Perspectives in Biology and Medicine

BOUNDARIES OF IMMUNE REACTIVITY: IMPUCATIONS FOR THE RELATIONSHIP OF MAN TO HIS ENVIRONMENT DAVID R. KAPLAN* It is a phenomenon characteristic of the mammalian immune system that immunoglobulins can be produced that recognize foreign organisms . This characteristic is important in thwarting pathological infestations , but the implications of the potential recognition of diverse elements in the human ecosystem extend further. Immunoglobulins do not recognize everything. There are boundaries to their potential repertoire that define the sphere of immune reactivity. To consider that sphere is to explore the edges of the immune system—an exploration that is, I believe, interesting and informative. Immunoglobulins can bind to multicellular parasites, eukaryotic amoebas, fungi, bacteria, and viruses; but this list does not really describe the range of immune reactivity since immunoglobulins bind to molecular structures on these organisms and not to the whole organisms . What molecular structures are recognized? Immunoglobulins can bind to protein macromolecules, to nucleic acid macromolecules, and to sugar macromolecules. It is important to note that they cannot recognize amino acids, nucleic acids, or simple sugars by themselves but instead require interaction with larger determinants. It was demonstrated in a series of experiments with proteins and sugars containing increasing numbers ofsubunits that immunoglobulins can recognize as few as three of these subunits combined in a chain but not less [I]. It appears that immunoglobulins can bind to determinants with molecular weights greater than 250 daltons or with dimensions in the range of tens to Supported in part by PHS grants A122505 and CA36189 awarded by the NIH and by a Hartford Foundation fellowship. The author thanks Drs. K. Smachlo and M. Lamm for their helpful suggestions and Ms. J. Nagy for secretarial assistance. This essay received honorable mention in the 1986 Dwight J. Ingle Memorial Writing Award for authors under 36. ?Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106.© 1987 by The University of Chicago. AU rights reserved. 0031-5982/88/3101-0558$01.00 42 I David R. Kaplan ¦ Boundaries ofImmune Reactivity hundreds of angstroms. To further define the boundaries of immunoglobulin recognition, we have to consider what is missing from our list of macromolecules. Lipids found inside membranes are not recognized by immunoglobulins; hydrocarbons polymerized as plastics are not bound by immunoglobulins. With these considerations in mind, we can define the boundaries of immune reactivity. Immunoglobulins recognize any three-dimensional spatial configuration of matter in an aqueous phase that exists within certain size limitations in the range of tens to hundreds of angstroms. Within these boundaries the immune system is remarkably flexible and capable. The potential mammalian immunoglobulin repertoire has been estimated to consist of more than 10,000,000 specificities representing virtually any conceivable configuration within the domain of the immune system [2, 3]. Since immunoglobulins bind to determinants on the molecules of foreign organisms, the immune system represents a library of knowledge about the environment on a molecular level. This molecular ecosystem is the domain of the immune system. Immunoglobulins do not recognize elephants or tsetse flies in the ecosystem of the African savannah, but they can specifically recognize elephant serum albumin and distinguish it from the serum albumin of any other species, and they can recognize the molecular determinants of trypanosomal parasites in the salivary glands of the flies. What does this potential reactivity engender? The immune system represents a molecular-level microscope through which the ecosystem can be viewed and monitored—an objective that focuses aqueous molecular configurations instead oflight. With our eyes we look out on the savannah and see the wildebeest herds; with our immune system we can sense the presence of wildebeest macromolecules in our gut or in our blood. The immune system does not reach out into the environment, but it monitors the ecosystem regardless. Why is this capability important? Why is it interesting? The ability to monitor our molecular ecosystem ensures our molecular integrity. It protects us at the molecular interface so that pneumococci do not colonize our lungs and wildebeest macromolecules are not incorporated whole into our bodies. The boundaries of immune reactivity do not direcdy account for the ability of the immune system to ensure our molecular integrity or to prevent infestation by a diverse array of...