Regulation of Immune Responses by Anti-receptor Antibody

Transcription

1 ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 8, No. 4 Copyright 1978, Institute for Clinical Science Regulation of Immune Responses by Anti-receptor Antibody HEIN Z KÖHLER, M.D. La Rabida-University o f Chicago Institute and Department o f Pathology, Biochemistry and Microbiology, University o f Chicago, Chicago, IL ABSTRACT A new function of antibodies in the regulation of immune responses is proposed. Antibodies have specific variable sequence determ inants which are detected by anti-idiotypic antisera. Anti-idiotypic antibodies can suppress the production of the complementary idiotypic antibody and are, therefore, specific anti-receptor antibodies. Experiments in inbred mice have shown that mutual and reciprocal functional interactions of idiotype and anti-idiotype can occur. These findings give evidence for regulatory m echanism s in the expressions of immune clones by com plem entary idiotypes. Introduction The structure and function of immunoglobulins and their role in the defense against bacterial and viral intruders are known. However, a second function of im m unoglobulins is co n n e cte d in tim ately w ith im m une defense m echanisms. In fact, it seems that without the second function the im m une system could not work properly and thus could not exist. Each antibody has specific structures which bind the antigen. The specificity and the uniqueness of an antibody are determ ined by its binding site configuration. Since the experiments of O udin11 and Kunkel10 in 1963, it is known that the uniqueness and the specificity of an antibody can be d e scrib e d by a second criteria which does not involve the antigen. These investigators have prepared antisera which were specific for a given antibody or im m unoglobulin. The specificity of these antisera was so high th at not only th e a n tig en b in d in g specificity but also the donor or the individual animal from which the antibody was obtained could exactly be identified. Since these specific anti-antibody recognized very u n iq u e and in d ividual structural features on an antibody m olecule, they were called individual specific determ inants or idiotypes. Antibodies which bind to these determ inants are called anti-idiotypic antibodies. The sec /78/ $00.90 Institute for Clinical Science, Inc.

2 REGULATION O F IMMUNE RESPONSES BY A N TI-RECEPTO R ANTIBODY 319 ond function of antibody mentioned earlier deals with its potential to act as an antiidiotypic antibody or to be the target for recognition as idiotype by another antiidiotypic antibody. For this biological function, antibody and anti-antibody, i.e., idiotype and anti-idiotype, are present in the same individual, produced by the same individual. Specific Suppression by Anti-idiotypic Antibody B-lymphocytes which can be triggered by antigen to produce antibody carry receptors for antigen on th eir surfaces. These receptors are immunoglobulins in nature and essentially copies of the later synthesized antibodies.4 Thus, receptors and antibody specific for the same antigen share at least the same combining site structure. It follows from this that anti-idiotypic antib o d ies w hich b ind specifically to a given antibody also will react with the receptor immunoglobulin of that cell clone which can produce this antibody. This line of reasoning was used by us3 and others5,8 in designing experimental systems in which an anti-idiotypic antibody su p p resses specifically the re sponse to a defined antigen. The simplest model for anti-idiotypic suppression is com petition of an tig en w ith antiidiotypic antibody for the receptor on B-cells (figure 1). Consequentially, antiidiotypic antibody functions here as anti-receptor antibody.13 More recently, evidence has b e e n o b tained that an tiidiotype suppression is a complex reaction involving the additional interaction of the Fc-portion of anti-idiotypic antibody with the Fc-receptor on B-cell or macrophages.9 Evidence for Regulation by Anti-idiotypic Antibody Anti-idiotypic suppression offers an attractive m odel for mechanism s regulating F ig u re 1. Suppression by anti-receptor antibody. An immunocompetent B-cell has receptor specific for a given antigen, (Ag). Binding of Ag to the receptor triggers the production of antibodies. The receptor can also bind to specific anti-receptor antibody (ARA). If all receptors are occupied by ARA, the B-cell cannot be triggered by Ag. im m une responses. Idiotype and antiidiotype are both immunoglobulins and the mutual affinity of both is based on the com plem entarity of their binding site structures. Chem ically speaking, the affinity of idiotype and anti-idiotype re sides e n tirely in th e ir V -region sequences. Therefore, there is no a-priori reason to designate one antibody the idiotype and th e com plem entary a n tibody the anti-idiotype. For example, if the idiotype in figure 2 is assigned to the left hand corner, the com plem entary antibody of the right side becomes the anti-idiotype. However, the model can be reversed to make the idiotype an anti- «anti-id F ig u r e 2. Com plem entary idiotypes. Two kinds of antibodies have complementary combining site structures which fit like key and lock. Depending on the experimental design either antibody can function as idiotype or anti-idiotype.

3 320 K Ö H LER idiotype. Transposing this system to the cell receptor level it could work as a closed feedback loop in which the synthesis and the activity of both com plem entary antibody are controlled. What is the evidence that such a mechanism might be operating in the regulation of immune responses? The first support for this model comes from the observation that idiotype and anti-idiotype can be made by the same individual.12 F u r thermore, the appearance of idiotype and anti-idiotype occurs sequentially during an immune response. If Balb/c mice are im m unized w ith a phosphorylcholine containing antigen, they first produce antibody against phosphorylcholine (PC) and, subsequentially, anti-idiotypic antibody against the idiotype of the anti-pc antibody.1,8 Recently, a sim ilar sequential appearance o f com p lem entary idiotypes has been observed during the I. Coexisting Complementary Responses F ig u r e 4. T and B-cells have receptors for antigens which can engage in a functional relationship based on the principle of complementary idiotypes. Therefore, B and T-cells can be paired as B-B doublets or B-T doublets. I B inding to Ag H. Priority of the First Induced Response I t Binding to Receptor FIGURE 3. Com plem entary antibody responses. Groups of mice were immunized with phosphorylcholine containing antigen (PC) to produce the anti-pc idiotype or with the anti-pc idiotype to produce anti-idiotypic antibodies. Depending on the timing of immunization both complementary responses can coexist in the same animal (upper panel I) or the first established response suppresses the subsequently induced response (lower panel II). T15 is the idiotype of the anti-pc response. F ig u r e 5. Dual function of antibody. Cell receptors and antibodies bind to antigen. In addition the antibodies produced by the same cell can also bind to the receptor of another cell. This induces specific suppression of the target cell. It is hypothesized that antibody binding to cell receptors is involved in the regulation of the immune response.

