Disease relevance of HLA-E

• We then identify the residues in HLA-C and HLA-E that protect them from HIV down-regulation [1].
• We present evidence that HIV-1 selectively downregulates HLA-A and HLA-B but does not significantly affect HLA-C or HLA-E [1].
• Human cytomegalovirus (HCMV) infection as well as the HLA-E and killer immunoglobulin-like receptor (KIR) genotypes were considered as potentially relevant variables associated with CD94/NKG2C expression [2].
• Importantly, HLA-E tetramer-positive or NKG2A+ T cells from HTLV-1 patients do not express Tax and display different TCR usage from the immunodominant Tax11-19-specific CD8+ T cells, suggesting that they do not encounter HTLV-1-infected cells [3].
• Finally, HLA-E expression at the cell surface of melanoma cells decreased their susceptibility to CTL lysis [4].

Psychiatry related information on HLA-E

• It has been suggested that class I and class II MHC are contributing factors for numerous diseases including autoimmune thyroid diseases, type 1 diabetes, rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis [5].
• MHC typing in variant Creutzfeldt-Jakob disease [6].
• The MHC class II molecule DQ0602 confers strong susceptibility to narcolepsy but dominant protection against type 1 diabetes [7].
• BsAb were directed against immunoglobulin-idiotype (Id), major histocompatibility class II (MHC II), or CD19 on the tumors and huCD64 on the effectors [8].
• These results establish that human CD4+ T cells present in the peripheral blood of a patient with lung cancer are able to orchestrate cytokine-dependent killing of an autologous MHC-negative tumor indirectly and without codependence on CD8+ T cells [9].

High impact information on HLA-E

• MHC tetramers, intracellular cytokine staining, an increasing repertoire of transgenic and "knockout" mice, and the detailed characterization of a variety of infectious models have all facilitated more precise and definitive analyses of the generation and function of cytotoxic T lymphocytes (CTL) [10].
• The conversion of exogenous and endogenous proteins into immunogenic peptides recognized by T lymphocytes involves a series of proteolytic and other enzymatic events culminating in the formation of peptides bound to MHC class I or class II molecules [11].
• The recognition of peptide MHC class II complexes on activated antigen-presenting cells is critical for effective Th cell selection, clonal expansion, and effector Th cell function development (Phase I) [12].
• Human vascular endothelial cells (EC) basally display class I and II MHC-peptide complexes on their surface and come in regular contact with circulating T cells [13].
• Their deaths are prevented in animals by IL-7 and contact with MHC [14].

Chemical compound and disease context of HLA-E

• Deficiency alleles at the C4 loci within the MHC are associated with autoimmune diseases in Caucasoids and possibly other races [15].
• 59 unselected patients with primary glomerulonephritis were phenotyped for alleles of the MHC-linked complement genes, C4A, C4B, and BF [16].
• We aimed to find associations between MHC alleles and abacavir hypersensitivity in HIV-1-positive individuals treated with abacavir [17].
• Expression of the gene encoding the transactivator CIITA in C6 gliomas using an EBV-based transduction system led to induction of MHC I and II and thereby mimicked therapeutic responses that could not operate in syngeneic models [18].
• The protease has proposed physiological roles in antigen presentation by the MHC class II system, in the biogenesis of the vasoconstrictor peptide endothelin, and in neurodegeneration associated with brain ischemia and aging [19].

Biological context of HLA-E

• The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability [20].
• The non-polymorphic, non-classical MHC class I gene products (HLA-E, -F, -G) are not restricting elements for the majority of T lymphocytes [21].
• It is shown that, independently of the transporter associated with antigen processing, gpUL40 can up-regulate expression of HLA-E, which protects targets from NK cell lysis [22].
• The human, nonclassical class I gene, HLA-E, was found to be ubiquitously transcribed, whereas cell surface expression was difficult to detect upon transfection [23].
• Cloning and physical mapping of the HLA class I region spanning the HLA-E-to-HLA-F interval by using yeast artificial chromosomes [24].

Anatomical context of HLA-E

• Pulse chase experiments revealed that the HLA-E heavy chain in transfectants, obtained with the murine myeloma cell line P3X63-Ag8.653 (X63), displays a significant reduction in oligosaccharide maturation and intracellular transport compared with HLA-B27 in corresponding transfectants [23].
• Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease [25].
• HLA-E had no apparent inhibitory effect mediated through the identified Ig superfamily (Ig-SF) human killer cell inhibitory receptors or ILT2/LIR1 [26].
• The human major histocompatibility complex (MHC) class Ib gene, HLA-E, codes for the major ligand of the inhibitory receptor NK-G-2A, which is present on most natural killer (NK) cells and some CD8(+) cytotoxic T lymphocytes [27].
• In line with these in vitro data we found enhanced intrahepatic HLA-E expression on antigen-presenting cells in HCV-infected patients [28].

