Research on the regulatory mechanisms that control the differential expression of MHC genes in different cell types is still in its infancy, but much has been learned. The publication of the complete genomic map of the MHC complex is expected to greatly accelerate the identification and investigation of coding and regulatory sequences, leading to new directions in research on how the system is controlled.
Both class I and class II MHC genes are flanked by 5' promoter sequences, which bind sequence-specific transcription factors. The promoter motifs and transcription factors that bind to these motifs have been identified for a number of MHC genes. Transcriptional regulation of the MHC is mediated by both positive and negative elements. For example, an MHC II transactivator, called CIITA, and another transcription factor, called RFX, both have been shown to bind to the promoter region of class II MHC genes. Defects in these transcription factors cause one form of bare lymphocyte syndrome (see the Clinical Focus box in Chapter 8). Patients with this disorder lack class II MHC molecules on their cells and as a result suffer a severe immunodeficiency due to the central role of class II MHC molecules in T-cell maturation and activation.
The expression of MHC molecules is also regulated by various cytokines. The interferons (alpha, beta, and gamma) and tumor necrosis factor have each been shown to increase expression of class I MHC molecules on cells. Interferon gamma (IFN-7), for example, appears to induce the formation of a specific transcription factor that binds to the promoter sequence flanking the class I MHC genes. Binding of this transcription factor to the promoter sequence appears to coordinate the up-regulation of transcription of the genes encoding the class I a chain, p2-microglobulin, the protea-some subunits (LMP), and the transporter subunits (TAP). IFN-7 also has been shown to induce expression of the class II transactivator (CIITA), thereby indirectly increasing expression of class II MHC molecules on a variety of cells, including non-antigen-presenting cells (e.g., skin keratin-ocytes, intestinal epithelial cells, vascular endothelium, placental cells, and pancreatic beta cells). Other cytokines influence MHC expression only in certain cell types; for example, IL-4 increases expression of class II molecules by resting B cells. Expression of class II molecules by B cells is down-regulated by IFN-7; corticosteroids and prostaglandins also decrease expression of class II molecules.
B virus (HBV), and adenovirus 12 (Ad12). In some cases, reduced expression of class I MHC molecules on cell surfaces is due to decreased levels of a component needed for peptide transport or MHC class I assembly rather than in transcription. In cytomegalovirus infection, for example, a viral protein binds to ^-microglobulin, preventing assembly of class I MHC molecules and their transport to the plasma membrane. Adenovirus 12 infection causes a pronounced decrease in transcription of the transporter genes (TAP1 and TAP2).As the next chapter describes, the TAP gene products play an important role in peptide transport from the cytoplasm into the rough endoplasmic reticulum. Blocking of TAP gene expression inhibits peptide transport; as a result, class I MHC molecules cannot assemble with ^-microglobulin or be transported to the cell membrane. Decreased expression of class I MHC molecules, by whatever mechanism, is likely to help viruses evade the immune response by reducing the likelihood that virus-infected cells can display MHC-viral peptide complexes and become targets for CTL-mediated destruction.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.