230 Immunology 7oday, vol. 3, ,No. 9, 1982

(,°,,,.- ) Regulatory idiotopes and immune networks"

a hypothesis William E. Paul and Constantin Bona

Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20205 and the Department of Microbiology, Mount Sinai Medical School, New York, NY 10029, U.S.A.

A re-examination of the Jerne network theory in the h'ght of recent developments.

Idiotopes are unique antigenic determinants found on the conformational structures which distinguish the variable (V) regions of one set of antibody molecules from those of other sets~, 2 (see glossary on page 234). Some idiotopes have other properties of importance to the immune system. Idiotopes may be autoimmuno- genic3-6; such determinants are capable of eliciting the endogenous synthesis of anti-idiotope antibody and the expansion of idiotope-specific T cells. Idiotopes of this type are potentially important clonal markers expressed on the receptors of B cells and, as evidence has increasingly demonstrated, on the receptors of certain types of T cell 7-~°, Through these idotopes, a receptor-specific regulation of the immune system may be mediated.

A key factor in the appreciation of the potential importance of receptor-specific regulation of the immune response was the proposal by Niels Jerne of the 'network theory of the immune system 'n. This theory views the immune system as a collection of ele- ments, each capable of binding an antigenic deter- minant through its combining site, designated as its paratope, and each capable of being recognized by some other element of the system because it displays one or many idiotopes. Furthermore, Jerne proposed that every member of the system is actually interacting with other members of the system. That is, the paratope of virtually every antibody molecule recog- nizes the idiotope of some other antibody molecule, and regulates the level of its expression. Similarly, the idiotope(s) of individual antibody molecules, ex- pressed on lymphocyte receptors, are recognized by the paratopes of other molecules and, thus, the level of expression of the antibodies bearing those idiotopes is regulated. The idea that each paratope recognizes an idiotope obviously requires that 'conventional' anti- genic determinants, expressed on molecules other than immunoglobulins (Igs) and designated as epi- topes, must cross-react with idiotopes (i.e., epitopes are recognized by idiotope-specific paratopes). An alternative way of stating this is that for each epitope on a foreign antigen there is an ' internal image of the antigen' (i.e. an idiotope) ~.

Elsevier Biomedical Press 1982 0167-4919/82/0000 000fl/$1 00

Furthermore, Jerne proposed that there is a vectorial character in these paratope- idiotope regulatory interactions. That is, the concentration of Igs expressing a given idiotope is diminished by interaction with antibody bearing the complementary paratope; the interaction is suppressive to cells bearing the idiotope on their receptors. On the other hand, the concentration of Igs expressing a paratope is increased as a result of interaction with antibody bearing the complementary idiotope; this interaction is viewed as being stimulatory to cells bearing the involved paratope on its receptors. That is, interac- tions with receptors through their paratopes are stimulatory while interactions through the idiotopes of these same receptors are suppressive.

Finally, implicit in Jerne's proposal is that the role of foreign antigen is not primarily to stimulate cells that bear receptors specific for the epitopes of that antigen, but rather to disturb the dynamic equilib- rium in which these 'epitope-specific' cells are being simultaneously stimulated by elements expressing the idiotope for which the receptors of the 'epitope- specific' cells are '.cross-reactive' and suppressed by elements expressing paratopes specific for the idiotopes found on the receptors of the 'epitope- specific' cells. Indeed, Jerne proposed that the first effect of antigen was to diminish, through immune clearance, the concentration of antibodies specific for the epitopes expressed on that antigen. Since these antibodies have the role of suppressing lymphocytes which express idiotopes cross-reactive with the epitopes of the foreign antigen, diminishing the con- centration of epitope-specific antibodies should lessen this suppression. That is, the suppression normally exerted on the set of cells which express the internal image of the antigen should be diminished. This should lead to an increase in the concentration of the idiotopes which cross-react with the epitopes on the foreign antigen. The increase in the concentration of these idiotopes was proposed to be responsible for the stimulation of cells bearing receptors specific for the epitopes. Thus, production of epitope-specific anti- bodies would actually result from an increase in the

Immunology Today, vol. ,3, No. 9, 1982 23I

Animal 1 Animal 2 Animal 3 Animal 4

A__gg Ab 1 Ab 2 Ab_~3 Ab_.~4 - - Pl "~" i

(e) (Pl, il) (P2, i2) (P3, i3) (P4, i4)

Fig. 1. Conventlona|vlew ofldiotope-paratope immunlzation pathways.

interaction of idiotopes with the receptors of the cell, not from the interaction of epitopes with these receptors.

