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

• Published in: Immunology Vol. 128; no. 1pt2; pp. e462 - e470
• Main Authors: Amicosante, Massimo, Berretta, Floriana, Dweik, Raed, Saltini, Cesare
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.09.2009; Blackwell Publishing Ltd; Blackwell Science Inc
• Subjects: Adult; antigen presentation; Antigens, Differentiation, B-Lymphocyte; Antigens, Differentiation, B-Lymphocyte - immunology; Antigens, Differentiation, B-Lymphocyte - metabolism; Berylliosis; Berylliosis - immunology; Berylliosis - metabolism; beryllium; Beryllium - immunology; Beryllium - metabolism; biosynthesis; chemistry; CLIP; Female; Histocompatibility Antigens Class II; Histocompatibility Antigens Class II - immunology; Histocompatibility Antigens Class II - metabolism; HLA-DP Antigens; HLA-DP Antigens - chemistry; HLA-DP Antigens - immunology; HLA-DP Antigens - metabolism; human leucocyte antigen; human leucocyte antigen-DP; Humans; immunogenetic; immunogenetics; immunology; Interferon-gamma; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Lymphocyte Activation; Lymphocyte Activation - immunology; Male; metabolism; Middle Aged; Original; peptide-based therapy; T cells; T-lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0019-2805; 1365-2567; 1365-2567
• DOI: 10.1111/j.1365-2567.2008.03000.x

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 β69 (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-γ (IFN-γ) 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-γ response to beryllium. Anti-HLA-DP monoclonal antibody blocked the beryllium-induced IFN-γ release in the presence of CLIP-QY (88%) and CLIP-RF (76%). A similar effect was observed for CLIP-YY capability to block IFN-γ 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.