4 REGULATION O F IMM UNE RESPONSES BY A N TI-RECEPTO R ANTIBODY o n togenic d e v elo p m en t in n eo n atal B alb/c m ice. The serum of new born Balb/c mice contains, for the first four to five days of life, anti-idiotypic antibodies against the anti-pc idiotype and from day five on, the anti-pc idiotype increases steadily w hile the anti-idiotype d isap pears. Thus it seems that idiotype and anti-idiotype are constituents of the naturally occurring antibodies. At present, the se q u e n tia l appearance of a n tiidiotype and idiotype in the ontogeny of Pc-responsive clones is not understood, but it can be speculated that these early events are important steps for the maturation of the immune response. To add further evidence for the proposed model of regulation by interacting com plem entary idiotypes, adult mice were im m unized with antigen to produce idiotype or w ith idiotype to make antiidiotype. The effect of either response upon the complementary responses was observed. It has been found that a preceding idiotype response sp o iled attem pts to induce an anti-idiotype re sponse and, vice versa, a p reced in g anti-idiotype response did not perm it a later idiotype pro d u ctio n. It can be learned from these findings that the first established response had gained priority of the possible complementary response. H ow ever, if both com plem entary idiotype responses w ere in itia te d at about the same tim e, both responses occurred (figure 3). The priority of the prevailing response is entirely determ ined by the tim e sequence of immunization. Thus, it is conceivable that the principle of the priority of the first response plays an important role in the immunological adaptation to environm ental stim uli. T he clonal interactions of two com plem entary antibodies or idiotypes provide the minimum requirem ents for a fu n ctional netw ork of cells an d a n tibodies in the immune system. Recent data2,7 allow us to include into this model both B- and T-cells since B- and T-cells can carry either idiotypic or anti-idiotypic receptors (figure 4). So far it is known that anti-idiotypic T-cells can suppress or help idiotypic B-cells. It has also been learned that B-cell products, i.e., antibodies, can stim ulate T suppressor cells. From these experim ents a new concept emerges: the immune system is under internal self-control including the B- and T-cell compartm ents. However, several questions and details in this model are still unanswered and missing. What is the chemical equivalent for idiotype on T-cell receptors? What are the connections betw een the control of im m une responses by the im m une response genes (Ir-genes) and the regulation by complementary idiotypes? What are the consequences of having com plementary idiotypes for understanding the generation of anti-body diversity and evolution of V-genes? It w ill require more careful experim entation and im agination to reconcile apparent discrepancies in our current thinking on models of immune regulation based on the dual function of antibodies (figure 5). References 1. Au g u s t in, A. and C o s e n z a, H.: Expression of new idiotypes following neonatal idiotypic suppression of a dominant clone. Eur. J. Immunol. 6:497, C o s e n z a, H., J u l iu s, M. H., and Au g u s t in, A.: Idiotypes as variable region markers: analogies between receptors on phosphorylcholine-specific T & B lymphocytes. Transplant Rev. 34 :3, C o s e n z a, H. and K ö h l e r, H.: Specific suppression of the antibody response by antibodies to receptors. Proc. Nat. Acad. Sci. 69:2701, E h r l ic h, P.: On immunity with special reference to cell life. Proc. Roy Soc B. 66:424, ElCHMANN, K.: Idiotype suppression. I. Influence of the dose and the effector function of anti-idiotypic antibody on the production of an idiotype. Europ. J. Immunol. 4:296, H a r t, D. A., W a n g, A. L., P a w l a k, L. L., and N lso N O FF, A.: Suppression of idiotypic specificities in adult mice by administration of anti-idiotypic antibody. J. Exp. Med. 135:1293, 1972.

5 3 2 2 K Ö H LER 7. J a n e w a y, C. A. and P a u l, W. E.: Haptenspecific augmentation of the anti-idiotype antibody response to hapten-myeloma protein conjugates. Europ. J. Immunol. 3:340, K l u s k e n s, L. and Kö h l e r, H.: Regulation of immune response by autogenous antibody against receptor. Proc. Nat. Acad. Sei. 71:5083, Kö h l e r, H., R ic h a r d s o n, B., R o w l e y, D. A., and S m y k, S.: Immune response to phosphorylcholine III. Requirements of the Fc portion and equal effectiveness of IgG subclasses in anti-receptor antibody-induced suppression. J. Immunol. 119:1979, Ku n k e l, H. G., M a n n ik, M., and W il l ia m s, R. C.: Individual antigenic specificity of isolated antibodies. Science 140:1218, O UDIN, J. and M ICHEL, M.: Une nouvelle forme d allotypie des globulins & du serum de lapin, apparemment liü a la function et a la spécificité anticorps. Comp. Rendu. Acad. Sei. 257:805, Ro d k e y, L. S.: Studies of idiotypic antibodies. Production and characterization of auto antiidiotypie antisera. J. Exp. Med. 139:712, R o w l e y, D. A., F it c h, F. W., St u a r t, F. P., Kö h l e r, H., and C o s e n z a, H.: Specific suppression of imm une responses. Science I8i:1133, 1973.