|Sherman, Mark - CITY OF HOPE|
|Goto, Ronald - CITY OF HOPE|
|Moore, Roger - CITY OF HOPE|
|Lee, Terry - CITY OF HOPE|
|Miller, Marcia - CITY OF HOPE|
Submitted to: Immunogenetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 6, 2008
Publication Date: September 30, 2008
Citation: Sherman, M.A., Goto, R.M., Moore, R.E., Hunt, H.D., Lee, T.D., Miller, M.M. 2008. Mass Spectral Data for 64 Eluted Peptides and Structural Modeling Define Peptide Binding Preferences for Class I Alleles in Two Chicken MHC-B Haplotypes Associated with Opposite Responses to Marek's Disease. Immunogenetics. 60(9):485-555. Interpretive Summary: Marek's disease (MD), a virus induced cancer like disease of chickens, is considered as a major disease problem in commercial poultry. Vaccination has dramatically reduced the incidence of the disease, but very little is known about the viral products involved in the induction of disease. The objective of this research was to characterize the mechanism by which MD virus (MDV) influence the immune response of the host. We have identified and characterized a process by which certain lines of chickens may be more immuno-responsive to MDV compared to other lines of chickens. The information obtained from this research is of great interest to scientists in industry and academia as it will aid in developing the new generation of vaccine viruses capable of inducing immuno-responsiveness in chicken flocks.
Technical Abstract: Major histocompatibility complex haplotypes are known to influence disease resistance in the chicken. The MHC-B*21 haplotype is especially associated with resistance to the T-cell lymphomas that form following infection with the highly oncogenic Marek’s herpesvirus. Since only a single MHC class I locus is predominantly expressed in the chicken it could be that this strong association with MHC haplotype is the result of pathogen selection for disease resistance at this single MHC I locus called BF2. To identify the peptide binding motif of BF2*21, we eluted and analyzed by LC/MS/MS endogenous peptides derived from a transduced FLAG epitope-tagged cDNA BF2*21 clone. Sequences of 34 eluted peptides (mostly decamers) revealed that a C-terminal aliphatic residue, nearly always leucine, is the major anchor residue for peptides bound by the BF2*21 allele with a somewhat weaker anchor at a second position (XXXXXXX[DEQ]X[LIV]). Motif scanning of viral protein sequences revealed that the BF2*21 motif is present in a broad variety of peptides derived from many different viral pathogens. There is likely a general benefit to possessing B21 haplotypes, since birds carrying the BF2*21 allele are likely capable of responding to a variety of pathogens including multiple strains of Marek’s herpesvirus. The peptide binding motif for the BF2 allele encoded in B13, a haplotype associated with Marek’s disease susceptibility, revealed striking contrasts. The BF2*13 peptide binding motif, derived from 30 eluted endogenous peptide sequences, is unusual in that there are strong dominant anchor residues at four positions (X[DE][IVL]X[DE]XX[ED]X) that limits the types of candidate peptides likely to bind within the BF2*13 antigen binding groove. Very limited numbers of candidate peptides were found in scans of viral proteins. Matches are most often within DNA and RNA polymerases with these being the only matches in the proteins of some viruses with small genomes. It may be that the BF2*13 allele provides selective advantage in the face of challenge from a subset pathogens via the capacity to present these unusual peptides derived from polymerases. Overall these findings indicate a role of BF2 polymorphisms in disease responses in the chicken, but they provide little evidence supporting the likelihood that BF2*21 was specifically selected for its role in Marek’s disease.