250 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS ANTIGENS, ANTIBODIES, AND ALLERGENS Immunology is concerned with the response of the organism to antigenic challenge. Antigenic stimulation results either in the formation of humoral (fluid-like) antibodies known as immunoglobulins or alters the reactivity or response of certain cells, e.g., lymphocytes, which, when primed with antigen specificity, are referred to as immuno- logically competent cells. Their reaction with antigen is termed a cell-mediated re- sponse. Thus, the term "immunocompetence" refers to the ability or capacity of an organism to develop an immune response (i.e., antibody production and/or cell-me- diated immunity) following antigenic challenge. It has been hypothesized that the lym- phocytes reaching the epidermis may, to a large extent, be noncompetent lymphoid cells that become competent during or shortly after a stay in the epidermis or close to it in the dermis. Antigens that commonly sensitize persons to anaphylactic or to delayed-type hypersen- sitivities are known as allergens. The properties that confer allergenic potential are not definitely known, but molecular size, chemical composition, and the ability to bind to tissue may be important. Certain substances, among which are low-molecular-weight chemicals, are unable to stimulate formation of antibodies unless they are combined with protein. Such substances are known as haptens. When combined with protein they stimulate antibodies specific for the hapten. Haptens are important sensitizing agents in contact dermatitis. Antibodies may render the individual allergic to that antigen. The term allergy desig- nates a specific altered reactivity of the tissues to substances compared with the response to the first exposure to the same substance. In contrast to immune responses that pro- tect the organism from pathogens, allergies are immune responses that produce dam- aging effects on the organism. Cutaneous anaphylactic responses are allergic responses that occur in skin or on mucous membranes. Thus urticaria (hives), allergic rhinitis (hay fever), and some forms of asthma represent localized responses to environmental an- tigens-for example, in food or air. These allergic reactions are rapid, occurring within minutes of exposure to the antigen. LYMPHOCYTES Lymphocytes are the key cells associated with the immune response. They mediate and monitor immunological competence and responses, being the effector cells of delayed- type hypersensitivity and the precursors of plasma cells synthesizing antibody. They are formed from stem cells in the blood marrow and released into the blood, whence some pass to the thymus to proliferate and to become modified in their properties. These are the T-cells (T designating thymus) or thymus-dependent cells. Other lymphocytes are not modified by the thymus, having distinctly different properties, and are known as B-cells or thymus-independent cells. T-cells comprise about 60% of the lymphocytes in the blood of normal adults, and B-cells comprise about 10% (3). T-lymphocyte-specific properties are acquired after stimulation by a thymic hormone, thymosin, present in the thymus gland and the blood. This hormone induces matura- tion of T-precursor cells to T-lymphocytes. T-cells treated with thymosin in vitro, or fetal calf serum that contains thymosin activity, show enhanced mitogenic responses when treated with antigens thus, it is possible that the amount of thymosin formed in

SKIN AND IMMUNITY 251 each individual will influence the response of the person to immunological stimuli and account for reduced responsiveness in aged persons because the thymus regresses with age, resulting in lowered levels of thymosin (3). The initial or primary stimulation of an immunological response is induced by antigen taken up by macrophages (phagocytes), in which much of it is degraded and excreted. A small amount persists in a modified form and is passed by direct contact between the macrophage and the T- or B-cells, which then become endowed with immunological specificity for that antigen. Langerhans cells (LC) in the skin and lymphoid tissue ap- pear to have this property of macrophages. Most antigens inducing formation of antibody are thymus-dependent and therefore T- cell-dependent. On primary stimulation there is an interaction or cooperation between T-helper cells and B-cells. The stimulated B-cells divide, and some eventually trans- form into plasma cells synthesizing and releasing antibody (4). B-cells synthesize im- munoglobulin, which remains bound on their membrane. Plasma cells derived from the B-cells form the large amounts of antibody that are released into the plasma. The immunoglobulins formed as a result of T-cell cooperation are known as IgG, IgE, and probably most of the IgA. IgG is the most important of the Ig antibodies in limiting the harmful effects of bacteria, virus, and parasites. T-cells circulate in the blood and act as "responder cells." They "recognize" foreign antigens and are stimulated by them to send signals to attract macrophages to the site (chemotaxis) for phagocytosis (engulfing of the foreign particles for example, microor- ganisms, by phagocytes). Thus, T-cells and antigens stimulate both antibody produc- tion and cellular defensive mechanisms. They do not produce antibodies per se, but they do bear specific T-cell receptors on their surface that selectively bind antigens. Like B-cells, T-cells react to antigen stimulation by secreting molecules that mediate their immune function. On the basis of the molecules they secrete, T-cells have been subcategorized as helper T-cells and cytotoxic T-cells. Today it is clear that helper T-cells fulfill their role by secreting interleukins. Cytotoxic T-cells, in contrast, make direct contact with infected cells and, by secreting toxic molecules, kill the cells and the microbes they contain (4). In addition to the helper and cytotoxic cells, the occurrence and intensity of an immu- nological response is regulated by subsets of T-cells termed suppressor cells. Suppressor cells reduce or inhibit the activity of T-cells in delayed hypersensitivity, and of B-cells in the formation of antibody. They participate in maintaining tolerance to tissue and other antigens. Failure of suppressor cell activity can result in disorders associated with T-cell abnormalities. Thus, the clinical manifestations of an immunological response are due to the activities of the effector T- and B-lymphocytes and of the suppressor cells. Allergic contact dermatitis or delayed type contact hypersensitivity (CH) to conjugates of simple chemical haptens is an example of the exquisite specificity of T-lymphocytes for small defined antigens. In general, the ability of a chemical to elicit contact sensi- tivity has been shown to directly correlate with its ability to combine with proteins. These observations led to the concept that the antigen recognized by T-cells in contact sensitivity was hapten-conjugated epidermal proteins. Several studies have shown that T-cells from contact-sensitized human or guinea pig donors could be activated in vitro by haptens conjugated to epidermal extracts, erythrocytes, or leucocyte antigens, all of which may be normal carriers for in vitro hapten sensitization. In delayed CH, antigen-