Abstract
Metal hypersensitivity is a common immune disorder. Human immune systems mount the allergic attacks on metal ions through skin contacts, lung inhalation and metal-containing artificial body implants. The consequences can be simple annoyances to life-threatening systemic illness. Allergic hyper-reactivities to nickel (Ni) and beryllium (Be) are the best-studied human metal hypersensitivities. Ni-contact dermatitis affects 10 % of the human population, whereas Be compounds are the culprits of chronic Be disease (CBD). αβ T cells (T cells) play a crucial role in these hypersensitivity reactions. Metal ions work as haptens and bind to the surface of major histocompatibility complex (MHC) and peptide complex. This modifies the binding surface of MHC and triggers the immune response of T cells. Metal-specific αβ T cell receptors (TCRs) are usually MHC restricted, especially MHC class II (MHCII) restricted. Numerous models have been proposed, yet the mechanisms and molecular basis of metal hypersensitivity remain elusive. Recently, we determined the crystal structures of the Ni and Be presenting human MHCII molecules, HLA-DR52c (DRA*0101, DRB3*0301) and HLA-DP2 (DPA1*0103, DPB1*0201). These structures revealed unusual features of MHCII molecules and shed light on how metal ions are recognized by T cells.
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References
Budinger L, Hertl M. Immunologic mechanisms in hypersensitivity reactions to metal ions: an overview. Allergy. 2000;55(2):108–15.
Schiraldi M, Monestier M. How can a chemical element elicit complex immunopathology? Lessons from mercury-induced autoimmunity. Trends Immunol. 2009;30(10):502–9.
Vas J, Monestier M. Immunology of mercury. Ann N Y Acad Sci. 2008;1143:240–67.
Rowley B, Monestier M. Mechanisms of heavy metal-induced autoimmunity. Mol Immunol. 2005;42(7):833–8.
Li H, Llera A, Malchiodi EL, Mariuzza RA. The structural basis of T cell activation by superantigens. Annu Rev Immunol. 1999;17:435–66.
Papageorgiou AC, Baker MD, McLeod JD, Goda SK, Manzotti CN, Sansom DM, et al. Identification of a secondary zinc-binding site in staphylococcal enterotoxin C2. Implications for superantigen recognition. J Biol Chem. 2004;279(2):1297–303.
Li H, Zhao Y, Guo Y, Li Z, Eisele L, Mourad W. Zinc induces dimerization of the class II major histocompatibility complex molecule that leads to cooperative binding to a superantigen. J Biol Chem. 2007;282(9):5991–6000.
Yu M, Lee WW, Tomar D, Pryshchep S, Czesnikiewicz-Guzik M, Lamar DL, et al. Regulation of T cell receptor signaling by activation-induced zinc influx. J Exp Med. 2011;208(4):775–85.
Bordon Y. T cell signalling: heavy metal rocks T cells. Nat Rev Immunol. 2011;11(5):300–1.
Anthony TJ, Goon CLG. Metal allergy in Singapore. Contact Dermatitis. 2005;52(3):130–2.
Loh J, Fraser J. Metal-derivatized major histocompatibility complex: zeroing in on contact hypersensitivity. J Exp Med. 2003;197(5):549–52.
Büdinger MH, Hertl M. Immunologic mechanisms in hypersensitivity reactions to metal ions: an overview. Allergy. 2000;55(2):108–15.
Militello G, Jacob SE, Crawford GH. Allergic contact dermatitis in children. Curr Opin Pediatr. 2006;18(4):385–90.
Hogeling M, Pratt M. Allergic contact dermatitis in children: the Ottawa hospital patch-testing clinic experience, 1996 to 2006. Dermatitis. 2008;19(2):86–9.
McGinley EL, Moran GP, Fleming GJ. Base-metal dental casting alloy biocompatibility assessment using a human-derived three-dimensional oral mucosal model. Acta Biomater. 2012;8(1):432–8.
Fors R, Persson M, Bergstrom E, Stenlund H, Stymne B, Stenberg B. Lifestyle and nickel allergy in a Swedish adolescent population: effects of piercing, tattooing and orthodontic appliances. Acta Derm Venereol. 2012 [Epub ahead of print].
