Some thoughts on idiotypic networks and immunoregulation
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Immunoglobulin Idiotypes
Idiotopes
Constant (computer programming)
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The idiotype defined by the levan-specific BALB/c myeloma protein ABPC48 (A48) has previously been encountered only in antibodies the variable regions of which derive from the VHX24 and V kappa 10 gene families. We have demonstrated expression of the idiotope recognized by the monoclonal anti-A48 idiotype antibody IDA10 on five monoclonal antibodies from different mouse strains, with different specificities including foreign and self antigens and deriving their variable regions from families other than VHX24 and V kappa 10. We analyzed variable region protein structure (deduced from nucleotide sequences) and hydrophilicity profiles of idiotype+ and idiotype- antibodies. We identified four surface-exposed areas (one in the heavy chain and three in the light chain) that may contribute to expression of the idiotope defined by antibody IDA10.
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Monoclonal anti-HLA-DR antibody (anti-DR mAb) reactivity was investigated at the idiotypic level; three syngeneic anti-idiotype (Id) sera were raised against three monomorphic anti-DR mAb (206, BM 50, and D 1.12). The syngeneic anti-Id responses exhibited some differences in their intensity and the idiotypic determinants recognized by the three anti-Id sera were localized, at least in part, on the antigen combining site of the respective anti-DR mAb. Idiotype analysis of 24 anti-DR mAb was performed with these anti-Id sera by Id-binding inhibition assays. Idiotypic cross-reactivity was demonstrated for 12 out of the 24 anti-DR mAb, indicating a large degree of idiotypic recurrence. Analysis of the cross-inhibition patterns led us to define at least five sets of recurrent idiotopes: one set cross-reacting with anti-206 Id, the second with both anti-BM 50 and anti-D 1.12 Id, the third with anti-BM 50 Id only, the fourth with anti-D 1.12 Id only, and a fifth set was shared by D 1.12 and NE 4. Eleven monomorphic anti-DR mAb and one polymorphic anti-DR 3 mAb (16.23) did not cross-react with the three anti-Id sera. These results suggest that the mouse antibody response to monomorphic determinants on human Ia antigens is based on a limited number of recurrent idiotopes. In two cases, recurrent idiotopes could be related to a similar anti-DR mAb fine specificity. These anti-Id provide useful reagents to classify and compare anti-DR mAb.
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Eight monoclonal antibodies were selected from BALB/c mice immunized with two different monoclonal anti-idiotypic antibodies recognizing two discrete idiotopes characteristic of the anti-poly(Glu60Ala30Tyr10) (GAT) antibody response. These monoclonal antibodies were previously classified as Ab1 (anti-GAT-like) and Ab3 (anti-anti-idiotype) on the basis of expression of the public idiotypic specificity (p.GAT) studied with a xenogeneic serum, anti-GAT activity, and expression of various public idiotopes. All the heavy chain variable region (VH) sequences from Ab1 are nearly identical to the VH sequences of Ab1 anti-GAT monoclonal antibodies. The same type of results has been found with the Ab1 kappa light chain variable region (V kappa) sequences. Confirming our classification, Ab3 VH and V kappa sequences were found to be completely different from Ab1 VH and V kappa sequences. The Ab1 diversity (D) regions are different from one another and different from the D regions found on monoclonal anti-GAT antibodies but function similarly. These D regions are not simply derived from already described D genes. Finally, our results suggest that in the anti-GAT response VH and V kappa sequence are mainly responsible for idiotype expression.
