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Polyspecific Antibodies in the Idiotype Network

Contents of this File

  1. General
  2. Idiotype-network
  3. Evidence for the importance of an Id-network in man
  4. Experimental evidence of the Id-network
  5. Functional consequences of network interactions
  6. The physiologic masking of IgM
  7. Antibody-dependent cytotoxic cell-mediated cytotoxicity
  8. Role of the complement system in clearance of opportunistic microorganisms
  9. The development of the Idiotype-network since early ontogeny
  10. Conclusions
  11. References

1. General

It is common textbook information that self-recognition by the immune system is a normal phenomenon. It is, however, perhaps less generally known that immunologic self-recognition by B- and T-cells is modulated by the "anti-idiotype network" during ontogeny and shortly after birth by a "natural auto-antibody system" [1]. This system involves a polyspecific IgM B-cell repertoire. This repertoire is characterized by extensive interconnectivity, multispecificity and auto-reactivity. "Natural auto-antibodies" can be found in normal sera of young and adult individuals and appear to be primarily IgM polyspecific antibodies of low affinity.

Antibodies (immunoglobulin molecules) bear three major categories of antigenic determinants:

  1. idiotypic determinants(since early in evolution)
  2. isotypic determinantsand
  3. allotypic determinants

  1. Idiotypic determinants, or idiotopes (Id), are markers of the V (variable) region structure of antibodies.
  2. Each V region, being relatively large, may bear several idiotopes each capable of interacting with a different antibody combining site.
  3. An antibody which combining site (its paratope) interacts with an antigenic determinant on another antibody (Ab) V region (idiotope) is called an anti-idiotypic antibody.

Note: The 'set of idiotopes' expressed on a single antibody V region constitutes the antibody idiotype.

2. Idiotype Network

Antibody (and T-cell receptor) V regions, because of their tremendous diversity, carry within the immune system a repertoire of idiotopes which are indistinguishable from the repertoire of potential foreign antigen epitopes. For every foreign antigenic determinant there exists within the immune system a structurally identical idiotope: the "internal image" (Ab1) of the epitope [2,3]. These entities of "internal image" and "exogenous antigen" are cross-reactive and are not distinguished by the complementary paratopes.

3. Evidence for the importance of an Id-network in man

Studies by Mouton et al. [4,5]and by Settmacher et al. [6]indicate that the self-reactive antibody repertoire of IgM differentiates during the first years of life and remains relatively constant thereafter. However, the differentiation of the repertoire regarding bacterial and other microbial (exo-) antigens continues much longer than the first years and differs interindividually since birth.

4. Experimental evidence to support the functioning of the Id-network

Experimental evidence to support the existence of Id-antibody network [7]

  1. Poly-specific IgM antibodies (Ab2), reacting with Id on other antibodies (Abl), can be induced artificially by immunization with antigens or antibodies, and also occur spontaneously during "natural immune responses".
  2. Idiotopes have been identified which are shared by both B-cell (BcRs) and T-cell receptors (TcRs).
  3. Idiotopes shared by B and T-cell receptors have been shown to be recognized by both anti-Id B-cells and anti-Id T-cells.
  4. Idiotopes or anti-Id IgG antibodies induced in, respectively administered to, pregnant animals (like rodents and primates) are transferred across the placenta and influence Id expression in offspring by suppression/elimination of related clones. This cytolytic anti-idiotype action is MHC II restricted and presumably mediated by antibody dependent cytotoxicity (ADCC).
  5. Anti-idiotype IgG antibodies from allogeneic sources in adult subjects, like after passive immunisation, may also modify the Id-network by Ab1 or TcR expressing clonal suppression/elimination.

5. Functional consequences of network interactions

The interaction of immune cell receptors via paratopes or idiotopes has functional consequences:

  1. The binding of an antibody-cell-receptor (Acr) by its paratope (with antigen epitopes or internal images) is a stimulatory interaction. If the Acr 'catches', it stimulates the clone involved.
  2. The binding of an idiotope on a receptor by the paratope of another receptor is a suppressive interaction. If the Acr 'is caught', it suppresses the clone involved.

Note: Idiotype suppression is induced at microgram concentrations of the anti-idiotope. When the concentration of an anti-idiotope falls below that (microgram) level, recovery from suppression sets in.

Two types of suppression are induced:

  1. a direct antibody-mediated blockade of B-cell maturation(is short-lived)
  2. involves the induction of 'regulatory cells' (is long-lived)

"Idiotype (Ab1) suppression" by regulatory (B and T) cells may be perpetuated by (auto- and exo-) antigen interacting with anti-idiotypic antibodies (Ab2) on the B-cell surface [8].

6. The physiologic masking of IgM

The presence of polyreactive IgM antibodies in the circulation, which belong to the Id-network, is easily "masked" by binding to (circulating) antigens/epitopes.

7. Antibody-dependent cytotoxic cell-mediated cytotoxicity

Cells expressing idiotypic determinants on their surfaces like for example polyspecific B-cells, can be specifically destroyed by anti-idiotypic antibodies; i.e. by an antibody-dependent cytotoxic cell-mediated cytotoxicity (ADCC) [10].

