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.

Loss of heterozygosity, a frequent but a non‐exclusive mechanism responsible for HLA dysregulation in non‐Hodgkin's lymphomas

“…In contrast and similar to our data, studies that employed microsatellite methodology also detected alteration of the chromosome 6p arm, suggesting that deletions involving the HLA locus are not particularly large and subsequently are not detected by cytogenetic methods (Rigaud et al, 2001). Two studies that used a large number of microsatellites markers located in the HLA locus also found frequent deletions in FLs or extra-nodal DLBCL (Randerson et al, 1996;Riemersma et al, 2000). However, to our knowledge, no data comparing DNA abnormalities to mRNA or protein expression are available.…”

How we diagnose and treat vitreoretinal lymphoma

“…The most common subtype is systemic DLBCL (Coupland & Damato, 2008) but secondary infiltration of the eye by other B-NHL subtypes include chronic lymphocytic leukaemia (Coupland et al, 2001), plasma cell neoplasms (Fung et al, 2005) and, rarely, Burkitt lymphoma (Payne et al, 1971;Wysenbeek et al, 1987) as well as intravascular large B-cell lymphoma (Mudhar et al, 2007). A peculiar phenomenon is the increased risk for secondary vitreoretinal or CNS involvement by DLBCL of the testis, another immune-privileged site, which shares many features with PVRL and PCNSL, including predominance of the ABC type, common loss of HLA class I and II expression and common MYD88 mutations (Riemersma et al, 2000;Kraan et al, 2013). Of interest, joint MYD88 L265P mutations, indicating a common clonal origin, were identified in two cases of VRL with a history of testicular lymphoma in our recent VRL series (Bonzheim et al, 2015).…”

“…However, manifest VRL often contains an abundance of reactive T-cells and macrophages, indicating that the development of clinically manifest lymphoma is associated with a breakdown of the immuneprivileged state. Of note, PCNSL as well as DLBCL arising in the testis, another immune-privileged site, frequently show lack of human leucocyte antigen (HLA) class I and II expression, due to deletions of chromosome 6p21Á32 harbouring the HLA locus, which may allow escape from immune attack (Riemersma et al, 2000).…”

Enteropathy‐associated T‐cell lymphoma, lacking MHC class II, with immune‐privileged site recurrence, presenting as bilateral ocular vitreous humour involvement – a case report

“…5 It is known from studies of primary diffuse large B-cell lymphomas (DLBCLs) of the CNS and testis that DLBCLs arising in these sites show decreased or absent expression of MHC-II, allowing tumour cells to escape from immune attack. 2,3 By extrapolation, it is distinctly possible that lack of MHC-II on the EATL type II in this case allowed it to home-in on immuneprivileged sites, probably explaining the clinical presentation of vitreous involvement and imaging-confirmed brain involvement. Once in these sites, the lymphoma could expand unchecked, probably explaining the rapid neurological deterioration of the patient.…”

“…This was carried out in the knowledge that some high-grade B-cell lymphomas arising in immune-privileged sites show decreased MHC class I (MHC-I) and MHC-II expression, allowing them to escape immune attack. 2,3 Immunohistochemistry showed no expression of MHC-II on the bowel EATL ( Figure 1H) or on the vitreous metastasis (not shown).…”