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Role of repetitive antigen patterns for induction of antibodies against antibodies.

Fehr T, Bachmann MF, Bucher E, Kalinke U, Di Padova FE, Lang AB, Hengartner H, Zinkernagel RM - J. Exp. Med. (1997)

Bottom Line: Experience shows that they are usually difficult to induce experimentally.Why and how such anti-antibodies are induced during autoimmune diseases, has remained largely unclear.The results indicate a novel link between anti-antibody responses and infectious agents, and suggest a similar role for repetitive self-antigens such as DNA or collagen involved in chronic immunopathological diseases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Immunology, University of Zürich, CH-8091 Zürich, Switzerland.

ABSTRACT
Antibody responses against antibodies, such as rheumatoid factors, are found in several immunopathological diseases and may play a role in disease pathogenesis. Experience shows that they are usually difficult to induce experimentally. Antibodies specific for immunoglobulin constant regions (anti-allotypic) or for variable regions (anti-idiotypic) have been investigated in animal models; the latter have even been postulated to regulate antibody and T cell responses via network-like interactions. Why and how such anti-antibodies are induced during autoimmune diseases, has remained largely unclear. Because repetitively arranged epitopes in a paracrystalline structure of a viral envelope cross-link B cell receptors efficiently to induce a prompt T-independent IgM response, this study used immune complexes containing viruses or bacteria to evaluate the role of antigen pattern for induction of anti-antibody responses. We present evidence that antibodies bound to strictly ordered, but not to irregularly arranged, antigens dramatically enhance induction of anti-antibodies, already after a single immunization and without using adjuvants. The results indicate a novel link between anti-antibody responses and infectious agents, and suggest a similar role for repetitive self-antigens such as DNA or collagen involved in chronic immunopathological diseases.

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Anti-antibody response upon immunization with a recombinant VSV-G–huHγ1 fusion protein alone or complexed with anti-VSV-G  IgM or IgG antibodies. BALB/c mice were immunized with 10 μg of the  fusion protein VSV-G-huHγ1 alone (vertically striped bars), the fusion protein complexed with 1 μg of M1 (closed bars) or 1 μg of a monoclonal  VSV-G–specific IgG2a antibody (E5A7C9; open bars) or with 1 μg of M1  alone (horizontally striped bars). Mouse IgG (mIgG) anti-human IgG titers  of 20-fold prediluted sera were determined on day 12 after primary and  on day 5 after secondary immunization (day 18). Bars represent geometrical means of two to three mice per group. Standard deviation was within ±  one dilution step.
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Figure 4: Anti-antibody response upon immunization with a recombinant VSV-G–huHγ1 fusion protein alone or complexed with anti-VSV-G IgM or IgG antibodies. BALB/c mice were immunized with 10 μg of the fusion protein VSV-G-huHγ1 alone (vertically striped bars), the fusion protein complexed with 1 μg of M1 (closed bars) or 1 μg of a monoclonal VSV-G–specific IgG2a antibody (E5A7C9; open bars) or with 1 μg of M1 alone (horizontally striped bars). Mouse IgG (mIgG) anti-human IgG titers of 20-fold prediluted sera were determined on day 12 after primary and on day 5 after secondary immunization (day 18). Bars represent geometrical means of two to three mice per group. Standard deviation was within ± one dilution step.

Mentions: The notion that antibodies bound to repetitively ordered viral or bacterial antigens induced anti-antibodies was further tested with a sort of inversed IC. Complexes were formed between a VSV-G–specific decavalent IgM (M1) or a bivalent IgG2a antibody (VI49; reference 30) as core of the complex that binds a fusion protein of VSV-G plus constant part of the human IgG1 H chain (huHγ1) molecule. These IC display the Fc portions of huIgG1 as repetitive domains and form under optimal conditions decameric (with IgM) or dimeric (with IgG) complexes. In primary and secondary immune responses of BALB/c mice, the fusion protein complexed with the decavalent IgM induced much higher titers of anti-antibodies to huHγ1 than bivalent IgG-complexed or the noncomplexed fusion protein alone (Fig. 4). These anti-antibodies were of IgG isotype and T-help dependent, as shown by the negative effect of in vivo CD4+ T cell depletion. Although a very rigid IC structure cannot be assumed in this model, the results show that antibody responses to a foreign constant IgG region, which involves species differences, can be markedly enhanced by multimeric aggregation compared with dimers or monomers. Importantly, they may even suggest that IgM-bound antigen in turn binding IgG may be able to induce anti-IgG antibodies.


