Molecules And Their Modulated Expression

The major histocompatibility complex (MHC), or human leukocyte antigens (HLA) molecules, are membranal, heterodimeric glycoproteins, comprising of a and ft polypeptide chains. MHC class II molecules consist of several isotypes (in humans HLA-DR, DP and DQ), which are encoded by a highly polymorphic gene cluster, and expressed as co-dominant alleles [1], In humans the HLA class II cluster of genes is located on chromosome 6, and spans for at least 1000 kb. This region encodes HLA-DR, -DQ and -DP, and includes genes encoding the a and ft chains as well as pseudo-genes. The a chain is mostly invariant (with the exception of HLA-DQ), whereas the ft chains are highly polymorphic. MHC molecules enable the interaction between the T-cell receptor (TCR) and antigenic peptides, which are previously processed in the cell. Two distinct classes of MHC molecules have been characterized with respect to antigen presentation: class I molecules, which generally present endogenous antigens to cytotoxic T cells, and MHC class II molecules, which are responsible mainly for the presentation of exogenous antigens to helper T cells. Whereas, class I molecules are expressed on all nucleated cells, expression of MHC class II molecules is normally restricted to cells of the immune system, including B lymphocytes, dendritic and langerhans cells, monocytes, tissue macrophages and activated T cells. Nonimmune cells express MHC class II molecules only in abnormal situations, such as viral infection, autoimmune diseases and malignancies. This expression is coordinated, i.e., HLA-DR, HLA-DQ, HLA-DP, as well as HLA-DM and invariant chain (Ii) are expressed co-incidentally. Not only the genetic composition, but also changes in the amount of surface MHC class II molecules determine the type and magnitude of antigen presentation, and hence the consequences of the immune response [2-4], Therefore, their expression is very carefully regulated.

Regulation of immune cells expression of MHC class II molecules differs by cell type. The expression of MHC class II molecules on B cells changes during their developmental stage: Pre-B cells do not express them, whereas basal expression on resting B cells is low and is increased upon activation [5]. Constitutive expression of MHC class II molecules on mature B cells can be modulated mainly by interleukin-(IL)-4 [6], prostaglandins [7], glucocorticoids [8], and intetferon-y (IFN-y) [9]. Finally, in plasma cells their expression is completely shut off [5, 10-12],

IFN-y is the most potent enhancer of MHC class II molecules on monocytes and macrophages, and a synergistic effect has been observed with tumor necrosis factor a (TNF-a) [13], MHC class II expression on macrophages can be downregulated by cytokines such as transforming growth factor-/? (TGF-ft) and IL-4 [14],

Nonimmunological cells do not normally express MHC class II molecules. However, their appearance can be induced in vitro mainly by IFN-y, and syner-gistically with TNF-a, on a wide variety of nonimmunological cells, such as astrocytes, keratinocytes, melanocytes, fibroblasts, endothelial cells, intestinal epithelial cells, and thyrocytes [15-19]. Expression of MHC class II molecules can be induced on tissue cells, including thyrocytes, during viral infection, independent of cytokine effects [20]. In vivo aberrant expression of MHC class II molecules has been observed on autoimmune and malignant tissue cells, including autoimmune and neoplastic thyrocytes.

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