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Immunology
A Possible Mechanism of Abrogating Progression of Web Beyond Anti-Idiotypic Antibody and a Non Traditional Pathway of Complement Activation
Hari Mohan
Saxena
Professor of Immunology & Head of Department,Department of Veterinary Microbiology, GADVASU, Ludhiana,India
* E-mail:hmsaxena@hotmail.com
Competing Interests:
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Copyright: © 2011 Webmed Ltd
2011
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
The progression of immune response is currently believed to give rise to anti-anti-idiotypic antibodies. This new hypothesis offers an explanation for the termination or abrogation of potentially endless progression of immune response after the elimination of antigen from the system.
Background
It is presumed that the formation of antibodies complementary to antibodies under normal conditions of natural exposure to antigen continues beyond anti-idiotypic antibodies leading to anti-anti-idiotypic antibodies [1,2]. Presently there is no logical explanation against this notion. The complement is activated by classical pathway only if the antibody has bound an antigen. On the other hand, antibody is not required in complement activation by the alternative pathway. However, these pathways do not elaborate on any interaction of complement with the idiotypic network in the absence of antigen.
Results
I propose here a pathway of complement activation which is different from the currently accepted classical and alternative pathways of complement activation. This involves complement activation after pairing of complementary surface immunoglobulins (i.e. idiotypic and anti-idiotypic antibodies) on B cells in the absence of antigen. By definition, the two known traditional pathways do not cover this possibility. I, therefore, propose to call this third pathway as neo-classical pathway of complement activation.It is known that the antigen â specific immune response may progress even after the elimination of the antigen due to the generation of anti-idiotypic antibodies against the antigen â binding site associated idiotopes. However, if the idiotypic and anti-idiotypic antibodies continue to stimulate each otherâs production endlessly, it could lead to exhaustion of resources for other immune responses and harmful consequences for the host.According to my hypothesis, following engagement of idiotypic and anti-idiotypic antibodies on the surface of respective immunoglobulin bearing B lymphocytes, the complement may get activated by both the surface immunoglobulins and may cause the lysis of respective target B cells through the formation of membrane attack complexes (MAC). Such assured mutual destruction (AMD) may keep a check on undesirable and potentially endless proliferation of complementary B cells (Fig. 1.).Antibody dependent cellular cytotoxicity (ADCC) â mediated killing of idiotypic antibody bearing B lymphocytes by anti-idiotypic antibody â guided ADCC effector killer cells and of anti-idiotypic antibody bearing lymphocytes by idiotypic antibody â guided ADCC effector killer cells could also be another modality for assured mutual destruction of antibody bearing B cells by the secreted form of complementary antibody (Fig. 2.). This may take care of cells refractory to complement mediated lysis (e.g. cells protected with complement regulatory proteins). It has already been shown experimentally earlier by several researchers that monoclonal antibodiescan effect tumor cell killing by activating complement-mediatedplus cell-mediated antibody-dependent cytotoxicities. Antitumorantibodies belonging to subclasses such as mouse IgG2a, mouseIgG3, or mouse-human IgG1 chimeric have been used successfullyin clinical trials [3, 4].Similar mechanism could be envisaged for lysis of surface idiotype / anti â idiotype immunoglobulin bearing B cells by idiotype / anti â idiotype â reactive cytotoxic T lymphocytes as well as for suppression of surface immunoglobulin bearing B cells by secreted complementary antibody induced through Fc receptor bearing suppressor cells. Such assured mutual destruction of immunoglobulin â bearing B lymphocytes by complementary antibody in the form of surface immunoglobulins through complement activation or in the form of secreted immunoglobulins through ADCC should be sufficient to ensure that the antibody formation does not progress beyond the level of second antibody (i.e. anti-idiotypic antibody). Thus the formation of anti-anti-idiotypic antibody and so on, as believed by some researchers [2, 4], may not be happening in vivo under natural conditions (of course, by experimental immunization with idiotypic antibody it is possible to raise anti-idiotypic antibody which may lead to a complementary (anti-anti-idiotypic) antibody and by injecting anti-idiotypic antibody it is possible to raise (anti-anti-idiotypic) antibody, which do not qualify for being natural third antibody of the idiotypic cascade). This regulation seems logical as it would be economic and resource saving for the immune system of the individual host.B cells which escape destruction because of complement regulatory proteins or formation of immunoconglutinins or B cells engaged in low affinity interactions (e.g. through framework associated idiotopes, not located in antigen binding site of immunoglobulin) may be prevented from antigen binding site associated idiotypic- antiidiotypic pairing and may possibly lead to memory B cells. Such cells may be incompletely activated so are unable to divide, but nevertheless may express some markers associated with activated cells. Such cells possibly fall a little short of being tolerized, do not undergo apoptosis, and may revert to fully activated state upon encountering antigen with a high affinity later in life. Memory cells are indeed known to share some markers with activated cells.
