title: Role of high-affinity HLA-DP specific CLIP-derived peptides in beryllium binding to the HLA-DPGlu69 berylliosis-associated molecules and presentation to beryllium-sensitized T cells.
abstract: Berylliosis is driven by the accumulation in the lung of beryllium-specific T helper type 1 (Th1) cells recognizing beryllium as antigen when presented principally by human leucocyte antigen DP molecules carrying a glutamate at position beta69 (HLA-DPGlu69). This study was designed to clarify the precise role of peptides in beryllium binding to the HLA-DP groove's pocket 4 and to identify peptides with higher affinity for pocket 4 that might prevent beryllium presentation and T-cell stimulation. Beryllium/HLA-DP interactions were analysed by the ability of beryllium to compete with CLIP and CLIP-derived peptides to HLA-DPGlu69 soluble molecule. The CLIP-derived low-affinity peptide CLIP-AA, could not outcompete beryllium; while the CLIP-derived high-affinity peptides CLIP-YY, CLIP-QY and CLIP-RF were only marginally influenced by the presence of beryllium in the competition assay. The effect of these CLIP-derived high-affinity peptides on beryllium presentation was determined by measuring interferon-gamma (IFN-gamma) release upon beryllium stimulation of peripheral blood mononuclear cells obtained from beryllium-hypersensitive subjects. CLIP-YY did inhibit beryllium presentation and T-cell activation, while CLIP-QY and CLIP-RF markedly enhanced the IFN-gamma response to beryllium. Anti-HLA-DP monoclonal antibody blocked the beryllium-induced IFN-gamma release in the presence of CLIP-QY (88%) and CLIP-RF (76%). A similar effect was observed for CLIP-YY capability to block IFN-gamma release by beryllium stimulation in the presence of CLIP-QY (79%) and CLIP-RF (76%). Overall, these data support the proposal that HLA-DP high-affinity peptides might be used as a model for specific berylliosis therapy.
authors.affiliation: Dipartimento di Medicina Interna, Università di Roma Tor Vergata, Roma, Italy. amicosan@uniroma2.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Amicosante
authors.forename: Floriana
authors.initials: F
authors.lastname: Berretta
authors.forename: Raed
authors.initials: R
authors.lastname: Dweik
authors.forename: Cesare
authors.initials: C
authors.lastname: Saltini
mesh_terms: D000328:Adult; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D001607:Berylliosis / Q000276:immunology* / Q000378:metabolism; D001608:Beryllium / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006682:HLA-DP Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D006682:HLA-DP Antigens; D000949:Histocompatibility Antigens Class II; C045084:invariant chain; D007371:Interferon-gamma; D001608:Beryllium