Abstract
Loss of expression of human leukocyte antigen (HLA) class II molecules on tumor cells affects the onset and modulation of the immune response through lack of activation of CD4+ T lymphocytes. Previously, we showed that the frequent loss of expression of HLA class II in diffuse large B-cell lymphoma (DLBCL) of the testis and the central nervous system (CNS) is mainly due to homozygous deletions in the HLA region on chromosome band 6p21.3. A minority of cases showed hemizygous deletions or mitotic recombination, implying that mutation of the remaining copy of the class II genes might be involved. Here, we studied three DLBCLs with loss of HLA-DQ expression for mutations in the DQB1 and DQA1 genes and three tumors with loss of HLA-DR expression for mutations in the DRB1 and DRA genes. In one case, a point mutation in exon 2 of the DQB1 gene, leading to the formation of a stop codon, was detected at position 47. In a second case, a stop codon was found at position 11 due to a deletion of 19 bp in exon 1 of the DRA gene. No mutations were found in the promoter sequences of the DRA, DQA1 and DQB1 genes. We conclude that both homozygous deletions and hemizygous deletions or mitotic recombination with mutations of the remaining allele may lead to loss of expression of the HLA class II genes, which is comparable to the mechanisms affecting HLA class I expression in solid cancers.
Similar content being viewed by others
References
Ansell SM, Stenson M, Haberman TM, Jelinek DF, Witzig TE (2001) CD4+ T-cell immune response to large B-cell non-Hodgkin's lymphoma predicts patient outcome. J Clin Oncol 19:720–726
Bashir R, Chamberlain M, Ruby E, Hochberg FH (1996) T-cell infiltration of primary CNS lymphoma. Neurology 46:440–444
Benoist C, Mathis D (1990) Regulation of major histocompatibility complex class-II genes: X, Y and other letters of the alphabet. Annu Rev Immunol 8:681–715
Bohme J, Andersson M, Andersson G, Moller E, Peterson PA, Rask L (1985) HLA-DR beta genes vary in number between different DR specificities, whereas the number of DQ beta genes is constant. J Immunol 135:2149–155
Brady CS, Bartholomew JS, Burt DJ, Duggan-Keen MF, Glenville S, Telford N, Little AM, Davidson JA, Jimenez P, Ruiz-Cabello F, Garrido F, Stern PL (2000a) Multiple mechanisms underlie HLA dysregulation in cervical cancer. Tissue Antigens 55:401–411
Brady MS, Lee F, Petrie H, Eckels DD, Lee JS (2000b) CD4(+) T-cells kill HLA-class-II-antigen-positive melanoma cells presenting peptide in vitro. Cancer Immunol Immunother 48:621–626
Das HK, Lawrance SK, Weissman SM (1983) Structure and nucleotide sequence of the heavy chain gene of HLA-DR. Proc Natl Acad Sci USA 80:3543–3547
Dziembowska M, Fondaneche MC, Vedrenne J, Barbieri G, Wiszniewski W, Picard C, Cant AJ, Steimle V, Charron D, Alca-Loridan C, Fischer A, Lisowska-Grospierre B (2002) Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency. Immunogenet 53:821–829
Garrido F, Algarra I (2001) MHC antigens and tumor escape from immune surveillance. Adv Cancer Res 83:117–158
Glimcher LH, Kara CJ (1992) Sequences and factors: a guide to MHC class-II transcription. Annu Rev Immunol 10:13–49
Gobin SJ, van Zutphen M, Westerheide SD, Boss JM, van den Elsen PJ (2001) The MHC-specific enhanceosome and its role in MHC class I and beta(2)-microglobulin gene transactivation. J Immunol 167:5175–5184
Guerra CB, Busch R, Doebele RC, Liu W, Sawada T, Kwok WW, Chang MD, Mellins ED (1998) Novel glycosylation of HLA-DRalpha disrupts antigen presentation without altering endosomal localization. J Immunol 160:4289–4297
Harton JA, Ting JP (2000) Class II transactivator: mastering the art of major histocompatibility complex expression. Mol Cell Biol 20:6185–194
Hishii M, Kurnick JT, Ramirez-Montagut T, Pandolfi F (1999) Studies of the mechanism of cytolysis of tumor-infiltrating lymphocytes. Clin Exp Immunol 116:388–394
Jordanova ES, Riemersma SA, Philippo K, Giphart-Gassler M, Schuuring E, Kluin PM (2002) Hemizygous deletions in the HLA region account for loss of heterozygosity in the majority of diffuse large B-cell lymphomas of the testis and the central nervous system. Genes Chromosomes Cancer 35:38–48
Koopman LA, Corver WE, van der Slik AR, Giphart MJ, Fleuren GJ (2000) Multiple genetic alterations cause frequent and heterogeneous HLA class I loss in cervical cancer. J Exp Med 191:961–976
Leech N, Sorrentino R, McCulloch DK, Nepom GT (1995) Ultrastructural allelic variation in HLA-DQB1 promoter elements. Hum Immunol 43:251–258
Marsh SG (1998) HLA class II region sequences, 1998. Tissue Antigens 51:467–507
Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Gerghty GE, Hansen JA, Mach B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GM, Strominger JL, Svejgaard A, Terasaki PI (2002) Nomenclature for factors of the HLA system, 2002. Eur J Immunogenet 29:463–515
