title: Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites.
abstract: In B-cell lymphomas, loss of human leukocyte antigen (HLA) class I and II molecules might contribute to immune escape from CD8(+) and CD4(+) cytotoxic T cells, especially because B cells can present their own idiotype. Loss of HLA expression and the possible underlying genomic alterations were studied in 28 testicular, 11 central nervous system, and 21 nodal diffuse large B-cell lymphomas (DLCLs), the first two sites are considered as immune-privileged sites. The analysis included immunohistochemistry, loss of heterozygosity analysis, and fluorescent in situ hybridization (FISH) on interphase cells and isolated DNA fibers. Total loss of HLA-A expression was found in 60% of the extranodal cases and in 10% of the nodal cases (P <.01), whereas loss of HLA-DR expression was found in 56% and 5%, respectively (P <.01). This was accompanied by extensive loss of heterozygosity within the HLA region in the extranodal DLCLs. In 3 cases, retention of heterozygosity for D6S1666 in the class II region suggested a homozygous deletion. This finding was confirmed by interphase FISH that showed homozygous deletions in the class II genes in 11 of the 18 extranodal lymphomas but in none of the 7 nodal DLCLs (P <.001). Mapping by fiber FISH showed variable deletions that always included HLA-DQ and HLA-DR genes. Hemizygous deletions and mitotic recombinations often involving all HLA genes were found in 13 of 18 extranodal and 2 of 7 nodal lymphomas. In conclusion, a structural loss of HLA class I and II expression might help the B-cell lymphoma cells to escape from immune attack.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. s.a.riemersma@lumc.nl
authors.forename: S A
authors.initials: SA
authors.lastname: Riemersma
authors.forename: E S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: R F
authors.initials: RF
authors.lastname: Schop
authors.forename: K
authors.initials: K
authors.lastname: Philippo
authors.forename: L H
authors.initials: LH
authors.lastname: Looijenga
authors.forename: E
authors.initials: E
authors.lastname: Schuuring
authors.forename: P M
authors.initials: PM
authors.lastname: Kluin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D020732:Cytogenetic Analysis; D005260:Female; D017353:Gene Deletion; D005802:Genes, MHC Class II / Q000235:genetics* / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics / Q000378:metabolism; D006683:HLA-DQ Antigens / Q000235:genetics / Q000378:metabolism; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008198:Lymph Nodes / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013736:Testicular Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D015234:HLA-A Antigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens