Abstract
High levels of antibodies to mucin 1 (MUC1), a membrane-bound glycoprotein that is overexpressed in adenocarcinomas, are associated with good prognosis in patients with breast cancer. The aim of the present investigation was to determine whether GM and KM allotypes—genetic markers of IgG heavy chains and κ-type light chains, respectively—contribute to the magnitude of natural antibody responsiveness to MUC1 in patients with breast cancer. A total of 153 Caucasian subjects with breast cancer were allotyped for several GM and KM markers. These subjects were also characterized for IgG and IgM antibodies to MUC1. Anti-MUC1 IgG antibody levels in subjects who were carriers of the immunoglobulin γ2 allele GM 23 were significantly higher than in those who were noncarriers (P = 0.003). These results could potentially divide the population into high or low responders to MUC1, which has important implications for MUC1-based immunotherapeutic interventions in breast cancer.
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References
Pandey JP (2001) Immunoglobulin GM and KM allotypes and vaccine immunity. Vaccine 19:613–617
Ovsyannikova IG, Jacobson RM, Vierkant RA, Pankratz VS, Poland GA (2007) HLA supertypes and immune responses to measles–mumps–rubella viral vaccine: findings and implications for vaccine design. Vaccine 25:3090–3100
Dhiman N, Ovsyannikova IG, Cunningham JM, Vierkant RA, Kennedy RB, Pankratz VS, Poland GA, Jacobson RM (2007) Associations between measles vaccine immunity and single-nucleotide polymorphisms in cytokine and cytokine receptor genes. J Infect Dis 195:21–29
Forthal DN, Gilbert PB, Landucci G, Phan T (2007) Recombinant gp120 vaccine-induced antibodies inhibit clinical strains of HIV-1 in the presence of Fc receptor-bearing effector cells and correlate inversely with HIV infection rate. J Immunol 178:6596–6603
Lieberman R, Stiffel C, Asofsky R, Mouton D, Biozzi G, Benacerraf B (1972) Genetic factors controlling anti-sheep erythrocyte antibody response and immunoglobulin synthesis in backcross and F2 progeny of mice genetically selected for “high” or “low” antibody synthesis. J Exp Med 136:790–798
Pandey JP, Shannon BT, Tsang KY, Fudenberg HH, Camblin JG (1982) Heterozygosity at Gm loci associated with humoral immunity to osteosarcoma. J Exp Med 155:1228–1232
Sarvas H, Rautonen N, Käyhty H, Kallio M, Mäkelä O (1990) Effect of Gm allotypes on IgG2 antibody responses and IgG2 concentrations in children and adults. Int Immunol 2:317–322
Pandey JP, Page GP, Silver RM, LeRoy EC, Bona CA (2001) Anti-fibrillin-1 autoantibodies in systemic sclerosis are Gm and Km allotype restricted. Exp Clin Immunogenet 18:123–129
Pandey JP, Nietert PJ, Mensdorff-Pouilly S, Klaamas K, Kurtenkov O (2008) Immunoglobulin allotypes influence antibody responses to mucin 1 in patients with gastric cancer. Cancer Res 68:4442–4446
Vlad AM, Kettel JC, Alajez NM, Carlos CA, Finn OJ (2004) MUC1 immunobiology: from discovery to clinical applications. Adv Immunol 82:249–293
von Mensdorff-Pouilly S, Verstraeten AA, Kenemans P, Snijdewint FG, Kok A, Van Kamp GJ, Paul MA, Van Diest PJ, Meijer S, Hilgers J (2000) Survival in early breast cancer patients is favorably influenced by a natural humoral immune response to polymorphic epithelial mucin. J Clin Oncol 18:574–583
von Mensdorff-Pouilly S, Gourevitch MM, Kenemans P, Verstraeten AA, van Kamp GJ, Kok A, van Uffelen K, Snijdewint FG, Paul MA, Meijer S, Hilgers J (1998) An enzyme-linked immunosorbent assay for the measurement of circulating antibodies to polymorphic epithelial mucin (MUC1). Tumour Biol 19:186–195
Schanfield MS, van Loghem E (1986) Human immunoglobulin allotypes. In: Weir DM (ed) Handbook of experimental immunology. Blackwell, Boston, pp 94.1–94.18
Granoff DM, Suarez BK, Pandey JP, Shackelford PG (1988) Genes associated with the G2 m(23) immunoglobulin allotype regulate the IgG subclass responses to Haemophilus influenzae type b polysaccharide vaccine. J Infect Dis 157:1142–1149
Granoff DM, Holmes SJ (1992) G2 m(23) immunoglobulin allotype and immunity to Haemophilus influenzae type b. J Infect Dis 165:S66–S69
Ambrosino DM, Schiffman G, Gotschlich EC, Schur PH, Rosenberg GA, DeLange GG, van Loghem E, Siber GR (1985) Correlation between G2 m(n) immunoglobulin allotype and human antibody response and susceptibility to polysaccharide encapsulated bacteria. J Clin Invest 75:1935–1942
Pandey JP, French MAH (1996) Gm phenotypes influence the concentrations of the four subclasses of immunoglobulin G in normal human serum. Hum Immunol 51:99–102
Morell A, Skvaril F, Steinberg AG, Van Loghem E, Terry WD (1972) Correlations between the concentrations of the four sub-classes of IgG and Gm Allotypes in normal human sera. J Immunol 108:195–206
von Mensdorff-Pouilly S, Petrakou E, Kenemans P, van Uffelen K, Verstraeten AA, Snijdewint FG, van Kamp GJ, Schol DJ, Reis CA, Price MR, Livingston PO, Hilgers J (2000) Reactivity of natural and induced human antibodies to MUC1 mucin with MUC1 peptides and n-acetylgalactosamine (GalNAc) peptides. Int J Cancer 86:702–712
Martin SW, Goodnow CC (2002) Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory. Nat Immunol 3:182–188
Wakabayashi C, Adachi T, Wienands J, Tsubata T (2002) A distinct signaling pathway used by the IgG-containing B cell antigen receptor. Science 298:2392–2395
Morahan G, Berek C, Miller JFAP (1983) An idiotypic determinant formed by both immunoglobulin constant and variable regions. Nature 301:720–722
Moxley G, Gibbs RS (1992) Polymerase chain reaction-based genotyping for allotypic markers of immunoglobulin kappa shows allelic association of Km with kappa variable segment. Genomics 13:104–108
Pritsch O, Hudry-Clergeon G, Buckle M, Petillot Y, Bouvet JP, Gagnon J, Dighiero G (1996) Can immunoglobulin CH1 constant region domain modulate antigen binding affinity of antibodies? J Clin Invest 98:2235–2243
Torres M, Fernández-Fuentes N, Fiser A, Casadevall A (2007) The immunoglobulin heavy chain constant region affects kinetic and thermodynamic parameters of antibody variable region interactions with antigen. J Biol Chem 282:13917–13927
Nimmerjahn F, Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8:34–47
Moreno M, Bontkes HJ, Scheper RJ, Kenemans P, Verheijen RH, von Mensdorff-Pouilly S (2007) High level of MUC1 in serum of ovarian and breast cancer patients inhibits huHMFG-1 dependent cell-mediated cytotoxicity (ADCC). Cancer Lett 257:47–55
Pandey JP, Prohászka Z, Veres A, Füst G, Hurme M (2004) Epistatic effects of genes encoding immunoglobulin GM allotypes and interleukin-6 on the production of autoantibodies to 60- and 65-kDa heat-shock proteins. Genes Immun 5:68–71
Lenoir AA, Pandey JP, Granoff DM (1988) Antibody responses of black children to Haemophilus influenzae type b polysaccharide-Neisseria meningitidis outer membrane protein conjugate vaccine in relation to the Km(1) allotype. J Infect Dis 157:1242–1245
Grubb R (1995) Advances in human immunoglobulin allotypes. Exp Clin Immunogenet 12:191–197
Acknowledgments
This work was supported in part by grants from the US Department of Defense and from the Estonia Science Foundation (# 6726). We thank Ms. Shannon Stockham for expert technical assistance and Dr. Silvia von Mensdorff-Pouilly for providing the MUC1 peptide.
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Pandey, J.P., Nietert, P.J., Klaamas, K. et al. A genetic variant of immunoglobulin γ2 is strongly associated with immunity to mucin 1 in patients with breast cancer. Cancer Immunol Immunother 58, 2025–2029 (2009). https://doi.org/10.1007/s00262-009-0709-4
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DOI: https://doi.org/10.1007/s00262-009-0709-4