Modifications toJerne's hypothesis Jerne's views have had a great impact on scientists

interested in the regulation of the immune system. Nonetheless, certain aspects of his theory do not appear to be in keeping with more recent develop- ments in our understanding of immune responses. In particular, the notions that paratope-idiotope inter- actions have vectorial properties and that idiotopes, rather than epitopes, are the actual stimulants of receptor-bearing cells seem to be incorrect. Thus, treatment with paratope-bearing antibody (i.e., anti- idiotope antibody) can prime, as well as suppress, animals for the subsequent expression of that idiotope in response to stimulation with epitope 12,13. Similarly, cloned lines of T lymphocytes and of T-lymphocyte hybridomas can be stimulated to expand and/0r to secrete factors, such as interleukin 2, by antigen in association with antigen-presenting cells, in the com- plete absence of any possible source of idiotope 14 ~6.

However, the central theme of Jerne 's argument remains one of the major concepts of modern immunology. The notion that clones of lymphocytes are actually interconnected by paratope-idiotope interactions is quite well accepted. Many endogenous examples of receptor-based regulation can be noted. Among the most striking are idiotype-spccific help in control of expression of T15 + anti-phosphorylcholine antibodies 17, idiotype-specific suppression of M460 + anti-trinitrophenyI antibodies~% and the critical involvement of T cells specific for the cross-reactive idiotope(s) of anti-arsonate antibody in the suppres- sion of arsonate-specific delayed hypersensitivity 19.

Consequently, there has been continuing interest in exploring the structure of idiotope-paratope pathways in the regulation of immune responses. One approach pioneered by Cazenave ~°, and by Urbain and his group 2°a, has been to examine elements in a given pathway by producing the individual elements in distinct animals of the same (or related) genotype.

That is, one uses animal 1 to produce antibody to a (Abl) (Fig. 1). Ab I expresses a paratope (or family of paratopes) designated p~ and an idiotope (or family of idiotopes) termed i 1. Ab 1 (Pl, il) is purified from the sera of animal 1 and used to immunize animal 2 which, in order to reflect the physiologic situation as

closely as possible, should be syngeneic to animal 1. Animal 2 produces Ab2, which expresses P2, a paratope specific for il, and which presumably bears an idiotope, i 2. Ab 2 (P2, i2) may be used to immunize animal 3, which should produce Ab 3. This should be of the formula P3, i3. In turn, Ab 3 should stimulate animal 4 to produce Ab4, whose formula should be P4, i4" This linear pathway is certainly the one to be anticipated, based on Jerne 's postulate that the inter- action of an idiotope (in) and its complementary paratope (Pn+I) stimulates production of Pn+l-bearing molecules and suppresses production of in-bearing molecules.

However, other outcomes of this immunization scheme are possible, particularly if one rejects any directionali ty in i . . . . p interactions. For example (Fig. 2), immunization of animal 3 with Ab 2 could lead not only to stimulation of anti-i 2 (i.e. P3- bearing molecules) but, just as plausibly, to stimula- tion of production of i~-bearing molecules, since the interaction of il-bearing cells with P2 (i.e., anti-i~)- bearing molecules could stimulate i I secretion. In several systems, immunization with Ab 2 has been shown to lead to the direct expression of i, and to the priming of i~-bearing cells 12,1321,22. Indeed, two recent sets of experiments, one performed by Urbain and his associates 23, and one performed in our laboratories 24, have indicated that the major outcome of immuni- zation with Ab e (P2, i2) is the stimulation of il-bearing cells rather than of p3-bearing cells.