Role of repetitive antigen patterns for induction of antibodies against antibodies.

Fehr T, Bachmann MF, Bucher E, Kalinke U, Di Padova FE, Lang AB, Hengartner H, Zinkernagel RM - J. Exp. Med. (1997)

Anti-antibody response upon immunization with a recombinant VSV-G–huHγ1 fusion protein alone or complexed with anti-VSV-G  IgM or IgG antibodies. BALB/c mice were immunized with 10 μg of the  fusion protein VSV-G-huHγ1 alone (vertically striped bars), the fusion protein complexed with 1 μg of M1 (closed bars) or 1 μg of a monoclonal  VSV-G–specific IgG2a antibody (E5A7C9; open bars) or with 1 μg of M1  alone (horizontally striped bars). Mouse IgG (mIgG) anti-human IgG titers  of 20-fold prediluted sera were determined on day 12 after primary and  on day 5 after secondary immunization (day 18). Bars represent geometrical means of two to three mice per group. Standard deviation was within ±  one dilution step.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196322&req=5

Figure 4: Anti-antibody response upon immunization with a recombinant VSV-G–huHγ1 fusion protein alone or complexed with anti-VSV-G IgM or IgG antibodies. BALB/c mice were immunized with 10 μg of the fusion protein VSV-G-huHγ1 alone (vertically striped bars), the fusion protein complexed with 1 μg of M1 (closed bars) or 1 μg of a monoclonal VSV-G–specific IgG2a antibody (E5A7C9; open bars) or with 1 μg of M1 alone (horizontally striped bars). Mouse IgG (mIgG) anti-human IgG titers of 20-fold prediluted sera were determined on day 12 after primary and on day 5 after secondary immunization (day 18). Bars represent geometrical means of two to three mice per group. Standard deviation was within ± one dilution step.
Mentions: The notion that antibodies bound to repetitively ordered viral or bacterial antigens induced anti-antibodies was further tested with a sort of inversed IC. Complexes were formed between a VSV-G–specific decavalent IgM (M1) or a bivalent IgG2a antibody (VI49; reference 30) as core of the complex that binds a fusion protein of VSV-G plus constant part of the human IgG1 H chain (huHγ1) molecule. These IC display the Fc portions of huIgG1 as repetitive domains and form under optimal conditions decameric (with IgM) or dimeric (with IgG) complexes. In primary and secondary immune responses of BALB/c mice, the fusion protein complexed with the decavalent IgM induced much higher titers of anti-antibodies to huHγ1 than bivalent IgG-complexed or the noncomplexed fusion protein alone (Fig. 4). These anti-antibodies were of IgG isotype and T-help dependent, as shown by the negative effect of in vivo CD4+ T cell depletion. Although a very rigid IC structure cannot be assumed in this model, the results show that antibody responses to a foreign constant IgG region, which involves species differences, can be markedly enhanced by multimeric aggregation compared with dimers or monomers. Importantly, they may even suggest that IgM-bound antigen in turn binding IgG may be able to induce anti-IgG antibodies.

Bottom Line: Experience shows that they are usually difficult to induce experimentally.Why and how such anti-antibodies are induced during autoimmune diseases, has remained largely unclear.The results indicate a novel link between anti-antibody responses and infectious agents, and suggest a similar role for repetitive self-antigens such as DNA or collagen involved in chronic immunopathological diseases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Immunology, University of Zürich, CH-8091 Zürich, Switzerland.

ABSTRACT
Antibody responses against antibodies, such as rheumatoid factors, are found in several immunopathological diseases and may play a role in disease pathogenesis. Experience shows that they are usually difficult to induce experimentally. Antibodies specific for immunoglobulin constant regions (anti-allotypic) or for variable regions (anti-idiotypic) have been investigated in animal models; the latter have even been postulated to regulate antibody and T cell responses via network-like interactions. Why and how such anti-antibodies are induced during autoimmune diseases, has remained largely unclear. Because repetitively arranged epitopes in a paracrystalline structure of a viral envelope cross-link B cell receptors efficiently to induce a prompt T-independent IgM response, this study used immune complexes containing viruses or bacteria to evaluate the role of antigen pattern for induction of anti-antibody responses. We present evidence that antibodies bound to strictly ordered, but not to irregularly arranged, antigens dramatically enhance induction of anti-antibodies, already after a single immunization and without using adjuvants. The results indicate a novel link between anti-antibody responses and infectious agents, and suggest a similar role for repetitive self-antigens such as DNA or collagen involved in chronic immunopathological diseases.

Show MeSH
Related in: MedlinePlus