Masternak K, Reith W (2002) Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation. EMBO J 21:1379–1388
Morzycka-Wroblewska E, Harwood JI, Smith JR, Kagnoff MF (1993) Structure and evolution of the promoter regions of the DQA genes. Immunogenetics 37:364–72
Morzycka Wroblewska E, Munshi A, Ostermayer M, Harwood JI, Kagnoff MF (1997) Differential expression of HLA-DQA1 alleles associated with promoter polymorphism. Immunogenetics 45:163–170
Nagy ZA, Hubner B, Lohning C, Rauchenberger R, Reiffert S, Thomassen-Wolf E, Zahn S, Leyer S, Schier EM, Zahradnik A, Brunner C, Lobenwein K, Rattel B, Stanglmaier M, Hallek M, Wing M, Anderson S, Dunn M, Kretzschmar T, Tesar M (2002) Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells. Nat Med 8:801–807
Newell MK, van der Waal J, Beard KS, Freed JH (1993) Ligation of MHC class II molecules mediates apoptotic cell death in resting B-lymphocytes. Proc Natl Acad Sci USA 90:10459–10463
Nie Y, Yang G, Song Y, Zhao X, So C, Liao J, Wang LD, Yang CS (2001) DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas. Carcinogenesis 22:1615–1623
Olerup O, Zetterquist H (1992) HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens. 39:225–235
Olerup O, Aldener A, Fogdell A (1993) HLA-DQB1 and -DQA1 typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours. Tissue Antigens 41:119–134
Paludan C, Bickham K, Nikiforow S, Tsang ML, Goodman K, Hanekom WA, Fonteneau JF, Stevanovic S, Munz C (2002) Epstein-Barr nuclear antigen 1-specific CD4(+) Th1 cells kill Burkitt's lymphoma cells. J Immunol 169:1593–1603
Rebai N, Malissen B, Pierres M, Accolla RS, Corte G, Mawas C (1983) Distinct HLA-DR epitopes and distinct families of HLA-Dr molecules defined by 15 monoclonal antibodies (mAb) either anti-DR or allo-anti-Iak cross-reacting with human DR molecule. I. Cross-inhibition studies of mAb cell surface fixation and differential binding of mAb to detergent-solubilized HLA molecules immobilized to a solid phase by a first mAb. Eur J Immunol 13:106–111
Reith W, Mach B (2001) The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol 19:331–373
Riemersma SA, Jordanova ES, Schop RF, Philippo K, Looijenga LH, Schuuring E, Kluin PM (2000) Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune- privileged sites. Blood 96:3569–3577
Robinson J, Waller MJ, Parham P, Bodmer JG, Marsh SG (2001) IMGT/HLA Database — a sequence database for the human major histocompatibility complex. Nucleic Acids Res. 29:210–213
Roushdy J, Santoso S, Kalb R, Meier Ewert K, Albert ED, Mueller Eckhardt G (1993) A deletion in the second exon of an HLA-DRB1 allele found in a DR2-negative narcolepsy patient. Hum Immunol 37:1–6
Schwiebert LM, Hughes A, Monos DS, Ono SJ (1997) HLA-DRA promoter polymorphism and diversity generation within the immune system. Hum Genet 99:801–805
Serrano A, Tanzarella S, Lionello I, Mendez R, Traversari C, Ruiz-Cabello F, Garrido F (2001) Rexpression of HLA class I antigens and restoration of antigen-specific CTL response in melanoma cells following 5-aza-2′-deoxycytidine treatment. Int J Cancer 94:243–251
Spierings E, de Boer T, Wieles B, Adams LB, Marani E, Ottenhoff TH (2001) Mycobacterium leprae-specific, HLA class II-restricted killing of human Schwann cells by CD4+ Th1 cells: a novel immunopathogenic mechanism of nerve damage in leprosy. J Immunol 166:5883–5888
Ting JP, Trowsdale J (2002) Genetic control of MHC class II expression. Cell 109 [Suppl]:S21-S33
Vidovic D, Toral JI (1998) Selective apoptosis of neoplastic cells by the HLA-DR specific monoclonal antibody. Cancer Lett 128:127–135
Vinci G, Tabilio A, Deschamps JF, Van Haeke D, Henri A, Guichard J, Tetteroo P, Lansdorp PM, Hercend T, Vainchenker W (1984) Immunological study of in vitro maturation of human megakaryocytes. Br J Haematol 56:589–605
Watson AJ, DeMars R, Trowbridge IS, Bach FH (1983) Detection of a novel human class II HLA antigen. Nature 304:358–361
Woolfrey AE, Nepom GT (1995) Differential transcription elements direct expression of HLA-DQ genes. Clin Immunol Immunopathol 74:119–126
Xu Y, Kroft SH, McKenna RW, Aquino DB (2001) Prognostic significance of tumour-infiltrating T-lymphocytes and T-cell subsets in de novo diffuse large B-cell lymphoma: a multiparameter flow cytometry study. Br J Haematol 112:945–949
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jordanova, E.S., Philippo, K., Giphart, M.J. et al. Mutations in the HLA class II genes leading to loss of expression of HLA-DR and HLA-DQ in diffuse large B-cell lymphoma. Immunogenetics 55, 203–209 (2003). https://doi.org/10.1007/s00251-003-0563-z
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-003-0563-z