Associations of HLA-E with chemical compounds

• Signal peptides derived from certain HLA-B proteins with threonine in position 2 only marginally up-regulated HLA-E surface expression in .221 cells [29].
• Peptides bound to HLA-E consisted of nine amino acids, with methionine at position 2 and leucine in the carboxyl-terminal position, and were nearly identical to the leader sequence-derived peptide previously shown to be a predominant peptide bound to the murine Qa-1 Ag [29].
• The replacement substitution changes an arginine to a glycine at position 107, defining two alleles at the HLA-E locus [30].
• We first demonstrated the role of DNA methylation in the repression of class I genes (except HLA-E) in JAR by the use of the 5-Azacytidine demethylating agent [31].
• Extended MHC haplotypes and CYP21/C4 gene organisation in Irish 21-hydroxylase deficiency families [32].

Physical interactions of HLA-E

• Thus, during cellular stress an increased proportion of HLA-E molecules may bind the nonprotective hsp60 signal peptide, leading to a reduced capacity to inhibit a major NK cell population [33].
• HLA-E presents closely related nonameric peptide epitopes derived from the highly conserved signal sequences of classical major histocompatibility complex class I molecules as well as HLA-G [34].
• Furthermore, we show that the vast majority of decidual NK cells bind to HLA-E tetrameric complexes and this binding is inhibited by mAb to CD94 [35].
• We now show that the extracellular region of HLA-E forms a stable complex with beta2 microglobulin and can be refolded around synthetic peptide [36].
• CD94-T4/NKG2B is capable of binding HLA-E and, when expressed in E6-1 Jurkat T cells, inhibits TCR mediated signals, demonstrating that this heterodimer is functional [37].

Regulatory relationships of HLA-E

• Previous studies using human 721.221 cell line have shown that peptides derived from the leader sequence of the HLA-G binds and up-regulates the surface expression of HLA-E molecules, which was considered to consequently provide negative signals to human NK cells [38].
• The CD94/NKG2C heterodimer constitutes an activating receptor involved in NK cell-mediated recognition of the class lb molecule HLA-E [39].
• The aberrant HLA-E expression might be of particular biological relevance in those HLA tumor phenotypes that express a single HLA-A allele when NK inhibition is markedly reduced due to the downregulation of HLA-B and -C alleles [40].
• In contrast, co-culture of LGL with HLA-E-expressing cells significantly (P < 0.01) decreased only IL-10 production, although a strong tendency towards reduced IL-13 levels was also observed [41].
• To investigate the involvement of killer-inhibitory/killer-activatory receptors in trophoblast recognition, we tested the effect of CD94 block on cytotoxic activity of Vdelta2(+) enriched gammadelta T cells to HLA-E- and/or HLA-G-transfected targets [42].

Other interactions of HLA-E

• The third expressed non-A, -B, and -C class I gene, HLA-E, is located between HLA-A and HLA-C (4) [43].
• This peptide gains access to HLA-E intracellularly, resulting in up-regulated HLA-E/hsp60 signal peptide cell-surface levels on stressed cells [33].
• Furthermore, functional transfer of KIR2DL4 into the cell line NK-92 resulted in inhibition of lysis of target cells that express HLA-G, but not target cells that express other class I molecules including HLA-E [44].
• HLA-G and HLA-E: fundamental and pathophysiological aspects [45].
• One of the most important of these mechanisms of regulation is the recognition of the non-classical class I MHC molecule HLA-E, in complex with nonamer peptides derived from the signal sequences of certain class I MHC molecules, by heterodimers of the C-type lectin-like proteins CD94 and NKG2 [46].

Analytical, diagnostic and therapeutic context of HLA-E

• To analyze whether HLA-E binds peptides and to identify the corresponding ligands, fractions of acid-extracted material from HLA-E/X63 transfectants were separated by reverse phase HPLC and were tested for their ability to enhance HLA-E cell surface expression [23].
• Rejection of skin grafts from HLA-E transgenic mice demonstrates that HLA-E behaves as a transplantation Ag in mice [47].
• Cell surface HLA-E was detected on lymph node cells by flow cytometry only in the presence of endogenous human beta2m [47].
• Cell surface labeling of transfectants and immunoprecipitation with a monomorphic HLA class I-specific antibody or an antibody against human beta 2m confirmed the presence of an HLA-E H chain on the cell surface [48].
• In particular, expression of HLA-E might favor tumor cell escape from CTL and NK immunosurveillance [4].

References