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Immunology Today, vol. 3, Nil. 4, 1982

rostrum Some thoughts on idiotypic networks and immunoregulation J. Urbain and C. Wuilmart Laboratory of Animal Physiology, Universite Libre de Bruxelles, B1640 Rhode-St-Genese, Belgium

The firxl of two arluies in lohirh J. Vrhain and C. Wmlmarl disats.s Ihe rnanipulatwn of idiotype-anti-idiotype internctions in inimnne resfxmses. Many recent data, it is claimed, support Jerne's idiotype network hypothesis' (for review, see Refs 2 and 3). However, it is fair to say that the network hypothesis is not universally accepted'. This could be due partly to the fact that, in discussing it, many people do not talk about the same things even when they use the same words. The functional relevance of some data is questioned and, furthermore, different contradictory network models have been put forward (for examples, see Refs 5-8). Let us first define a minimum idiotypic network hypothesis. The word 'network' implies connectivity between different elements of the immune system and 'idiotype network' means that idiotypes are involved in clonal interactions. In a broad and clear sense, the network hypothesis states that immune regulation is due partly to signals generated within the immune system - more precisely, to idiotypic-anti-idiotypic interactions. The minimum network hypothesis does not state that idiotypic interactions are the only means of interlymphocytic communication. A minimum network theory does not claim that all idiotopes are connected (some idiotopes could have no regulatory significance). And it does not state that physiological signals (activation or suppression) are given through idiotypic-anti-idiotypic interactions. A large body of data suggests that at least three kinds of connectivity are used in the immune system. (1) an antigen with different epitopes can bridge idiotypic communities which normally ignore each other when antigen is absent. Associative recognition of different epitopes, linked to the same backbone, allows transmission of signals between lymphocytes displaying receptors of different specificities (the Mitchisonian link). (2) As a rule, T lymphocytes seem to be indifferent to free circulating antigens and idiotypes. They recognize antigens or idiotypes only in the context of membrane markers encoded by the major histocompatibility complex ( M H C ) . These M H C markers or restriction elements serve as a cellular semaphore, as passwords which identify the compartment to which a given cell belongs. It could be

said that restrictive recognition gives arrows in the idiotypic network. A given T lymphocyte can be defined by two types of potential: functional (help or suppression) and interactive (defined by immunological and physiological receptors). From available data, these two kinds of potential are independent. A T-helper lymphocyte can display idiotypic or anti-idiotypic receptors. Within the immune system, one immunoglobulin (Ig) cannot know whether it is an idiotype or an anti-idiotype. (3) Idiotypic interactions can bring lymphocytes into close contact, even though physiological signals (activation, differentiation or suppression) are not transmitted via these interactions. Signals are defined by the compartments to which interacting lymphocytes belong. Associative recognition of M H C and idiotypes governs the fate of interactions. As a result of successful interactions, physiological signals (interleukins?) are released in the vicinity of activated T cells. Are all T cells M H C restricted? There is some evidence that the answer is no. This important point deserves more investigation. Cohn"' has stated that the network theory cannot deal with the problem of discrimination between self idiotopes and self epitopes. Theoretically, the problem can easily be solved by postulating the existence of T cells restricted for Igs. For example, the physiological receptor of T cells could recognize isotypic determinants of Ig or some la determinants present only on B lymphocytes. The immunoglobulin receptor would recognize idiotypic determinants. Several proposals have been put forward to deal with some aspects of immune regulation (see box). (a) The two signal theory of Bretscher-Cohn'. T h e original hypothesis was put forward before the discovery of suppressor T cells. Therefore, a third signal was incorporated in the theory to account for class regulation, on the basis of positive unresponsiveness'". (b) The one (non-specific) signal hypothesis" '^. (c) The idiotype network hypothesis'.

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A comparative discussion of liiese pr()|)osals is instructive and revealine;. In tlic original lorm. they all appear to be fragmentarx- (this is in fact exjiected from anv Iheorv). However, it is more intereslint:; to stress that some part of the truth was guessed in each proposal: Associative recognition is indeed a crucial event in immune regulation; Ig rece[)tors of mature B lymphocytes pick up antigen but these isolated interactions are insufficient lo ensure complete activation and differenliation: most antigens lack an inherent triggering ability; Idiotypic interactions are used in the language of lymphocyte communication. Broadly speaking, regulatory mechanisms operating in the immune system can be divided into at least two first-order phenomena, hirstly, an initial repertoire is built in each individual. This initial repertoire stems mainly from the random (.^) association of germ line pieces (V. I), J . . .) for heavy and light chains. Some lluctuations seem to occur at the border of gene pieces during the process of recombination. This initial repertoire re})rcsents the potential repertoire and is much larger than the final rejiertoire that is accessible for antigens. This reduction is linked lo the establishment of natural tolerance and to su|)pression of many idiotypes (see below). One of the inajor problems is to understand the rules which sha[)e the final repertoire. .Secondlv, the available repertoire is itself submitted to fine control mechanisms involving the action of different sets o f f cells. Is the network a logical necessity? The most astonishing property of the immune repertoire is diversity. The immune system is complete, able to respond to a vast array ol antigenic stimuli. Being com[)lete, the immune system cannot

