[CANCER RESEARCH 28, 1423-1429,July 19«8] Bases for the Recognition of Antigenicity1 G. J. V. Nossal and A. Abbot The Walter and Eliza Hall Institute of Medical Research, Melbourne 3060, Australia Summary immune studies, and cancer research. In this brief review, I The recognition of antigenicity is a problem that can be will attempt to outline our current concepts of how mammalian broken into two main portions. First, there is the response of species actually do recognize antigenic molecules and what re the immune system to antigens and second, the recognition of actions may follow such recognition. Broadly speaking, the foreignness at the local tissue level. The former is best separated problem may be broken into two major portions. First, there operationally into two parts, the response to soluble or par- is the general response of the lymphoid and reticuloendothelial ticulate-injected antigens, and the response to antigens of systems to the entry or emergence of antigens. This is the prov grafted cells. ince of students of inflammation and immunology. Second, The present paper deals mainly with the basis for recogni there is the problem of local tissue reactions which may occur tion of injected antigens. Evidence is presented that a specific following the appearance of cells with changed surface antigens in an organ. This is a much less well-defined area of study, but antibody, either natural or immune, is an important steering mechanism for immune responses. It influences not only the one which may turn out to have great significance in cancer extent of antigen capture, but, just as important, the internal research. The first area, which will be the major subject of this distribution of antigen between certain well-defined compart paper, can again be broken into two parts, purely for didactic ments of the reticuloendothelial system of lymph nodes. Spe purposes. These are the response to soluble or paniculate cifically, if antibody or natural opsonin to an injected antigen antigens introduced by infection or injection, and the reaction is present in an animal, localization of antigen in primary lym- to cellular antigens such as grafts. phoid follicles and in germinal centers is an inevitable conse Recognition of Foreignness of Injected Materials quence. In these locations electron microscopic autoradiography shows that antigen in follicles is held in an extracellular, mem The most precise information that we have on recognition brane-associated location without being subjected to phagocy of foreignness comes from direct examination of what actually tosis. The immunologie consequences of follicle antigen-trapping happens to foreign materials when they are injected into the are germinal center formation and, in all probability, the de body of an adult animal. Even here, definition of the problem velopment of memory cells. Whether membrane-associated an is not easy, because in each case we must compare the way tigen is important in primary immune responses is not known. that a foreign material is distributed with the way in which Some key papers in the literature concerning early recogni an autologous constituent of similar physical and chemical tion steps in antibody formation are briefly reviewed. The characteristics would have been handled in the body. Obviously, if we had a window into an animal's own bloodstream and conclusion is reached that there may well be factors other than circulating or cell-bound antibodies concerned, some of which could determine the fate of its red cells, serum albumin, and are under genetic control. The chemical nature of these is not circulating insulin molecules, we would get widely differing known. answers. Therefore, it is reasonable to expect significant dif Present knowledge in the fields of cellular recognition of ferences in distribution pattern also among foreign constituents grafts, allogeneic inhibition, and tissue surveillance is briefly which enter the body. Nevertheless, there is one common fea surveyed. ture which applies to all but the smallest foreign molecules and that is their tendency to be taken up by the reticuloendo Introduction thelial system. Autologous constituents are not entirely exempt The current immunology research explosion has been moti from phagocytosis, as witness the disposal of effete red blood vated by many considerations far removed from the field of cells and the autophagocytosis of lymphocytes In germinal defense against microbial invasion. Among the most important centers. This has speculatively been ascribed to some antigenic factors has been the realization that recognition of foreignness change in the cells concerned, but concrete evidence is lacking. is a concept of great importance in organ transplantation, auto- In general, however, foreign red cells are phagocytozed much more rapidly and extensively than autologous red cells, and 1 This work was supported by grants and contracts from the the same is true of smaller foreign particles and molecules. This National Health and Medical Research Council, Canberra, much will have been familiar