Ed van der Heeft

Publications (4)10.84 Total impact

• Article: Dynamics of measles virus protein expression are reflected in the MHC class I epitope display.

  Carla A Herberts, Hugo M Meiring, Jacqueline A M van Gaans-van den Brink, Ed van der Heeft, Martien C M Poelen, Claire J P Boog, Ad P J M de Jong, Cécile A C M van Els
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  ABSTRACT: Following measles virus (MV) infection, viral peptides are presented to CTL by MHC class I molecules on infected antigen presenting cells at widely different epitope densities. Whereas three MV epitopes (MV-M(211-219), MV-F(438-446) and MV-H(30-38)) derived from different structural proteins occur at regular densities, one peptide derived from the non-structural C protein (MV-C(84-92)) fully dominates the MV peptide display in HLA class I molecules on end-stage-infected human B cells. Here we demonstrate that this hierarchy in MV epitope density is not a constant, but varies with progression of infection. While MV-M(211-219), MV-F(438-446) and MV-H(30-38) epitopes were already presented by HLA class I molecules early in infection, expression of MV-C(84-92) was restricted to the later phases of infection. These dynamics in epitope densities correlated with features of MV protein expression. Synthesis of C protein mainly focused towards the final stages of infection, while the other MV proteins were more readily synthesised from earlier time points on, in line with the emergence of their respective epitopes. Furthermore, the most abundant MV epitope was derived from the most unstable viral protein and vice versa, suggesting that the stability of viral proteins may be an indicator for the final abundance of their epitopes. Thus, even though many other factors may influence the generation of peptide-MHC class I complexes, we here report that the regulation of viral protein expression seems closely linked to the viral MHC class I epitope display. Finally, the observed dynamics in viral epitope hierarchy may have important implications for the induction of antiviral T cell immunity.
  Molecular Immunology 02/2003; 39(10):567-75. · 2.90 Impact Factor
• Article: Autoreactivity against induced or upregulated abundant self-peptides in HLA-A*0201 following measles virus infection.

  Carla A Herberts, Jacqueline van Gaans-van den Brink, Ed van der Heeft, Margot van Wijk, Jan Hoekman, Assan Jaye, Martien C M Poelen, Claire J P Boog, Paul J M Roholl, Hilton Whittle, Ad P J M de Jong, Cécile A C M van Els
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  ABSTRACT: Infectious agents have been implied as causative environmental factors in the development of autoimmunity. However, the exact nature of their involvement remains unknown. We describe a possible mechanism for the activation of autoreactive T cells induced by measles virus (MV) infection. The display of HLA-A*0201 associated peptides obtained from MV infected cells was compared with that from uninfected cells by mass spectrometry. We identified two abundant self peptides, IFI-6-16(74-82) and Hsp90beta(570-578), that were induced or upregulated, respectively, following infection. Their parental proteins, the type I interferon inducible protein IFI-6-16, and the beta chain of heat shock protein 90, have not been involved in MV pathogenesis. MV infection caused minor and major changes in the intracellular expression patterns of these proteins, possibly leading to altered peptide processing. CD8+ T cells capable of recognizing the self-peptides in the context of HLA-A*0201 were detectable at low basal levels in the neonatal and adult human T cell repertoire, but were functionally silent. In contrast, peptide-specific producing IFN-gamma producing effector cells were present in MV patients during acute infection. Thus, MV infection induces an enhanced display of self-peptides in MHC class I, which may lead to the temporary activation of autoreactive T cells.
  Human Immunology 02/2003; 64(1):44-55. · 2.84 Impact Factor
• Article: A single naturally processed measles virus peptide fully dominates the HLA‐A*0201‐associated peptide display and is mutated at its anchor position in persistent viral strains

  Cécile A. C. M. van Els, Carla A. Herberts, Ed van der Heeft, Martien C. M. Poelen, Jacqueline A. M. van Gaans-van den Brink, Alexander van der Kooi, Peter Hoogerhout, G. Jan ten Hove, Hugo D. Meiring, Ad P. J. M. de Jong
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  ABSTRACT: We studied the natural MHC class I display of measles virus (MV) epitopes. Peptide ligands associated with HLA-A*0201 were purified from a B lymphoblastoid cell line prior to and after infection with MV. Infection-induced peptides were revealed using microcapillary reversed phase high performance liquid chromatography electrospray ionization / mass spectrometry (μLC-ESI / MS) by subtraction of the "infected" and "uninfected" ion traces. Three naturally processed viral epitopes derived from different MV proteins were identified through tandem MS sequencing. These peptides were expressed at widely divergent levels of HLA-peptide complexes, but had similar binding capacities to HLA-A*0201. The most abundant viral peptide species, identified as residues 84 – 92 (KLWESPQEI) of the MV nonstructural C protein, was expressed at an unprecedented high density (> 105 copies per cell) and was immunogenic in HLA-A2 / Kb-transgenic mice. Furthermore, natural mutants of this epitope, occurring in persistent lethal MV strains, were shown to have lost their HLA-A*0201 binding capacity. Thus, here we report for the first time the direct discovery through μLC-ESI / MS of a uniquely dominant viral HLA class I ligand, KLWESPQEI, with features eligible for immune selection pressure.
  European Journal of Immunology 04/2000; 30(4):1172 - 1181. · 5.10 Impact Factor
• Article: Dynamics of measles virus protein expression are reflected in the MHC class I epitope display

  Carla A Herberts, Hugo M Meiring, Jacqueline A.M van Gaans-van den Brink, Ed van der Heeft, Martien C.M Poelen, Claire J.P Boog, Ad P.J.M de Jong, Cécile A.C.M van Els
  [show abstract] [hide abstract]
  ABSTRACT: Following measles virus (MV) infection, viral peptides are presented to CTL by MHC class I molecules on infected antigen presenting cells at widely different epitope densities. Whereas three MV epitopes (MV-M211–219, MV-F438–446 and MV-H30–38) derived from different structural proteins occur at regular densities, one peptide derived from the non-structural C protein (MV-C84–92) fully dominates the MV peptide display in HLA class I molecules on end-stage-infected human B cells. Here we demonstrate that this hierarchy in MV epitope density is not a constant, but varies with progression of infection. While MV-M211–219, MV-F438–446 and MV-H30–38 epitopes were already presented by HLA class I molecules early in infection, expression of MV-C84–92 was restricted to the later phases of infection. These dynamics in epitope densities correlated with features of MV protein expression. Synthesis of C protein mainly focused towards the final stages of infection, while the other MV proteins were more readily synthesised from earlier time points on, in line with the emergence of their respective epitopes. Furthermore, the most abundant MV epitope was derived from the most unstable viral protein and vice versa, suggesting that the stability of viral proteins may be an indicator for the final abundance of their epitopes. Thus, even though many other factors may influence the generation of peptide–MHC class I complexes, we here report that the regulation of viral protein expression seems closely linked to the viral MHC class I epitope display. Finally, the observed dynamics in viral epitope hierarchy may have important implications for the induction of antiviral T cell immunity.
  Molecular Immunology.