Shared regulatory elements in the promoters of MHC class I and class II genes

Elsen, Peter J. van den; Peijnenburg, Ad; Eggermond, Marja C.J.A. van; Gobin, Sam J. P.

doi:10.1016/s0167-5699(98)01287-0

Cited by 97 publications

(64 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several mechanisms may explain the increased level of HLA-A expression on multiple myeloma cells. The transcription of HLA class I genes is regulated by two modules: an upstream module consisting of the enhancer A and IFN-stimulated response element and a downstream module containing the W/S, X1, site a, and enhancer B elements (36). Both modules are important for the constitutive and cytokine-induced expression of HLA class I genes.…”

Section: Discussionmentioning

confidence: 99%

A Single-Chain Fv Diabody against Human Leukocyte Antigen-A Molecules Specifically Induces Myeloma Cell Death in the Bone Marrow Environment

et al. 2007

View full text Add to dashboard Cite

Cross-linked human leukocyte antigen (HLA) class I molecules have been shown to mediate cell death in neoplastic lymphoid cells. However, clinical application of an anti-HLA class I antibody is limited by possible side effects due to widespread expression of HLA class I molecules in normal tissues. To reduce the unwanted Fc-mediated functions of the therapeutic antibody, we have developed a recombinant single-chain Fv diabody (2D7-DB) specific to the A2 domain of HLA-A. Here, we show that 2D7-DB specifically induces multiple myeloma cell death in the bone marrow environment. Both multiple myeloma cell lines and primary multiple myeloma cells expressed HLA-A at higher levels than normal myeloid cells, lymphocytes, or hematopoietic stem cells. 2D7-DB rapidly induced Rho activation and robust actin aggregation that led to caspase-independent death in multiple myeloma cells. This cell death was completely blocked by Rho GTPase inhibitors, suggesting that Rho-induced actin aggregation is crucial for mediating multiple myeloma cell death. Conversely, 2D7-DB neither triggered Rho-mediated actin aggregation nor induced cell death in normal bone marrow cells despite the expression of HLA-A. Treatment with IFNs, melphalan, or bortezomib enhanced multiple myeloma cell death induced by 2D7-DB. Furthermore, administration of 2D7-DB resulted in significant tumor regression in a xenograft model of human multiple myeloma. These results indicate that 2D7-DB acts on multiple myeloma cells differently from other bone marrow cells and thus provide the basis for a novel HLA class I-targeting therapy against multiple myeloma. [Cancer Res 2007;67(3):1184-92]

show abstract

Section: Discussionmentioning

confidence: 99%

A Single-Chain Fv Diabody against Human Leukocyte Antigen-A Molecules Specifically Induces Myeloma Cell Death in the Bone Marrow Environment

et al. 2007

View full text Add to dashboard Cite

show abstract

“…CIITA recognizes MHC promoters through interactions with the proteins regulatory factor X (RFX), CREB, and nuclear factor Y, which bind to the X1, X2 (site ␣), and Y enhancers, respectively, in MHC class II promoters (32). Homologous regions in the MHC class I promoters were noted by van den Elsen and colleagues (33). The HLA-A3 promoter contains a single base change in the site ␣ core sequence that would be expected to abolish CREB binding (27) (Fig.…”