Vollmer J, Weltzien HU, Gamerdinger K, Lang S, Choleva Y, Moulon C. Antigen contacts by Ni-reactive TCR: typical alphass chain cooperation versus alpha chain-dominated specificity. Int Immunol. 2000;12(12):1723–31.
Fontenot AP, Falta MT, Freed BM, Newman LS, Kotzin BL. Identification of pathogenic T cells in patients with beryllium-induced lung disease. J Immunol. 1999;163(2):1019–26.
Moulon C, Vollmer J, Weltzien HU. Characterization of processing requirements and metal cross-reactivities in T cell clones from patients with allergic contact dermatitis to nickel. Eur J Immunol. 1995;25(12):3308–15.
Romagnoli P, Labhardt AM, Sinigaglia F. Selective interaction of Ni with an MHC-bound peptide. EMBO J. 1991;10(6):1303–6.
Vollmer J, Weltzien HU, Moulon C. TCR reactivity in human nickel allergy indicates contacts with complementarity-determining region 3 but excludes superantigen-like recognition. J Immunol. 1999;163(5):2723–31.
Lu L, Vollmer J, Moulon C, Weltzien HU, Marrack P, Kappler J. Components of the ligand for a Ni++ reactive human T cell clone. J Exp Med. 2003;197(5):567–74.
Freiman DG, Hardy HL. Beryllium disease: the relation of pulmonary pathology to the clinical course and prognosis based on a study of 130 cases from the U.S. Beryllium case registry. Hum Pathol. 1970;1:25–44.
Kriebel D, Brain JD, Sprince NL, Kazemi H. The pulmonary toxicity of beryllium. Am Rev Respir Dis. 1988;137:464–73.
Kreiss K, Mroz MM, Newman LS, Martyny J, Zhen B. Machining risk of beryllium disease and sensitization with median exposures below 2 μg/m3. Am J Ind Med. 1996;30:16–25.
Kreiss K, Mroz MM, Zhen B, Martyny JW, Newman LS. Epidemiology of beryllium sensitization and disease in nuclear workers. Am Rev Respir Dis. 1993;148:985–91.
Kreiss K, Wasserman S, Mroz MM, Newman LS. Beryllium disease screening in the ceramics industry: blood test performance and exposure-disease relations. J Occup Med. 1993;35:267–74.
Van Dyke MV, Martyny JW, Mroz MM, Silveira LJ, Strand M, Cragle DL, et al. Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry. Occup Environ Med. 2011;68(11):842–8.
Amicosante M, Fontenot AP. T cell recognition in chronic beryllium disease. Clin Immunol. 2006;121(2):134–43.
Fontenot AP, Maier LA. Genetic susceptibility and immune-mediated destruction in beryllium-induced disease. Trends Immunol. 2005;26(10):543–9.
Fontenot AP, Kotzin BL, Comment CE, Newman LS. Expansions of T-cell subsets expressing particular T-cell receptor variable regions in chronic beryllium disease. Am J Respir Cell Mol Biol. 1998;18(4):581–9.
Fontenot AP, Palmer BE, Sullivan AK, Joslin FG, Wilson CC, Maier LA, et al. Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response. J Clin Invest. 2005;115(10):2886–93.
Saltini C, Winestock K, Kirby M, Pinkston P, Crystal RG. Maintenance of alveolitis in patients with chronic beryllium disease by beryllium-specific helper T cells. N Engl J Med. 1989;320:1103–9.
Richeldi L, Sorrentino R, Saltini C. HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science. 1993;262:242–4.
Sawyer RT, Maier LA. Chronic beryllium disease: an updated model interaction between innate and acquired immunity. Biometals. 2011;24(1):1–17.
Verreck FAW, van de Poel A, Drijfhout JW, Amons R, Coligan JE, Koning F. Natural peptides isolated from Gly86/Val86-containing variants of HLA-DR1, -DR11, -DR13, and -DR52. Immunogenetics. 1996;43(6):392–7.
