The role of structure in antibody cross-reactivity between peptides and folded proteins

Craig, Lisa; Sanschagrin, Paul C.; Rozek, Annett; Lackie, Steve J.; Kuhn, Leslie A.; Scott, Jamie K.

doi:10.1006/jmbi.1998.1907

Cited by 87 publications

(64 citation statements)

References 95 publications

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“…Importantly, the binding to the LACDE sequence is also inhibited by the purified PDC mitochondrial antigen, demonstrating that the cross-reactive microbial/self recognition targets the naturally occurring autoantigen. 25,32 These findings are in sharp contrast to those obtained for ECOLI PDC-E2 231-245 , which has proved to be a poor inhibitor of anti-human PDC-E2 212-226 reactivity.…”

Section: Discussioncontrasting

confidence: 60%

Primary biliary cirrhosis is characterized by IgG3 antibodies cross‐reactive with the major mitochondrial autoepitope and its Lactobacillus mimic†

et al. 2005

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The serological hallmark of primary biliary cirrhosis (PBC) is the presence of pyruvate dehydrogenase complex E2 subunit (PDC-E2) antimitochondrial antibodies (AMAs). Anti-PDC-E2 antibodies cross-react specifically with mycobacterial hsp65, and we have demonstrated that the motif SxGDL[ILV]AE shared by PDC-E2 212-226 and hsp's is a cross-reactive target. Having found that this same motif is present only in ␤-galactosidase of Lactobacillus delbrueckii (BGAL LACDE), we hypothesized that this homology would also lead to crossreactivity. The mimics were tested via ELISA for reactivity and competitive cross-reactivity using sera from 100 AMA-positive and 23 AMA-negative PBC patients and 190 controls. An Escherichia coli (ECOLI) PDC-E2 mimic that has been pathogenetically linked to PBC but lacks this motif has been also tested. Anti-BGAL 266-280 LACDE antibodies were restricted to AMA-positive patients (54 of 95, 57%) and belonged to immunoglobulin (Ig) G3. Of the 190 controls, 22 (12%; P < .001) had anti-BGAL 266-280 antibodies, mainly of the IgG4 subclass. ECOLI PDC-E2 reactivity was virtually absent. BGAL 266-280 /PDC-E2 212-226 reactivity of the IgG3 isotype was found in 52 (52%) AMA-positive PBC patients but in only 1 of the controls (P < .001). LACDE BGAL 266-280 /PDC-E2 212-226 reactivity was due to crossreactivity as confirmed via competition ELISA. Antibody affinity for BGAL 266-280 was greater than for PDC-E2 mimics. Preincubation of a multireactive serum with BGAL 266-280 reduced the inhibition of enzymatic activity by 40%, while marginal effect (12%) or no effect (2%) was observed in human or ECOLI PDC-E2 mimics. In conclusion, IgG3 antibodies to BGAL LACDE cross-react with the major mitochondrial autoepitope and are characteristic of PBC.

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Section: Discussioncontrasting

confidence: 60%

Primary biliary cirrhosis is characterized by IgG3 antibodies cross‐reactive with the major mitochondrial autoepitope and its Lactobacillus mimic†

et al. 2005

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“…Because of its length and extreme cost to produce, Santa Cruz does not offer a blocking peptide for the R-101 antibody, and it was for this reason that we tried the synthetic peptide antibodies that both have blocking peptides available as shown in Figures 4L and 4M (for the N-terminal antibody). It is not surprising that the R-101 antibody gave better overall results compared with the shorter synthetic peptide antibodies, because such an outcome can happen and is not unique to AQP 7 (Craig et al 1998). What is surprising is that neither of the synthetic peptide antibodies showed lateral or basal reactions characteristic of the R-101 antibody, and the C-terminal antibody was completely negative for AQP 7 in epididymis.…”

Section: Discussionmentioning

confidence: 99%

Membrane Domain Specificity in the Spatial Distribution of Aquaporins 5, 7, 9, and 11 in Efferent Ducts and Epididymis of Rats

Hermo

Schellenberg

Liu

et al. 2008

J Histochem Cytochem.

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S U M M A R Y Water content within the epididymis of the male reproductive system is stringently regulated to promote sperm maturation. Several members of the aquaporin (AQP) family of water channel-forming integral membrane proteins have been identified in epididymal cells, but expression profiling for this epithelium is presently incomplete, and no AQP isoform has yet been identified on basolateral plasma membranes of these cells. In this study, we explored AQP expression by RT-PCR and light microscopy immunolocalizations using peroxidase and wide-field fluorescence techniques. The results indicate that several AQPs are coexpressed in the epididymis including AQP 5, 7, 9, and 11. Immunolocalizations suggested complex patterns in the spatial distribution of these AQPs. In principal cells, AQP 9 and 11 were present mainly on microvilli, whereas AQP 7 was localized primarily to lateral and then to basal plasma membranes in a region-specific manner. AQP 5 was also expressed regionally but was associated with membranes of endosomes. Additionally, AQPs were expressed by some but not all basal (AQP 7 and 11), clear (AQP 7 and 9), and halo (AQP 7 and 11) cells. These findings indicate unique associations of AQPs with specific membrane domains in a cell type-and region-specific manner within the epididymis of adult animals.

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“…Molecular mimicry to the cognate antigen seems to be required for inducing a functional, cross-reactive immune response. 1 In several studies this functional molecular mimicry has been achieved by a trial-and-error approach, 2 -7 by combinatorial chemistry display techniques 8,9 or by structure-based design. 10 -12 Similar to approaches in structure-based drug design, crystal or solution structures of peptide-antibody complexes are often used to optimize the complementarity between a peptide and a functional antibody, which should thus lead to higher binding affinity.…”

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confidence: 99%

Immunogenicity of Peptide-vaccine Candidates Predicted by Molecular Dynamics Simulations

Oomen

Hoogerhout

Bonvin

et al. 2003

Journal of Molecular Biology

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We present an in silico, structure-based approach for design and evaluation of conformationally restricted peptide-vaccines. In particular, we designed four cyclic peptides of ten or 11 residues mimicking the crystallographically observed b-turn conformation of a predicted immunodominant loop of PorA from Neisseria meningitidis. Conformational correctness and stability of the peptide designs, as evaluated by molecular dynamics simulations, correctly predicted the immunogenicity of the peptides. We observed a peptide-induced functional antibody response that, remarkably, exceeded the response induced by the native protein in outer membrane vesicles, without losing specificity for related strains. The presented approach offers tools for a priori design and selection of peptide-vaccine candidates with full biological activity. This approach could be widely applicable: to outer membrane proteins of Gram-negative bacteria, and to other epitopes in a large range of pathogens.

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The role of structure in antibody cross-reactivity between peptides and folded proteins

Cited by 87 publications

References 95 publications

Primary biliary cirrhosis is characterized by IgG3 antibodies cross‐reactive with the major mitochondrial autoepitope and its Lactobacillus mimic†

Primary biliary cirrhosis is characterized by IgG3 antibodies cross‐reactive with the major mitochondrial autoepitope and its Lactobacillus mimic†

Membrane Domain Specificity in the Spatial Distribution of Aquaporins 5, 7, 9, and 11 in Efferent Ducts and Epididymis of Rats

Immunogenicity of Peptide-vaccine Candidates Predicted by Molecular Dynamics Simulations

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