occur when aminophylline is administered orally (6).

The oral mucosa also may be the site of a localized allergic contact reaction resulting in contact stomatitis or stomatitis venenata (7). The relatively low incidence of contact stomatitis compared with contact dermatitis is attributed to the brief duration of surface contact, the diluting and buffering action of saliva, and the rapid dispersal and absorption because of extensive vascularity. Agents capable of producing contact stomatitis include dentifrices, mouthwashes, dental materials such as acrylic and epoxy resins, and foods. The clinical response is most commonly inflammation of the lips, but cases of “burning mouth” syndrome have also been attributed to contact allergy.