to all readers, but there are Australia; the National Institute of Allergy and Infectious Dis eases (AI-0-3958) ; and the United States Atomic Energy Com subtleties to the role of the reticuloendothelial system in anti mission (AT-30-D-3695). This is Publication No. 1213 from The gen handling that are not as widely known and which we must Walter and Eliza Hall Institute of Medical Research. now discuss. JULY 1968 1423 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1968 American Association for Cancer Research. G. J. V. Nossal and A. Abbot The Role of Antibody in Antigen Trapping tion) has made a detailed study of what portion of the immuno- One of the most important factors in the recognition of globulin molecule is instrumental in bringing antigen into soluble or particulate antigens is antibody. Much attention follicles and holding it there. Most of the evidence indicates has been given to the role of a specific antibody in accelerating that there are one or more sites on the various immunoglobulin the rate of uptake of materials by the reticuloendothelial sys heavy chains which tend to bind to follicle reticular cells. A tem, but far less to the equally important question of the large number of different antigens have now been tested for effect of antibody on the internal distribution of antigens in follicular localization. In every case where there is antibody the different compartments of the reticuloendothelial system in the serum, follicular localization is a major feature of lym which exist in lymphoid tissue. We will deal first with evidence phoid antigen trapping. In fact, injection of labeled antigen into an animal and observation of follicular localization 4-24 which comes from use of specific, immune antisera and will then examine the role of natural antibodies or opsonins. hours later can be an exquisitely sensitive test for the presence A convenient way of illustrating the point is to compare the of antibody. This is illustrated by studies in tolerant animals distribution of an antigen in normal adult rats in the presence (2, 12) where a trace of antibody in an animal exhibiting sub and absence of antibody. If human scrum albumin (HSA) stantial partial tolerance can be picked up by the tendency labeled with 1-5I is injected into the hind footpad of a rat, for enhanced follicular localization even when sensitive serum- antibody-titration methods fail to reach threshold levels. only around 0.02% of it will be stably trapped in the popliteal nodes (15). Autoradiographic analysis shows that virtually all Specific antibody in immunized animals is thus a clear and of this is in macrophages in the lymph node medulla, chiefly obvious example of one basis for recognition of antigenicity. We now come to the more vexing question of how virgin, non- within the sinuses but also scattered through the cords. On the other hand, if HSA is complcxod with a specific antibody immunized animals recognize antigens. In an earlier study (1), either in vitro or in vivo, the amount trapped is increased by we noted that in unimmunized animals there was a broad a factor of about 10, and the internal distribution in the lymph correlation between the degree of immunogenicity of a material node is quite different. Some early medullary localization is and its tendency for follicular localization. Highly foreign ma present, but the most prominent stable antigen depots are in terials such as bacterial flagellar antigens showed excellent the cortical lymph node follicles. The antibody has little, if follicular localization; moderately immunogenic products such any, effect on the extent of medullary macrophage-trapping of as horse ferritin showed less; heterologous albumin showed the antigen, but it has a dramatic effect on retention in lym- less still; and minimally antigenic proteins such as gelatin showed no follicular localization at all. We now recognize that phoid follicles. The question immediately comes up as to other factors besides "degree of foreignness" influence follicular whether the size of the foreign particle is a major factor in antigen handling. This is not a likely complete explanation, as localization in virgin rats, such as particle size and other USA aggrega tcd by heat to a particle size comparable with physicochemical characteristics. For example, carbon particles antigen-antibody complexes can be shown to be trapped much (6, 18) and saccharated iron oxide (6) show some follicular better in the medulla of the nodes of normal rats than native localization though they are not generally considered to be HSA; but in the absence of antibody, heat-denatured HSA antigenic. Still, in all probability the reason why some smaller shows no tendency for follicular localization (10). molecules show follicular localization in virgin animals is the Further insights into the differences between follicular and presence in their serum of natural antibodies or opsonins fre medullary HSA localization can be gained by electronmiero- quently in amounts undetectable by standard serologie tech scopic autoradiography of lymph nodes.