In our system, Ab I was ABPC48 (A48, a BALB/c levan-binding myeloma protein). Thus, Pl is an anti- levan combining site and i~ is the collection of idiotopes (the idiotype) expressed by A48 (the A48 Id) 25. A48 conjugated to keyhole limpet hemocyanin (KLH) induces in BALB/c mice the production of Ab2, which has the property of binding i I and pre- sumably has its own idiotope(s) (i2). Immunization with Abe-KLH (Fig. 2) which contains p> i 2 molecules, (but which may also contain internal images of antigen - i.e., P0, i0 molecules) elicits what is generally termed Ab> since it binds Ab 2. When Ab 3- KLH, in turn, is used as an immunogen, it induces an antibody, termed Ab4, which binds Ab 3. Strikingly, the maiority ( > 60%) of Ab4 molecules bind Ab 1. That is, m o s t A b 4 molecules bind i 1 and express P2 or p2-1ike paratopes (i.e. they resemble Ab 2 molecules). The only obvious way that A b 4 could consist largely of pa-bearing-like molecules is if the population of Ab.~ antibodies really consists o f i rbearing molecules

232 Immunology Today, vol. 3, ~Nb. 9, 1982

Aq

,el

Animal 1 Ab 1

(Pl" i l)

Animal 2 Ab2

(Po, io) [internal image]

Fig. 2. A view of idiotope-paratope immuni- zation pathways which assumes that inter- actions of lymphocyte receptors through their paratopes and their idiotopes are physio- logically indistinguishable.

Not all the possible outcomes are shown, particularly in animal 4, where the dots emphasize that many other possible cases exist. The interac- tions enclosed within rectangles appear to be the most prevalent.

ra ther than p3-bearing molecules. On the other hand, Ab 3 has little, if any, binding activity for levan. Thus, the dominant set of molecules in Ab 3 is not p~, il, but ra ther Px, ii.

To explain this result, we postulate that Ab 1 molecules express a member of a special set of ' regulatory idiotopes' (ri) as well as several con- ventional idiotopes (Fig. 3). Thus Ab 1 would have the formula (p , i , rii). The main outcome of immuni- zation with A48-KLH is to elicit the product ion of anti-ri~ molecules because, we suggest, only regulatory idiotopes are immunogenic to any substantial degree in a syngeneic or autologous system. Ab 2 lacks a regulatory idiotope; it has the formula (P2, i2). Immuniza t ion with Ab2-KLH leads to the product ion of very limited amounts of p3-bearing molecules because no ri 2 is found on Ab 2 and because i 2 is a poor autoimmunogen. By contrast, Ab 2 activates cells expressing ri~ as a result of their s t imulation by P2. Thus, the populat ion of antibodies designated Ab 3 consists largely of ri 1- (and ril-like)-bearing molecules but only a limited number of i3-bearing molecules. In turn, Ab 4 is principally made up of anti-ri I (i.e., P2- bearing) ra ther than anti-i 3 (p4-bearing) antibodies.

R e g u l a t o r y i d i o t o p e s in a c t i o n The notion that a 'special ' class of idiotopes exists

which have unique function in regulatory interactions needs further discussion. Indeed, this concept is intimately involved in the question of whether the immune network exists, in a functional sense, prior to immunizat ion. Consider a 'convent ional ' idiotope, expressed principally on antibodies specific for an antigen to which an animal has not been immunized. If the formation of this idiotope requires contributions from both heavy and light Ig chains, as appears true for many idiotopes 2(', the library of different con- ventional idiotopes might be very large, perhaps

Animal 3

(P-l, i 1)

Pl' a

(P3, i3)

(Pl il)

" t ~ E ~ ( p x~, i 1)

Animal 4 Ab4

(P2, ib)

0

approaching in size the l ibrary of distinct antibodies. Thus, the concentration, in serum or on cells, of any conventional idiotope should be very small. Similarly, the concentrat ion of paratopes, specific for such idiotopes, should also be very low if, as we assume, the concentrat ion of a conventional idiotope is too low to stimulate expansion of cells bearing that paratope and if that idiotope does not cross-react with an epitope to which the animal has been sensitized. Thus, prior to immunization, no .functional connect ion exists between conventional idiotopes and the paratopes specific fi)r them since the effective concentrat ion of these two types of elements is too low for them to encounter one another with any reasonable frequency. Thus, con- ventional idiotopes and their complementary para- topes are not part of an interconnected network prior to the introduction of a foreign ant igen bearing an epitope recognized by the paratope of the idiotope- bearing cell.

