36 JOURNAL OF THE SOCIETY, OF COSMETIC CHEMISTS stituents. Actually, in the case of mustard gas, in animals that develop a sensitization to it, e.g., the guinea pig and man, Cullumbine (3) has shown that free mustard gas cannot be demonstrated beneath the epidermis. Second, it is known that if the simple chemical is introduced by an extra- epidermal route and precautions are taken to avoid contaminating the epidermis and adjuvants are not employed, an eczematous sensitization de- velops rarely, if at all. Now, if the simple chemical was absorbed as such and conjugates formed elsewhere than the skin, there would be no rational explanation for the foregoing facts. Assuming then a conjugate has been made, what happens to this conju- gate? Before attempting to answer this question, it might be well to digress a moment in order to point out the nature of the problem. If a small area of skin is painted with 2:az dinitrochlorobenzene, upon testing that person approximately three weeks later, assuming they become sensi- tized, all areas of the skin will be found to be reactive to concentrations to which previouslyunexposed individual do not react. The question is, by what /nechanism did the entire integument become allergically hypersensitive? One theory was that the simple chemical when applied to the skin surface either traversed the entire skin in a hypothetical lipid film that envelops the body, or it was disseminated within the epidermis by way of the inter- cellular bridges. (Whether or not these bridges actually function is, so far as I know, not certain.) An alternative hypothesis was that the simple chemical was not distributed in the aforementioned fashion but that it some- how caused antibodies to be manufactured locally, which were then dis- seminated by any route, but which were ultimately brought back to the epidermis and fixed there. None of these hypotheses have stood the test of experimentation in that one can disprove the intra-epidermal transmission by the fact that if an epidermal island is created, i.e., an area of epidermis is surgically isolated from the rest of the epidermis, and the sensitizing ma- terial applied to the island, the entire skin still becomes sensitized. It has also been shown that the site to which the sensitizing simple chemical has been applied can be surgically extirpated any time later than twenty-four hours after the application without interfering in any way with the subse- quent development of the sensitization. This disproves the local manu- facture of antibodies (at least the exclusive local manufacture) and their subsequent dissemination from that site. It would then seem that the conjugate as such must be absorbed at least in part from the site of its formation. The major channel for its absorption is probably the lym- phatics. So far as I know, there is no unequivocal proof for this, but there is much inferential evidence for it which I shall not review. The conjugate is probably then carried to the regional lymph nodes. It is now appropriate to inquire as to the nature of the changes induced by the conjugated protein. If the body regards this conjugated protein as

DEVELOPMENT OF AN ECZEMATOUS SENSI FIZ3_TION 37 an alien protein, the customary immunologic sequence of events would be that antibodies develop whose specificity is directed toward the protein conjugate. These antibodies would be found in the circulating gamma globulins. Actually, under appropriate circumstances, this can be shown to be so. Yet, it can be shown that, even though such antibodies exist, they have nothing to do with the development of the eczematous reaction. In fact, no circulating antibodies demonstrable by any techniques have been shown to be responsible for this type of reaction. This, then, raises the query as to the nature of the change which is responsible for the reaction. Some years ago, Burner (4), in an endeavor to explain the specific'ty of anti- body response, hypothesized that the antigen (alien protein) got to the site of globulin synthesis and there caused an enzymatic adaptation in the cells concerned with the synthesis of the globulin. As a consequence of this adaptation, these cells or the enzyme systems within them could utilize this new alien protein, but the globulin that they produced would be slightly different than that manufactured prior to the adaptation. This modification in the globulin would then be revealed by the attributes which are labeled as antibody properties. In view of the fact that each alien protein engenders a slightly different adaptation, the globulin synthes'zed by the adapted cell would be slightly different in each case, hence the specificity. Now, Burnet's views adequately take care of allergic situations in which there are circulating antibodies but offer no explanation for the type of reaction which is being considered here and in which, as has already been stated, circulating antibodies, if they exist at all, play no demonstrable role In an endeavor to explain the nature of the change in these types of reactions, Rostenberg and Brunner (5) extrapolated from Burnet's views. What they said in essence was that the basis of an allergic sensitization is the enzymatic adaptation to the antigen in question. If this adaptation takes place in a cell or system concerned with the synthesis of globulin, then there will be evidence of that adaptation in the form of circulating globulins with new properties which are labeled as antibodies. If, however, the adaptation takes place in a cell or system not concerned with the pro- duction of globulin, then there is, of course, no reason why there should be any evidence of that adaptation in the form of modified circulating globu- lins or, in other words, circulating antiboclies will either be not present, or, if they exist, can be shown to have nothing to do with the reaction in ques- tion however, the cell in which the enzymatic adaptation took place now displays a different reactivity toward the antigen (the material that caused the adaptation to take place) than the same cell did prior to this taking place. It is believed that in the delayed type of hypersensitivity, of which the eczematous reaction is one variety, the basis for the allergic state is an enzymatic adaptation in cells that are not concerned with the synthesis of globulin.