Date of Award
Doctor of Philosophy (PhD)
Melittin, a bee-venom peptide of 26 amino acids, has well-known amphiphilic properties. These properties result in a number of interesting biophysical behaviors and defined quaternary structures; knowledge of these activities has been exploited to understand the relationship of structure and immunogenicity of melittin and melittin analogs. From this analysis, a hypothesis for melittin's in vivo immunogenic structure predicated on binding to cell membranes or other lipophilic environments is suggested.
Immunogenicity for antibody responses depends on primary, secondary, and quaternary structure. The distribution of hydrophobic and hydrophilic amino acids determines "peptide-detergent" properties such as self-association and the ability to bind and oligomerize in cell membranes, and only peptides of a minimum size of 24 amino acids are immunogenic. Analogs of melittin that retain these properties elicit strong antibody responses; analogs that lack these properties are weak immunogens for antibody responses. As a result of these structural propensities, melittin-specific antibodies primarily react with the C-terminal epitope of the peptide.
The T-cell epitope of melittin in H-2d restricted mice is located primarily in residue 7-19. Melittin-specific T cell clones are CD4+, showed high egression of a CD45 R isoform associated with Th2 phenotype, and most appeared to secrete IL-4. Melittin-specific T-cell clones are restricted to both alleles of H-2d class II molecules, I-A and I-E. I-A restricted clones respond to lower concentrations of melittin and a wide variety of melittin analogs; I-E restricted clones require higher melittin concentrations and fail to recognize some melittin analogs. Differential la restriction results in different peptide-specific Ig isotype distribution. I-A only restriction is characterized by increased levels of specific IgG2a decreased levels of IgG1 and IgE.
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