Theories of immu ne regulation Twa-s^nal hypethmds If 8 given ar(lig«n carries at least two epitopes, one epitope can be recognized by the antigen-sensitive cell and the other by a regulatory T cell. Signal 1 Is delivered through the binding of one epitope to the immunoglobulin receptor of the antigen-sensitive cell. Signal 2 is delivered via restrictive recognition of the antigen-sensitive celt by the regulatory T cell. Signal 1 alone is paralytic (induces "negative unresponsiveness') and allows sstf-non-self discrimination but association of signal 1 with signal 2 leads to induction. If signal 2 is delivered by a cooperating T cell, an immune response is induced; but if it Is delivered by a suppressor T celt 'positive unresponsiveness' t= suppression) is established. On»-signsl i^fiothesis The bindiftg of antigen to immunoglobulin receptors of antigen-sensitive ceils does not deliver any activating

avoid the recognition of its own elements. In other words, within the repertoire of one individual, the coexistence of idiotypes and autoanti-idiotypes seems inescapable. The forinal idiotypic network is /i firmn a logical necessity, as was suggested by the genial hunch of i\. K. Jerne. This logical necessity has been proven experimentally (for review, see Refs 2 and ?>). The main Cjuestion becomes: is this co-existence of significance for immunoregulation:' When one rabl)it is injected with antibodies from another rabbit (matched for allotypes), it responds by the synthesis of anti-idiotypic antibodies (.'\b2 or antibodies of second g e n e r a t i o n " . ) T h e functional netvyork implies that this sort of event occurs also within one rabbit confronted with one antigen. Most experiments which support the functional idiotypic network hypothesis rest on the following principle: if idioty|)e-anti-idiotype interactions play a significant role in immune regulation, the modification of these interactions should lead to dramatic qualitative and cjuantitative alterations of an immune response. Many data, collected during the past few years, clearly show that this is indeed the case. We are next confronted with some kind of uncertainty princijile: are we looking just lor laboratory oddities created by the experimental procedures or are we looking into the real inner life of the immune system? (lohn has suggested that the occurrence of autoanti-idiotypic antibodies and of T helper or suppressor cells bearing autoanti-idiotypic receptors could be due to the breaking of natural tolerance (defined as 'negative unresponsiveness'). However, since the same Ig can be both an idiotype (recognizing antigen X) and an anri-idiotype, the two-signal theory would lead to an cm[)ty immune system, completely paralyzed by natural tolerance. signal. Immunoglobulin receptors are just 'concentration devices' to focus antigen on the cell. On the other hand, various mitogen receptors are polyclonaliy distributed among antigen-sensitive cells. Induction of humoral antibody responses requires the triggering of these nonimmunoglobulin receptors by mitogens - of either external type (i.e. fhymus-independent antigens like lipopolysacchartde) or internal type (signal from regulatory T cell). Self-non-self discrimination is not based on the elimination (paralysis) of self-reactive B celts but is mediated by regulatory T cells. Networic h y p o t h e c The co-existence of idiotypic and anti-idiotypic immunoglobulin receptors inside the immune system provides a new way to understand clonal interactions. Antigen stimulates idiotypic cells which in turn stimulate anti-idiotypic cells able to govern the intensity and duration of the immune response. In this ease, self-non-self discrimination can be due only to suppressor T cells bearing anti-idiotypic receptors (anti-ami-self).

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Is the idiotypic network an experimental necessity? As recalled from above, the problem of regulation can be divided into two questions. Given a potential repertoire (due to combination of germ line pieces VH,DH,JH,VL,JL.--):