On the other hand, some idiotopes do appear to be quite highly represented in the sera a n d / o r on lymphocytes of animals that have not been intentionally immunized to epitopes which normally elicit anti- bodies bearing those idiotopes. These idiotnpes may be especially prevalent because they represent confor- mations on immunoglobulins which tend to occur very fi'equently, or because their expression is favored by a genetically or environmental ly determined positive selection. In either case, a subset of idiotopes exists which has a substantially higher representat ion in serum and on lymphocyte receptors than do con- ventional idiotopes. Examples of these idiotopes include the idiotypic determinants of T15, normally expressed on anti-phosphorylcholine antibodies 27, and the El09 IdX, found on a majority of ant i- inulin anti- bodies of BALB/c mice 28. Since these idiotopes are present in relatively high concentration, they could quite reasonably elicit the appearance of regulatory

Immunology TMay, vol. 3, jVo, 9, 1982 233

cells which bear complementary paratopes. Alter- natively, these idiotopes may exist in high concentra- tion because pre-existing idiotope-specific regulatory cells favored the expansion of cells bearing these idio- topes on their receptors. In either case, for this class of idiotopes, an actually interconnected system of idio- topes and paratopes exists prior to the introduction of antigen. We refer to idiotopes of this type as regulatory idiotopes, because of their obvious poten- tial for involvement in regulatory processes.

B cells (and, presumably, T cells) bearing such regulatory idiotopes may be especially likely to be selected in immune responses to any foreign epitope for which their paratopes are complementary since the pre-existing idiotope-specific regulatory system should tavor their expansion. That is, regulatory idiotopes, in addition to being present at higher concentrations than conventional idiotopes, should also be found on antibodies of many distinct specificities (i.e. anti- bodies with differing paratopes). In a sense, once a regulatory idiotope, and the cells complementary to it, have established themselves in tme immune system, immunization with additional antigens is likely to favor the further expansion of these regulatory idio- topes and their representation among antibodies of varying specificity. It is by now well established that many of the well studied idiotypes may be expressed on antibodies of differing specificity 22,29-32.

Let us now re-examine the Abl-Abi-Ab3-Ab 4 pathway with these concepts in mind (Fig. 3). l fAb 1 is a member of the class of molecules which bear regulatory idiotopes, as seems to be true for A48 (Ref. 31), certain outcomes of this chain of immunizations can be expected. Ab 2 should represent p2-bearing molecules specific tbr the ri~ determinants of Abe. Ab 2 is likely to express conventional idiotopes rather than regulatory idiotopes since its presence in relatively high concentration is based on the specificity of its paratopes for a regulatory idiotope (ri~) not on its having been selected by cells specific for its idiotopes. The immunisation of animal 3 with Ab 2 should lead to the expansion of cells bearing complementary receptors. In animal 3, cells bearing ri~ on their receptors should be relatively numerous since, by definition, regulatory idiotopes are widely represented

in the system prior to intentional immunization and, potentially, are expressed on cells bearing receptors of many distinct specificities (i.e. having distinct para- topes). By contrast, cells bearing P3 (paratopes specific for i2) should be quite rare since i 2 is a con- ventional idiotope. Thus, the main outcome of immunization with Ab 2 should be the further stimula- tion of ri~-expressing cells, not p3-bearing cells. Since ri, is expected to be found on molecules of many different specificities, Ab 3 will contain few p~-bearing molecules. Indeed, as already noted, Ab3 generally has little binding specificity for the antigen for which Ab 1 is specific (i.e. Ievan) 23,24. However, Pi, r i rbearing cells are clearly primed as a result of immunization with Ab 2 since anti-levan antibodies bearing the A48 ld are found in high concentration upon subsequent immunization of these mice with bacterial levan 24 and, in some cases, Pl, ri,-bearing antibodies can be detected after Ab 2 immunization 2~. Finally, if Ab 3 is largely of the formula Px, ix, ril, Ab4 should have a

• high representation of p2-bearing antibodies.