Dai S, Crawford F, Marrack P, Kappler JW. The structure of HLA-DR52c: comparison to other HLA-DRB3 alleles. Proc Natl Acad Sci U S A. 2008;105(33):11893–7.
Fremont DH, Dai S, Chiang H, Crawford F, Marrack P, Kappler J. Structural basis of cytochrome c presentation by IE(k). J Exp Med. 2002;195(8):1043–52.
Carrington PE, Chivers PT, Al-Mjeni F, Sauer RT, Maroney MJ. Nickel coordination is regulated by the DNA-bound state of NikR. Nat Struct Biol. 2003;10(2):126–30.
Painter CA, Cruz A, Lopez GE, Stern LJ, Zavala-Ruiz Z. Model for the peptide-free conformation of class II MHC proteins. PLoS ONE. 2008;3(6):e2403.
Carven GJ, Chitta S, Hilgert I, Rushe MM, Baggio RF, Palmer M, et al. Monoclonal antibodies specific for the empty conformation of HLA-DR1 reveal aspects of the conformational change associated with peptide binding. J Biol Chem. 2004;279(16):16561–70.
Diaz G, Canas B, Vazquez J, Nombela C, Arroyo J. Characterization of natural peptide ligands from HLA-DP2: new insights into HLA-DP peptide-binding motifs. Immunogenetics. 2005;56(10):754–9.
Dai S, Murphy GA, Crawford F, Mack DG, Falta MT, Marrack P, et al. Crystal structure of HLA-DP2 and implications for chronic beryllium disease. Proc Natl Acad Sci U S A. 2010;107(16):7425–30.
Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, et al. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994;368(6468):215–21.
Berretta F, Butler RH, Diaz G, Sanarico N, Arroyo J, Fraziano M, et al. Detailed analysis of the effects of Glu/Lys beta69 human leukocyte antigen-DP polymorphism on peptide-binding specificity. Tissue Antigens. 2003;62(6):459–71.
Cho H, Wang W, Kim R, Yokota H, Damo S, Kim SH, et al. BeF3 − acts as a phosphate analog in proteins phosphorylated on aspartate: structure of a BeF3 − complex with phosphoserine phosphatase. Proc Natl Acad Sci U S A. 2001;98(15):8525–30.
Kapsenberg ML, Bos JD, Wierenga EA. T cells in allergic responses to haptens and proteins. Springer Semin Immunopathol. 1992;13(3–4):303–14.
Ortmann B, Martin S, von Bonin A, Schiltz E, Hoschutzky H, Weltzien HU. Synthetic peptides anchor T cell-specific TNP epitopes to MHC antigens. J Immunol. 1992;148(5):1445–50.
Preckel T, Breloer M, Kohler H, von Bonin A, Weltzien HU. Partial agonism and independent modulation of T cell receptor and CD8 in hapten-specific cytotoxic T cells. Eur J Immunol. 1998;28(11):3706–18.
Hughes EA, Kinnel G, Wickerham C, Atkeson B, Owen JA. Fine specificity analysis indicates that the primary and secondary fluorescein-specific cytotoxic T cell receptor repertoires are indistinguishable. Immunol Cell Biol. 1995;73(2):153–7.
Pichler WJ, Yawalkar N. Allergic reactions to drugs: involvement of T cells. Thorax. 2000;55(Suppl 2):S61–5.
Sinigaglia F. The molecular basis of metal recognition by T cells. J Invest Dermatol. 1994;102(4):398–401.
Maier LA, McGrath DS, Sato H, Lympany P, Welsh K, Du Bois R, et al. Influence of MHC class II in susceptibility to beryllium sensitization and chronic beryllium disease. J Immunol. 2003;171(12):6910–8.
Fontenot AP, Torres M, Marshall WH, Newman LS, Kotzin BL. Beryllium presentation to CD4+T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease. Proc Natl Acad Sci U S A. 2000;97(23):12717–22.
Hashizume H, Seo N, Ito T, Takigawa M, Yagi H. Promiscuous interaction between gold-specific T cells and APCs in gold allergy. J Immunol. 2008;181(11):8096–102.