Abbreviation(s)
ADCC = Antibody dependent cellular cytotoxicityAMD = assured mutual destructionMAC = membrane attack complex
References
1. Jerne N K. Toward a network theory of the immune system. Ann. Immunol. (Paris) 1974; 125C: 373-389.2. Kuby J. ed. Immunology. New York: W H Freeman & Co., 1997: 404-406.3. Schlom J. Monoclonal antibodies in cancer therapy: basic principles. In De Vita V T, Hellman S & Rosenberg S A, eds. Biologic Therapy of Cancer. 2nd ed. Philadelphia: J B Lippincott Co., 1995: 507-520.4. Cheung NK V, Guo HF, Heller G & Cheung I YÂ Induction of Ab3 and Ab3â antibody was associated with long-term survival after anti GD2 antibody therapy of stage 4 neuroblastoma. Clin Cancer Res 2000; 6: 2653-2660.
Citation: Saxena H .A Possible Mechanism of Abrogating Progression of Web Beyond Anti-Idiotypic Antibody and a Non Traditional Pathway of Complement Activation . WebmedCentral IMMUNOLOGY 2010;1(9):WMC00749
Pedro
Xavier-Elsas
Associate Professor, Instituto de Microbiologia Prof. Paulo de Góesl, UFRJ, CCS Bloco I Room I-2-066, Brazil
An idea worthy of experimental testing
The possibility that idiotype/anti-idiotype interactions play a significant role in physiological immunoregulation has been examined in many previous studies. While it is well established that purposeful immunization with purified monospecific idiotype-bearing antibodies may reproducibly lead to anti-idiotype antibody production, and that this phenomenon can be experimentally extended to the second and even third generations of antibodies, it has been difficult to explain why a potentially unlimited sequence of idiotype/anti-idiotype inductions is not a commonplace finding in the setting of natural immunity. Previous reviewers of this manuscript pointed out to very significant features of the idiotype/anti-idiotype interaction modes and of Complement activation that must be addressed in detail before the hypothesis is taken at its face value. Not being in the Complement or Idiotype fields, which are admittedly very complex, I will refrain from raising these types of objections. Instead, having a bias toward simple approaches in a more physiopathological setting, I would rather propose that the hypothesis can be boiled down to the idea that in vivo interactions between idiotypes and anti-idiotypes are self-limited because immune complex formation will lead to demise and clearance of the B cells displaying the corresponding epitopes. While two different effector mechanisms (Complement and cells capable of ADCC) are advanced, I would favor Complement as the variable that requires immediate experimental testing, because it is ubiquitous in the circulation, and because its depletion can be conveniently achieved by Cobra Venom Factor administration. If the authors can demonstrate that expansion of the idiotype network beyond its original limits occurs when Complement is no longer available, then a significant finding may be at hand. This is, of course, not identical with the demonstration of a novel pathway for complement activation, since there is no evidence to support the idea that the classical complement activation pathway is unable to carry out this function.