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Mouse alloantibodies to Ia.7 display a cross-reactive idiotype (CRI) recognized by xenogeneic anti-idiotypes. The CRI is expressed on serum Abs in all responding individuals and on all anti-Ia.7 mAbs, from mice of appropriate genetic types. In addition, both xenogeneic and allogeneic anti-idiotypes in this system have a striking ability to induce Ia.7-specific responses in mice never exposed to the Ag. Because of these unusual features, we have investigated the biologic and structural basis of the idiotypic sharing in this system. Ia.7-specific Ab populations induced by eight different Ab2 mAbs were analyzed for expression of each of the set of idiotopes. Two obvious explanations for the unusual properties of the system do not appear to be correct. 1) The induction of Ag-specific immunity was not caused by internal imagery; and 2) the Ab2s do not simply recognize the same idiotope, because they induce populations that were found to be distinct in idiotope expression. The biologic properties of the system are instead caused by a pattern of expression of idiotope sets on distinct but related Ab families, and a remarkable linkage of a series of different idiotopes to Ia.7-specific activity. Mouse anti-idiotypic responses failed to recognize the widely shared CRI site, even when sequential immunizations were performed. To examine the structural basis of Id sharing, light chains of three CRI+ mAbs were sequenced. They were found to be extremely homologous to each other and to the germ-line V kappa 21E gene, and they used either J1 or J2. A model containing families of distinct but related V regions is proposed for the anti-Ia.7 repertoire.
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Immunoglobulin Idiotypes
Immunogenetics
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Idiotopes
Immunoglobulin Idiotypes
Hypervariable region
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Abstract Alloantiserum and hybridoma‐derived anti‐Ia antibodies were investigated for their idiotypic similarity using 4 monoclonal anti‐idiotypes raised against monoclonal anti‐Ia. With one anti‐idiotype, idiotypic cross‐reactivity could be found between three independently derived monoclonal BALB/c anti‐Ia antibodies, all of which were directed against the same serological determinant, Ia.2. The respective idiotype, tentatively designated la.2 idiotope, could also be demonstrated on anti‐Ia.2 antibodies in BALB/c alloantisera, but not on anti‐Ia against other specificities. The expression of the Ia.2 idiotope is linked to the Igh allotype; the use of Ig‐recombinant mice allowed us to map the Igh‐Ia.2 locus to the left of the T1S marker in the Igha V region.
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Idiotopes
Immunoglobulin Idiotypes
clone (Java method)
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Abstract Seventeen hybridomas, secreting monoclonal anti‐idiotypic antibodies (IDA) directed against the BALB/c ABPC48 idiotype, were isolated from one immunized BALB/c mouse. Several IDA also bind another BALB/c idiotype: UPC10. ABPC48 and UPC10 are both myeloma proteins with a β(2→6)‐polyfructosan (levan) specificity. The binding of every IDA to the ABPC48 idiotype can be completely inhibited by levan molecules, but at different concentrations. Mutual inhibition assays between the IDA made it possible to define six groups of IDA which bind at least three different idiotopes of ABPC48. Sixteen IDA have been studied by means of mouse anti‐anti‐idiotypic antibodies (Ab3) directed against two of them, IDA3 and IDA10. Anti‐IDA3 Ab3 recognize idiotopes particular to IDA3 which are not found on other monoclonal anti‐idiotypic antibodies (Ab2). Anti‐IDA10 Ab3 cross‐reacts with several monoclonal Ab2, including Ab2 with different spectrotypes belonging or not to the same isotype and Ab2 with different specificities for the ABPC48 idiotype. Some IDA10 idiotopes are present in the polyclonal anti‐ABPC48 antibody response of BALB/c, A/J and CBA mice showing that they are recurrent and that their expression is not linked to a particular Igh‐C haplotype. In contrast, IDA3 idiotopes are not detected in the same anti‐ABPC48 antisera.
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Polyclonal antibodies
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Disease activity has been demonstrated to be one of the major factors contributing to fetal loss in SLE patients, and discontinuation of antimalarial therapy can precipitate a flare of disease. It is therefore important to determine whether it is safe to continue antimalarial therapy throughout pregnancy. We have previously stated that we consider lupus patients and their fetuses to be at risk for disaster if antimalarial therapy is discontinued during pregnancy, and it has been our experience that lupus patients can produce normal offspring even if they are taking daily chloroquine or hydroxychloroquine. Several other reports now support our findings that it is probably safe to continue antimalarial therapy during pregnancy, although there are no large studies published. Data on the secretion of hydroxychloroquine in the breast milk of patients on steady-state hydroxychloroquine therapy are minimal, and further studies are required to determine whether these women can safely nurse their infants while taking hydroxychloroquine daily.
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