Aspects of antigen mimicry revealed by immunization with a peptide mimetic of Cryptococcus neoformans polysaccharide.
We have recently identified peptide mimetics of the Cryptococcus neoformans capsular polysaccharide by screening phage display peptide libraries. 2H1, one of a large family of mAbs against the glucuronoxylomannan fraction (GXM), is highly protective and binds several peptide motifs. This study analyzes the immunologic properties of P601E (SYSWMYE), a peptide from the low affinity motif (W/YXWM/LYE) that has an extended cross-reactivity among anti-GXM mAbs and whose binding correlates with the protective potential of mAbs in experimental infection. P601E is a mimetic, since it competes for GXM binding to 2H1, but not a mimotope, since it does not elicit an anti-GXM response. Sequence analysis of 14 anti-P601E mAbs indicates that anti-P601E mAbs elicited in BALB/c mice have an order of homology with 2H1 of V kappa > J kappa >> V(H) > J(H) > D. Further screening of a peptide library with anti-P601E mAbs isolated peptides having a motif almost identical to the peptide motif selected by 2H1. When these results are compared to the crystal structure of a related peptide in complex with 2H1, there is a clear correlation between the ability to elicit V region components of 2H1 Ab and peptide association with the V region, suggesting that the completeness of the fit in the binding site is an important driving force for mimicry. As a consequence, improving affinity of a mimetic for the Ab binding site seems to be the most logical way to insure that all of the appropriate V region segments are elicited and that useful mimotopes are created.
Valadon
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P
Cell Biology Department, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Nussbaum
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Oh
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Scharff
M D
MD
D000595:Amino Acid Sequence; D000818:Animals; D000908:Antibodies, Fungal / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism; D000946:Antigens, Fungal / Q000008:administration & dosage / Q000276:immunology; D001483:Base Sequence; D001666:Binding Sites, Antibody; D003455:Cryptococcus neoformans / Q000276:immunology*; D007114:Immunization; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry / Q000276:immunology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000276:immunology*; D011134:Polysaccharides / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D000908:Antibodies, Fungal; D000911:Antibodies, Monoclonal; D000946:Antigens, Fungal; D007135:Immunoglobulin Variable Region; D010446:Peptide Fragments; D010455:Peptides; D011134:Polysaccharides; C027478:glucuronoxylomannan