Section: Transcription Factors Activating Hla Class I Promotersmentioning

confidence: 99%

Locus-Specific Constitutive and Cytokine-Induced HLA Class I Gene Expression

Johnson

2003

The Journal of Immunology

View full text Add to dashboard Cite

Cytokine induction of the MHC class I genes increases the nascent molecules available for binding potentially antigenic peptides. The human H chain loci, HLA-A, -B, and -C, encode highly homologous and polymorphic mRNAs. Here, these transcripts were resolved and measured by competitive PCR of cDNA using locus-specific primers. Endothelial cells expressed many HLA-A and -B, but fewer HLA-C, transcripts. In contrast, HeLa cells expressed many HLA-A and -C, but fewer HLA-B, transcripts. The inflammatory cytokines TNF-α, IFN-β, and IFN-γ induced HLA-B strongly, but HLA-A and -C weakly in both cell types. Combined treatment with IFNs and TNF further increased HLA-A and -B, but not HLA-C transcripts. The constitutive and inducible activities of transfected promoters correlated well with mRNA levels. The weak IFN response of the HLA-A2 promoter was not due to variations in the IFN consensus sequence, the site α, or a 3-bp insertion between them. The HLA-Cw6 promoter was less TNF responsive due to a variant κB enhancer, which also reduced the IFN responses. The NF-κB subunit RelA strongly activated the HLA-A2 and -B7 promoters but only weakly activated the HLA-Cw6 promoter due to the variant κB. Cotransfecting NF-κB1 with RelA further increased activity of the HLA-A2 and -B7, but not HLA-Cw6, promoters. All three promoters were activated by MHC class II trans-activator, but not CREB-binding protein, whereas IFN regulatory factor-1 and -2 weakly activated the HLA-B7 and -Cw6, but not HLA-A2, promoters. These studies illustrate common and locus-specific mechanisms that may be targeted to modulate immune reactions.

show abstract

“…The importance of these molecules is illustrated in patients suffering from MHC class II deficiency or bare lymphocyte syndrome (BLS), 5 a severe combined immunodeficiency. This disease, which is characterized by an absence of MHC class II expression and frequently also by a reduced level of MHC class I expression (3), results in the inability to present antigenic peptides to CD4 ϩ T cells for initiation of the immune response. BLS patients manifest severely impaired humoral and cellular immune responses, as well as impaired development of CD4 ϩ T cells (4,5) and therefore are extremely susceptible to many opportunistic infections (5).…”

Section: Novel Mutations Within the Rfx-b Gene And Partial Rescue Of mentioning

confidence: 99%

Novel Mutations Within the RFX-B Gene and Partial Rescue of MHC and Related Genes Through Exogenous Class II Transactivator in RFX-B-Deficient Cells

Nagarajan

Peijnenburg

Gobin

et al. 2000

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

MHC class II deficiency or bare lymphocyte syndrome is a severe combined immunodeficiency caused by defects in MHC-specific regulatory factors. Fibroblasts derived from two recently identified bare lymphocyte syndrome patients, EBA and FZA, were found to contain novel mutations in the RFX-B gene. RFX-B encodes a component of the RFX transcription factor that functions in the assembly of multiple transcription factors on MHC class II promoters. Unlike RFX5- and RFXAP-deficient cells, transfection of exogenous class II transactivator (CIITA) into these RFX-B-deficient fibroblasts resulted in the induction of HLA-DR and HLA-DP and, to a lesser extent, HLA-DQ. Similarly, CIITA-mediated induction of MHC class I, β2-microglobulin, and invariant chain genes was also found in these RFX-B-deficient fibroblasts. Expression of wild-type RFX-B completely reverted the noted deficiencies in these cells. Transfection of CIITA into Ramia cells, a B cell line that does not produce a stable RFX-B mRNA, resulted in induction of an MHC class II reporter, suggesting that CIITA overexpression may partially override the RFX-B defect.

show abstract

Shared regulatory elements in the promoters of MHC class I and class II genes

Cited by 97 publications

References 31 publications

A Single-Chain Fv Diabody against Human Leukocyte Antigen-A Molecules Specifically Induces Myeloma Cell Death in the Bone Marrow Environment

A Single-Chain Fv Diabody against Human Leukocyte Antigen-A Molecules Specifically Induces Myeloma Cell Death in the Bone Marrow Environment

Locus-Specific Constitutive and Cytokine-Induced HLA Class I Gene Expression

Novel Mutations Within the RFX-B Gene and Partial Rescue of MHC and Related Genes Through Exogenous Class II Transactivator in RFX-B-Deficient Cells

Contact Info

Product

Resources

About