ABSTRACT
Altered expression of major histocompatibility complex (MHC) class I molecules can be caused by defects in genes of the antigen-processing machinery (APM), and is often correlated to progression in solid tumours. However, little is known about expression of the APM components in blasts from patients with acute myeloid leukaemia (AML). In this study, we investigated the expression of the APM components large multifunctional peptidases (LMP) 2 and 7, transporter-associated with antigen processing (TAP) 1 and 2, beta-2-microglobulin (beta2m) and MHC class I heavy chain in situ by tissue microarray from bone marrow biopsies of 30 AML patients. APM components were heterogeneously expressed in all AML samples tested, but no significant correlation with the AML subtype according to the French-American-British classification was found. Depending on the APM component tested, up to 90% of the trephines showed no or weak expression, whereas the LMP7 protein was detected in 66% of all samples. By following disease progression in individual AML patients, we found severe downregulation of APM components in two out of four patients from initial diagnosis to relapse. We conclude that downregulation of APM components may play a role in the failure of immuno-surveillance and may therefore contribute to relapse in acute leukaemia.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , Cysteine Endopeptidases/metabolism , Histocompatibility Antigens Class I/metabolism , Leukemia, Myeloid, Acute/metabolism , Multienzyme Complexes/metabolism , beta 2-Microglobulin/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 2 , ATP Binding Cassette Transporter, Subfamily B, Member 3 , ATP-Binding Cassette Transporters/genetics , Antigen Presentation , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Blast Crisis/pathology , Bone Marrow , Case-Control Studies , Cysteine Endopeptidases/genetics , Down-Regulation , Gene Expression Regulation, Neoplastic , Histocompatibility Antigens Class I/genetics , Humans , Immunoenzyme Techniques , Interferon-gamma/pharmacology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Multienzyme Complexes/genetics , Proteasome Endopeptidase Complex , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tissue Array Analysis , Tumor Cells, Cultured , beta 2-Microglobulin/geneticsABSTRACT
Macrophages play a central role in establishing a specific immune response by acting as professional antigen presenting cells (APC) for T cells leading to a vigorous immune response. In order to analyze if Herpes simplex Virus (HSV) type 1 infection might affect the macrophage APC-function, monocyte-derived human macrophages were infected with HSV-1 strain F in vitro. Cocultures with allogeneic T cells revealed a strongly impaired stimulatory capacity of HSV-infected macrophages compared to uninfected controls which was not owing to a productive viral infection in macrophages. An increased expression of Fas ligand (FasL/CD95L) was detected in HSV-infected macrophages by FACS analysis. Although the majority of the macrophages expressed high levels of Fas (CD95/Apo-1), the HSV-induced upregulation of FasL did not result in an increased autocrine apoptosis of macrophages which might be related to endogenous expression of the apoptosis inhibitor FLICE inhibitory protein (FLIP). However, substantial apoptosis occurred in peripheral T cells as well as Fas-sensitive Jurkat T cells when cocultured with HSV-infected macrophages. These findings suggest that the paracrine killing of activated T cells by FasL expressing APC might be a novel strategy of immune evasion by HSV.