(a) What are the rules defining the selection of available repertoires? (b) What are the rules governing the regulation of the accessible repertoire? This second problem encompasses phenomena like the rise and fall in antibody affinity, switches of class, recruitment phenomena, feedback loops, the sharing of idiotypic specificities between antibody subpopulations present in an individual serum (some of these subpopulations are encoded by distinct germ line genes'). This last fact is an observation made in animals injected just with antigen and therefore we feel that we are looking here to the inner life of the immune system (for a discussion of these topics, see Ref. 2). Let us consider idiotypes a la Oudin (these idiotypes are mostly specific for one antigen and are mainly present in one or a few individuals). A prion, idiotypy can be explained in two ways: (a) idiotypes can be due to disparate genetic repertoires in different individuals. This would ensue if a large part of the immunological repertoire was built de novo in each individual by somatic mutations; (b) The potential repertoire could be more or less the same in all individuals, with regulatory p h e n o m e n a involving idiotypic interactions allowing the selection of different available repertoires. This view would predict the existence of silent idiotypes whose expression is prevented by natural suppressors. Let us consider two rabbits X and Y with no known familial relationship. Normally, Igs in rabbits X and Y immunized with antigen A will express, respectively, the idiotypes idx and idy. Would it be possible to reprogram the immune repertoire of rabbit Y and to favor in this rabbit the expression of id^? Id. is perhaps silent because of the presence of suppressors whose receptors are able to discriminate between id^ and idy! i.e. these receptors behave as internal anti-anti-A. Perhaps induction of immunity against these internal suppressors would relieve the silent id^ from suppression. Is it possible to orient the repertoire towards a predetermined goal? This was the rationale behind our development of an 'immunization cascade''''-'" (Fig. 1). O u r results have been extended and confirmed by o t h e r s " '". We start with a randomly chosen idiotype Abl (for example, a restricted anti-carbohydrate antibody). A similar idiotype has been detected in only 1 out of 60 other rabbits immunized in the same way. A second series of rabbits (allotype matched) are injected to induce classic anti-idiotypic antibodies (Ab2). Then

Immunology Today, vol. 3, No. 4, 1982

these purified Ab2 are injected into a third series of rabbits which make anti-anti-idiotypic antibodies (Ab3). Antigen is then given to the rabbits making Ab3 antibodies. The corresponding antibodies are called A b l ' (see Ref. 16). Ab4 antibodies can be induced by immunization with Ab3 antibodies. The results obtained so far are clear cut and highly reproducible with seven antigenic systems and two species. In nearly all cases, A b l ' antibodies are idiotypically similar to A b l , i.e. rabbit Y is now making the idiotype of rabbit X. It is important to stress that these data concern a large part of the response (50-70% of A b l ' antibodies display crossreactive idiotypic specificities with A b l ) . In most cases, Ab3 antibodies (defined operationally as antibodies which appear after Ab2) do not react with antigen. However, Ab4, raised against A b 3 , specifically recognize idiotopes on A b l . Therefore, Ab3 and Abl share idiotypic specificities and Ab4 behaves like Ab2. Let us discuss briefly the case of Ab3 antibodies. Three subsets can be found: one subset recognizes only Ab2 and does not share idiotypic specificity with A b l ; one subset (50-70%) shares idiotopes with Abl but does not bind antigen; the third subset is small (a few percent), shares idiotopes with Abl fl;2rf recognizes antigen. This last subset is clonally expanded after antigen injection and gives rise to A b l ' antibodies. T h e second subset is probably lacking some idiotopes necessary for antigen recognition. O u r working hypothesis is that Ab3 antibodies are heteroclitic antibodies i.e. induced by one antigen but with a higher affinity for a different though related antigen. In cases where the starting antigen is an alloantigen (H-2 and allotype b6, Ref. 20), some Ab3 antibodies recognize antigen. T h e most obvious difference between alloantigens and the antigens of Micrococcus, tobacco mosaic virus (TMV), and nuclease is that alloantigens are strongly homologous to self antigens. Therefore, the mechanisms of natural tolerance must come into play and strongly restrict the available repertoire.

Ag

->Ab

--

Fig. i. The 'immunization cascade' showing the relationships between the antibodies produced at each stage.

Immunolooy To/lay, ml. J. .\'n. I. 19S2

Recently. David Sachs and his collaborators" have studied the effects of a d m i n i s t r a t i o n in riro of heterologous anti-idiotypic antibodies directed against two monoclonal anti-H-2K'' monoclonal antibodies. In the .'\b3 sera of mice, they detected both antigenbinding and non-antigen-binding Id-positive molecules. The antigen-binding activity was detected in 20% of mice treated with .'\b2. Furthermore, injection of ,'\b2 considerably influenced the immune response after immunization with H-2 antigen: up to 6.5% of anti-H-2K'' antibodies were idiotype positive (these antibodies correspond to what we called . \ b l ' antibodies) despite the fact that conventional allo-antisera do not display these idiotopcs. Therefore, in these experiments the third subset of Af).^ antibodies (which is very minor when one uses antigen such as carbohydrate or peptidoglycan from Microawdis. ribonuclease, nuclease, tobacco mosaic virus, levan, beta-galactosidase or dinitrophenyl) can be easily characterized in the H-2 system (see also Ref 19). W\ these results and others (see Ref. 2) imply that: (1) There is no need to consider sequential networks growing a

Some thoughts on idiotypic networks and immunoregulation.

The first of two articles in which J. Urbain and C. Wuilmart discuss the manipulation of idiotype-anti-idiotype interactions in immune responses...
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