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Alka
Tomar
Senior Scientist, Indian veterinary Research Institute, IVRI, Izatnagar (UP), India, India
Anti_Id antibody_comments
Idiotype (Id) â anti-Id network theory is based on the fact that an Id is not a self determinant, as it is generated only following entry of an extraneous antigen into a host- body on induced antibody against the antigen (1st antibody). The paratopes of complementarity determining regions (CDRs) of first antibody (anti- antigen antibody) act as Id, which, in turn, induces 2nd antibody (anti-Id antibody) or 3rd antibody (anti- anti- Id antibody) etc., all of which have the potential to act as extraneous antigens. On binding of an epitope with its specific paratope, the CH2 domain of IgG and CH3 domain of IgM are exposed, enabling binding of 2 or more globular heads of C1q to allow assembly of activated C1qr2s2 that activates classical C3 convertase (C4b2b), and classical C5 convertase (C4b2b3b). If an extraneous antigen on occupying the CDRs of an antibody can activate classical complement pathway, an idiotope on occupying the CDRs of anti-Id antibody (2nd antibody), can as well stimulate a classical complement pathway, instead of proposal of a Neo-classical complement pathway, unless the authors have enough proof to present a new C3 or C5 convertase, other than the classical C3 and C5 convertase, the C4b2b and C4b2b3b, respectively. Similar situations will arise when the epitopes of 1st antibody (Id) will bind with the paratopes of CDRs of 2nd antibody (anti-Id antibody) or the epitopes of 2nd antibody (anti-Id antibody) with the paratopes of CDRs of 3rd antibody (anti- anti-Id antibody) and so on. The most important step is occupation of paratopes of CDRs of an antibody (Id) with its specific epitopes (idiotopes), so that the CH2 domain of IgG and CH3 domain of IgM antibodies are exposed for subsequent activation of classical C3 convertase.                                                                            If at all an abrogation of immune response is visualized, then even 1st antibody (eliciting idiotype or Id) onwards, the immune response should be terminated. Because, 1st antibody (Id) will provide the unique and specific CDRs on which not only an epitope binds, but also new antigenic determinants (idiotopes) will induce generation of 2nd antibody (anti-Id antibody), and 2nd antibody (anti-Id antibody) will induce 3rd antibody (anti-anti-Id antibody) and so on. Further, on binding of second antibody with the first antibody bearing B cells, the ADCC may also get activated against the first antibody bearing B lymphocytes, hence even the first antibody bearing B cell may be destroyed, thus, abrogating the immune response even against the original antigen. Thus, in principle, no immune response against a foreign antigen will be elicited. However, this does not happen in routine procedures. To me frankly, anti-anti-idiotypic antibodies appear just as a conceptualized phenomenon, which may not be occurring at all in the host, as under :1. If at all, anti-anti-idiotypic or even anti-idiotypic antibody network exists, then how unique specificity of B lymphocytes are maintained? So, do all B lymphocytes have some kind of more than 1 specificity?2. If at all, anti-anti-idiotypic antibody network exists, then complement / ADCC activation will kill even first antibody bearing lymphocytes creating tremendous âholesâ in B cell repertoire of an individual, but this is not a usual case of complement activation. 3. If at all membrane attack complex (MAC) kills anti-anti-idiotypic antibodies (third antibody onwards) bearing B cells, what stops it not to kill a 2nd antibody and 1st antibody bearing B cells? Hence, it may be concluded that the proposed theory of Neo-classical pathway of complement activation appears similar just as the classical pathway of complement activation, and may not be acceptable as of now, until and unless enough proof is provided for Neo- C3 or C5 convertases for establishing the theory.
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Azad
Kaushik
Associate Professor, Department of Molecular & Cellular Biology, University of Guelph, Department of Molecular & Cellular Biology, \nUniversity of Guelph, \nGuelph, Ontario, Canada , Canada
Untitled
The manuscript provides a novel perspective on in vivo complement activation as a result of id-anti-id interactions with profound implications on immunoregulation. While the thesis is plausible, there remain some important unanswered questions as recent studies on idiotypy have been few, given the complexity of idiotype-mediated immunoregulation. For example, dynamics of required hinge flexibility of B-cell surface immunoglobulin for complement fixation dependent upon C1q binding-site exposure is not yet defined; an outcome of cell signalling subsequent to 'id-anti-id interaction' remains an enigma as threshold and the resulting outcome is yet to be understood. In fact, id-anti-id interaction may not be 'endless' but may have a gradual ripple effect ensuring immunoregulation based homeostasis. it should be noted that for classical pathaway to be activated, at least 1000 IgM or IgG monomers need to be present in close proximity, during capping, to permit firm C1q binding to initiate the classical complement cascade. This likely would dtermine the required threshold for complement activation. The configuration of monomer IgM and IgG expressed on B cell surface needs to be determined if it is planar (C1q -binding site not exposed) or not (C1q -binding site exposed). Further, id-anti-id complexes are normally present in blood circulation and these should normally permit c1q biding resulting in complement cascade which must be tightly regulated given pathological consequences. Most of these areas are yet to be fully elucidated by experimentation. Nevertheless, the outlined thesis is much relevant to disease state, e.g., systemic autoimmune disease, where these idiotypic- anti-idiotypic poulations are likely to be dysregulated. hence, the proposed hypothesis needs to be tested experimentally in health and disease state. The hypothesis provides a logical and rational perspective that must be tested experimentally before any firm conclusions could be made.
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