IgG and IgM antibodies may activate ADCC but only in syngeneic cells expressing MHC II receptors binding to an idiotype/antigen [11].
ADCC may kill macrophages harboring (translocated) bacteria intra-cellularly in a 'dose dependent' way. Clearance (killing of those bactreria) occurs without inflammation [12].
It is still uncertain, however, to which extend the type of intra-cellular microorganisms can - or perhaps even do - dominate with their exo-antigens the type of response in terms of release of inflammation-associated interleukin(s) by the macrophages which ingested them.

8. Role of complement activation in the clearance of opportunistic microorganisms

Role of the complement system in the clearance of microorganisms from tissues seems to depend on:

  1. Low antigenconcentrations
    Low (bacterial or other exo-) antigens in tissues appear to disappear in an excess of IgM antibody (presence is only detectable by elution).
  2. High antigen concentrations
    High concentrations may develop when either (abnormal) high numbers of microorganisms can translocate, or in case translocated microorganisms are not readily killed and cleared and thus get/take a chance to multiply for some time in the tissues [13].

Note: Translocation of bacteria through the mucosal lining may occur along the entire mucosal surface of the gut [14].

If exo-antigens reach, in one way or another, a concentration in host tissues which is in excess of the available multi-reactive IgM (i.e. IgM which can bind the antigen), T-cells may get stimulated to transform into Th cells. This could be the start of an isotype switch to for example IgG secretion in the B-cells as well as to further selection towards increasing specificity of these antibodies produced. In this situation, with high antigen concentrations and specific antibodies, complement activation and inflammation is to be expected.

9. The development of the Idiotype-network since early ontogeny

The Id-network of B (and T-cells) largely develops during the ontogeny of the immune system. In animal species with a hemo-chorial placenta (man and mice), maternal IgG which passes the placenta appears to take a prominent role in the modulation of the early immune system.
Depending on the activity of the maternal immune system (hygienic conditions) during foetal life as well as after birth during lactation, the ontogeny of the immune system gets modulated by maternal (predominantly IgG isotype?) antibodies. Interactions with the T-cell regulated part of the immune system acting against exo-antigens may develop likewise.

10. Conclusions

  1. Before birth:
    The polyspecific IgM Id-network is predominant. During ontogeny the Id-network interacts with the T-cell controlled system. As a result of suppression, among else by maternal anti-Id antibodies, immune response/tolerance to exo-epitopes may develop.
  2. After birth:
    The anti-self part of the Id-network remains normally unchanged (except for cases in of autoimmune disease). The 'anti-exo-antigens reactive part', however, continues to develop as it is continuously modified by new exo-antigens. Contact with abundant) exo-antigens can result in isotype switches but also in clonal deletion and suppression.

References

  1. Cahill RNP, Kimpton WG, Cunningham CP, Washington EA: An immune system switch at birth triggers a change in the lifespan of peripheral T-cells. Seminars in Immunology, 1997; 9: 355-363
  2. Kohler H. The servant idiotype network. Scand J Immunol 1991; 33(5):495-497
  3. Augustin AA, Sim GK, Bona CA. Internal images of antigens within the immune network. Surv Jmmunol Res 1983; 2(1): 78-87
  4. Mouthon L, Lacroix-Desmazes S, Nobrega A, Barreau C, Coutinho A, Kazatchkine MD. The self-reactive antibody repertoire of normal human serum IgM is acquired in early childhood and remains conserved throughout life. Scand J Immunol 1996, 44(3): 243-251
  5. Mouthon L, Nobrega A, Nicolas N, Kaveri SV, Barreau C, Coutinho A, Kazatchkine MD. Invariance and restriction toward a limited set of self-antigens characterize neonatal IgM antibody repertoires and prevail in autoreactive repertoires of healthy adults. Proc Natl Acad Sci USA 1995 Apr 25,92(9):3839-3843
  6. Settmacher U, Delvig A, Jahn S. Anti-bacterial specificities in the human fetal B-cell repertoire. Hum Antibodies Hybridomas 1994; 5 (1-2):91-95
  7. Kearney JF, Bartels J, Hamilton AM, Lehuen A, Solvason N, Vakil M: Development and function of the early B-cell repertoire. Int Rev Immunol 1992; 8(2-3): 247-257
  8. Holmberg D, Wennerstrom G, Andrade L, Coutinho A. The high idiotypic connectivity of natural newborn antibodies is not found in adult mitogen-reactive B-cell repertoires. Eur J Immunol 1986; 16(1): 82-87
  9. 9. Sigounas G, Kolaitis N, Monell-Torrens E, Notkins AL: Polyreactive IgM antibodies in the circulation are masked by antigen binding. J Clin Immunol 1994; 14(6): 375-381
  10. Caraux J, Weigle WO: Anti-idiotype antibody-dependenT-cell-mediated cytotoxicity (ADCC) against idiotype-bearing cells. CelI immunol 1983; 78(1):23-32
  11. Bitoh S, Fujimoto S, Yamamoto H. Idiotypic and anti-idiotypic B-B-cell interaction is controlled by major histocompatibility-bearing cells. Immunology 1989; 66:479-484
  12. Kohler H. The servant idiotypic network. Scand J Immunol 1991; 33:495-497
  13. Wells CL, Maddaus MA, Erlandsen SL, Simmons RL. Evidence for the phagocytic transport of intestinal particles in dogs and rats. Infect & Immun 1988; 56: 278-282
  14. Fukushima R, Gianotti L, Alexander W: The primary site of bacterial translocation. Arch Surg 1994; 129: 53-58