MHC

Valitutti, Muller S, Celia M, Padovan E and Lanzavecchia A 1995 Serial triggering of many T-cells by a few peptide-MHC complexes Nature 375 148-51... 

The class II cytokine receptor family includes receptors for interferon a/P (lEN a/P) and y (lENy) and IL-10. lEN-y immunoreactivity has been found in neurons in the hypothalamus, cerebral cortex, mammilary nuclei, and dorsal tegmentum. Astrocytes and microglia in vitro can be stimulated to express class II histocompatibiHty complex (MHC-II) antigens by lEN-y, which may be involved in the presentation of antigen to T-ceUs by astrocytes. Thus lEN-y may be critical in CNS-immune function and dysfunction especially in regard to neuronal and gHal apoptotic processes. 

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

MHC molecules are composed of antigen-binding and immunoglobulin-like domains... 

The class 1 MHC structure is divided into two globular regions (Figure 15.18). One region is built up from the two immunoglobulin-like domains a3... 

Figure 15.18 (a) Schematic representation of the path of the polypeptide chain in the structure of the class I MHC protein HLA-A2. Disulfide bonds are indicated as two connected spheres. The molecule is shown with the membrane proximal immunoglobulin-like domains (a3 and Pzm) at the bottom and the polymorphic al and a2 domains at the top. 

Figure 15.19 Schematic representation of the peptide-binding domain of a class I MHC protein. The al and a2 domains are viewed from the top of the molecule, showing the empty antigen-binding site as well as the surface that is contacted by a T-cell receptor. (Adapted from P.J. Bjdrkman et al.. Nature 329 506-512, 1987.)...

Recognition of antigen is different in MHC molecules compared with immunoglobulins... 

The genes for MHC molecules, unlike immunoglobulin genes, do not undergo rearrangements to create structural diversity. The Pzm light chain is invariant, but the class I MHC heavy chain is the most genetically polymorphic... 

Peptides are bound differently by class I and class II MHC molecules... 

To date, there has not been a reported structure determination of a class 11 MHC-peptide-TCR complex. However, T-cell receptors that recognize class... 

I MHC-peptide complexes and those that recognize class 11 MHC-peptide complexes utilize the same set of Va and Vp genes, and the principal feature that defines the site of class 1 MHC-TCR interaction, the cleft formed by the a and az subunits of the MHC molecule, is shared by both class 1 and class... 

II proteins (see Figure 15.20b and c). Thus, the general mode of class 11 MHC interaction with TCR is expected to be similar to that determined for class 1 MHC. 

Class 1 and class II MHC molecules bind peptide antigens and present them at the cell surface for interaction with receptors on T cells. The extracellular portion of these molecules consists of a peptide-binding domain formed by two helical regions on top of an eight-stranded antiparallel p sheet, separated from the membrane by two lower domains with immunoglobulin folds. These domains are differently disposed between the two protein subunits in class I and class II molecules. 

Madden, D.R. The three-dimensional structure of pep-tide-MHC complexes. Annu. Rev. Immunol. 13 587-622, 1995. 

Wilson, I.A., Bjorkman, P.J. Unusual MHC-like molecules CDl, Pc receptor, the hemochromatosis gene product, and viral homologs. Curr. Opin. Struct. Biol. 10 67-73, 1998. 

Fremont, D.H., Hendrickson, W.A., Marrack, P, Kappler, J. 5tructures of an MHC class II molecule with covalently bound single peptides. Science 272 1001-1004,... 

Fremont, D.H., Matsumura, M., 5tura, E.A., Peterson, P.A., Wilson, I.A. Crystal structures of two viral peptides in complex with murine MHC class I H2-K . Science 257 919-927, 1992. 

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