Regulatory id iotopes in normal i m m u n e responses It may reasonably be asked to what extent such

processes actually occur in normal immune responses. Many examples of the appearance of p~-bearing anti- bodies and T cells in animals immunized to foreign antigens have been described 32 34 We have observed Ab3-1ike molecules (Px, rii) in animals immunized with A4824. However, study of such molecules has been hampered by the difficulty of detecting these distinct elements unambiguously, particularly when they are present at low concentration. The immortal- ization of the cellular members of these pathways derived from a single animal, as somatic cell hybrids, will make possible the detailed evaluation of these regulatory elements. In addition, it must be pointed out that many immune responses may not involve antibodies that express regulatory idiotopes; such instances will probably be found in responses to complex proteins and hapten-protein conjugates. In such cases, receptor-based regulation mediated through conventional idiotopes may come into play rather late in the response and the specificity of the regulatory pathway may vary from time to time and

Animal 1 Animal 2 Ag Ab 1 Ab 2

(e) (Pv il, ril) (P2' i2) Fig. 3. A view of idiotope-paratope immunization pathways based on the regulatory idiotope concept.

Conventional idiotopes (i) are not depicted in this model.

Animal 3 Animal 4 Ab 3 Ab 4

._~il

(Pl, i1' ril) (P2' 121

rll (Px' ix' ril) (P2' i2)

234 Immunology 7))day, vol. .3, No. 9, 7982

f rom indiv idua l to individual , d e p e n d i n g on the chance events tha t de t e rmine which , if any, set of an t ibodies t ends to d o m i n a t e the response in ques t ion .

O u r view of r ecep to r -based r egu la t ion of the i m m u n e re sponse t ends to r e e m p h a s i z e the role of idiotopes a n d thei r c o m p l e m e n t a r y pa r a t opes in deter- m i n i n g the o u t c o m e of any given i m m u n i z a t i o n . However , it n a r rows the focus of conce rn to a special subse t of idiotopes, here des igna t ed the regu la to ry idiotopes, a n d sugges t s tha t the i m m u n e sy s t em is not a single, h igh ly i n t e r connec t ed network, bu t r a the r a collect ion of m a n y ' m i n i - n e t w o r k s ' each ba sed on a single fami ly of re la ted r egu la to ry idiotopes. T h e s e min i -ne tworks wou ld be i n t e r connec t ed wi th one a n o t h e r t h r o u g h r a the r fragile links.

If ou r ideas abou t regu la to ry idiotopes p rove to be a r ea sonab ly correct e x p l a n a t i o n of r ecep to r -based regula t ion , it will raise the poss ibi l i ty tha t the ent i re ' l i b ra ry ' of such idiotopes could be ' c a t a l oged ' a n d t h r o u g h the j ud i c ious use of r eagen t s or cells bea r ing e i ther a given regu la to ry idiotope or its comple - m e n t a r y pa ra tope , m a n y i m m u n e re sponses of pa tho - genet ic s ignif icance could be precise ly control led. For example , an t ibod ies a n d T cells wh i ch are especial ly protect ive in i m m u n e re sponses to pa thogen ic micro- o r g a n i s m s ' a n d pa ras i t e s could be e x p a n d e d by i m m u n i z a t i o n wi th the app rop r i a t e Ab 2 r a the r t han , or in s equence with, an t igen . T h i s m i gh t be par- t icular ly re levant in s i tua t ions in wh ich the an t i gen is difficult to ob t a in or is poorly i m m u n o g e n i c .

T h e concep ts ou t l ined here r ep resen t a mode l of r ecep to r -based regu la t ion of the i m m u n e response . T h i s mode l is b a s e d on evidence f rom several well s tud ied sy s t ems bu t the extent to wh i ch it is a genera l r ep r e sen t a t i on of the r egu la t ion of i m m u n e re sponses can only be e s t ab l i shed by the e x a m i n a t i o n of these sy s t ems in g rea te r detail a n d t h r o u g h the ex tens ion of these s tud ies to o ther sys tems .

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Glossary

Idiotope (1): An antigenic determinant found on the contormational structures which distinguish one set of antibodies from those of other sets. The fraction of antibodies which express a given idiotope is usually very small, but some idiotopes are relatively frequent and are found on a few percent of all Ig molecules.

Idlotype: The collection of idiotopes found on any individual Ig molecule.

Paratope (p): The antigen-combining site of an Ig molecule.

Epitope (e): An antigenic determinant expressed on a conventional (i.e. non-Ig) antigen.

Internal image of the antigen: An idiotope cross- reactive with (i.e. having a structure similar to) an epitope found on a foreign antigen.

Regulatory idiotope (ri): An idiotope found on a relatively high proportion of Ig molecules and /o r lymphocytes which is capable of acting as a site for a receptor-specific regulatory system.