title: Influence of age and HLA type on interferon-gamma (IFN-gamma) responses to a naturally occurring polymorphic epitope of Plasmodium falciparum liver stage antigen-1 (LSA-1).
abstract: Antigenic polymorphism and HLA restriction may limit the immunogenicity of a subunit vaccine against liver-stage Plasmodium falciparum. We examined 59 clinical isolates and five laboratory clones of P. falciparum for polymorphism in the N- and C-terminal regions of LSA-1, evaluated binding of the corresponding peptides to selected HLA class I alleles, and measured IFN-gamma responses in residents of a malaria-endemic area of Papua New Guinea where HLA-A*1101, -24, -B13, and -B40 are the most common class I alleles. LSA-1 polymorphism was limited to a single non-synonymous mutation encoding serine (S), proline (P), or threonine (T) at amino acid 85. Nine-mer 84-92 peptides with S, T, or P at the primary anchor position bound differentially to HLA-A11, -A2, and -B7. IFN-gamma ELISPOT responses increased with age in malaria-exposed subjects: 14-16% and 30-36% of 2-5- and 6-54-year-olds, respectively, had > or =10 IFN-gamma-secreting cells/106 peripheral blood mononuclear cells when stimulated with at least one peptide variant (P<0.05). IFN-gamma responses to all three peptides were also greater for older than younger individuals. No children < 3 years old had lymphocytes that responded to all three 84-92 peptides, whereas 45% of adults (mean age 48 years) had aggregated IFN-gamma responses. These data support the notion that age-related cumulative exposure to P. falciparum increases the frequency of IFN-gamma responses to polymorphic epitopes of liver-stage antigens such as LSA-1.
authors.affiliation: Division of Geographic Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4983, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bucci
authors.forename: W
authors.initials: W
authors.lastname: Kastens
authors.forename: M R
authors.initials: MR
authors.lastname: Hollingdale
authors.forename: A
authors.initials: A
authors.lastname: Shankar
authors.forename: M P
authors.initials: MP
authors.lastname: Alpers
authors.forename: C L
authors.initials: CL
authors.lastname: King
authors.forename: J W
authors.initials: JW
authors.lastname: Kazura
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000276:immunology*; D000483:Alleles; D000818:Animals; D000940:Antigenic Variation / Q000235:genetics / Q000276:immunology*; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology*; D059870:HLA-A11 Antigen; D015789:HLA-A2 Antigen / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000276:immunology* / Q000503:physiopathology; D008875:Middle Aged; D010219:Papua New Guinea / Q000453:epidemiology; D010455:Peptides / Q000276:immunology; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D015789:HLA-A2 Antigen; D015235:HLA-B Antigens; D010455:Peptides; C067302:liver stage-specific antigen, Plasmodium; D007371:Interferon-gamma