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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.
AuthorsMassimo Amicosante, Floriana Berretta, Raed Dweik, Cesare Saltini
JournalImmunology (Immunology) Vol. 128 Issue 1 Suppl Pg. e462-70 (Sep 2009) ISSN: 1365-2567 [Electronic] England
PMID19191908 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antigens, Differentiation, B-Lymphocyte
  • HLA-DP Antigens
  • Histocompatibility Antigens Class II
  • invariant chain
  • Interferon-gamma
  • Beryllium
Topics
  • Adult
  • Antigens, Differentiation, B-Lymphocyte (immunology, metabolism)
  • Berylliosis (immunology, metabolism)
  • Beryllium (immunology, metabolism)
  • Female
  • HLA-DP Antigens (chemistry, immunology, metabolism)
  • Histocompatibility Antigens Class II (immunology, metabolism)
  • Humans
  • Interferon-gamma (biosynthesis, immunology)
  • Lymphocyte Activation (immunology)
  • Male
  • Middle Aged
  • T-Lymphocytes (immunology, metabolism)

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