B

Figure 1. (A) The structure HLA-DRa promoter. The W, XI, X2, Y boxes are bolded and boxed. The octamer, which is unique to the HLA-DRa promoter is boxed. The TATA box is only bolded. The consensus sequences within the boxes are underlined: the S box within the W box, the CCAAT box within the Y box. (B) The binding of transcription factors to the HLA-DRa promoter. The three complexes primarily regulating HLA-DRa expression are the RFX complex, which binds to the XI box and may also bind to the W box, the X2BP, which binds to the X2 box, the NF-Y, which binds to the Y box. The hXBP-1 and HB16 may compete for the binding of the X2 box, whereas, the YB-1, which may act as a repressor, may compete for the binding of the Y box. Oct-2, a transcription factor that is expressed in B cells, binds to the octamer, located only on the HLA-DRa promoter.

4.3. Polymorphism in the Promoter Region

MHC class II structural genes are highly polymorphic, and the allelic variations contribute to the specificity of antigen presentation, diversity of the immune system, as well as to susceptibility to autoimmune and malignant diseases. Allelic polymorphism also exists in the proximal promoter regions of these genes [114-116], and might contribute to differences in expression, inducibility or tissue specificity.

Several allelic differences in the HLA-DQB promoter were found, some of them mapping to known critical sequences such as the X box (which will be later discussed). Comparison between two of these allelic promoters using transient expression systems and measuring the transcription of chloramphenicol acetyltransferase (CAT), showed a marked difference in their strength [61]. Polymorphism in the three

DQA1 alleles was located to X and Y boxes (to be discussed Later), and differences in their ability to induce transcription in reporter gene system were observed [117]. Furthermore, TNF-a activated one promoter allele, but had little effect on the other two promoter alleles. Similarly, allelic polymorphism was found in the HLA-DRB promoter regions, and transfec-tion of these promoter-constructs into human B cells showed marked differences in their ability to induce a CAT-reporter gene [118],

Although promoter allelic polymorphism could be an additional level of regulation of the expression of MHC class II molecules, as suggested by these evidences, more research is required to establish such a role, and to determine whether specific promoter alleles are involved in the susceptibility to autoimmunity or malignancy.

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