Emtestam L, Zetterquist H, Olerup O. HLA-DR, -DQ and -DP alleles in nickel, chromium, and/or cobalt-sensitive individuals: genomic analysis based on restriction fragment length polymorphisms. J Invest Dermatol. 1993;100(3):271–4.
Thierse HJ, Gamerdinger K, Junkes C, Guerreiro N, Weltzien HU. T cell receptor (TCR) interaction with haptens: metal ions as non-classical haptens. Toxicology. 2005;209(2):101–7.
Marrack P, Scott-Browne JP, Dai S, Gapin L, Kappler JW. Evolutionarily conserved amino acids that control TCR-MHC interaction. Annu Rev Immunol. 2008;26:171–203.
Rudolph MG, Stanfield RL, Wilson IA. How TCRs bind MHCs, peptides, and coreceptors. Annu Rev Immunol. 2006;24:419–66.
Yin L, Huseby E, Scott-Browne J, Rubtsova K, Pinilla C, Crawford F, et al. A single T cell receptor bound to major histocompatibility complex class I and class II glycoproteins reveals switchable TCR conformers. Immunity. 2011;35(1):23–33.
Dai S, Huseby ES, Rubtsova K, Scott-Browne J, Crawford F, Macdonald WA, et al. Crossreactive T Cells spotlight the germline rules for alphabeta T cell-receptor interactions with MHC molecules. Immunity. 2008;28(3):324–34.
Feng D, Bond CJ, Ely LK, Maynard J, Garcia KC. Structural evidence for a germline-encoded T cell receptor-major histocompatibility complex interaction ‘codon’. Nat Immunol. 2007;8(9):975–83.
De Wall SL, Painter C, Stone JD, Bandaranayake R, Wiley DC, Mitchison TJ, et al. Noble metals strip peptides from class II MHC proteins. Nat Chem Biol. 2006;2(4):197–201.
Gamerdinger K, Moulon C, Karp DR, Van Bergen J, Koning F, Wild D, et al. A new type of metal recognition by human T cells: contact residues for peptide-independent bridging of T cell receptor and major histocompatibility complex by nickel. J Exp Med. 2003;197(10):1345–53.
Griem P, Panthel K, Kalbacher H, Gleichmann E. Alteration of a model antigen by Au(III) leads to T cell sensitization to cryptic peptides. Eur J Immunol. 1996;26(2):279–87.
Bowerman NA, Falta MT, Mack DG, Kappler JW, Fontenot AP. Mutagenesis of beryllium-specific TCRs suggests an unusual binding topology for antigen recognition. J Immunol. 2011;187(7):3694–703.
Adams JJ, Narayanan S, Liu B, Birnbaum ME, Kruse AC, Bowerman NA, et al. T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex. Immunity. 2011;35(5):681–93.
Maynard J, Petersson K, Wilson DH, Adams EJ, Blondelle SE, Boulanger MJ, et al. Structure of an autoimmune T cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity. Immunity. 2005;22(1):81–92.
Li Y, Huang Y, Lue J, Quandt JA, Martin R, Mariuzza RA. Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule. EMBO J. 2005;24(17):2968–79.
Hahn M, Nicholson MJ, Pyrdol J, Wucherpfennig KW. Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nat Immunol. 2005;6(5):490–6.
Nicholson MJ, Hahn M, Wucherpfennig KW. Unusual features of self-peptide/MHC binding by autoimmune T cell receptors. Immunity. 2005;23(4):351–60.
Deng L, Mariuzza RA. Recognition of self-peptide-MHC complexes by autoimmune T-cell receptors. Trends Biochem Sci. 2007;32(11):500–8.
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This work is supported by NIH KL2 TR000156 and the Boettcher Foundation.
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Wang, Y., Dai, S. Structural basis of metal hypersensitivity. Immunol Res 55, 83–90 (2013). https://doi.org/10.1007/s12026-012-8351-1
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DOI: https://doi.org/10.1007/s12026-012-8351-1