When disease associated proteins occur in a cell they are broken into pieces by the cells proteolytic machinery. Cell proteins become attached to antigen fragments and transport them to the surface of the cell, where they are "presented" to the bodies defence mechanisms. Without these, there would be no presentation of internal or external antigens to the T cells. The importance of MHC proteins is that they allow T cells to distinguish self from non-self. In every cell in your body, antigens are constantly broken up and presented to passing T cells. Without this presentation, other aspects of the immune response cannot occur.
CTLs which recognize self-peptides i. So, if a CTL can bind to a MHC-peptide complex on the cell surface, that cell is producing a peptide which is not native to the host. The MHC Class II proteins found only on B lymphocytes, macrophages, and other cells that present antigens to T cells , which primarily present peptides which have been digested from external sources, are needed for T-cell communication with B-cells and macrophages.
The MHC proteins, and several closely associated with them in the carrying out of their functions, are coded for by loci that are close together within the Human Genome. Major Histocompatibility Complex proteins and their associated molecules are fundamental in the process of antigen presentation. The following pages collect and collate some of the information relating to this process. Hughes AL , Molecular evolution of the vertebrate immune system. Bioessays 19 9 , All four mamu-AG genes have functional gene structures, indicating that they may all be active in the placental environment.
Two mamu-A genes with complete identity to mamu-A cDNA sequences are located centromeric in a region that appears to be part of an older duplication event Fig. Overall, the similarities between human and rhesus in this region include similar functional genes, whereas the differences include an increase in the number of genes and pseudogenes Table 1. Description of the expanded, relative to human, mamu-A class I gene region. A The 1. The positions of class I genes and pseudogenes are indicated by alphanumerical descriptions and bars with direction of transcription indicated by positioning above and below the line according to convention Table 1 contains a summary description.
The positions of homologs to non-class I human genes and pseudogenes are indicated with bars and symbols that are explained in the top, left box. Flanking genes outside of this duplicated area and homologous to those found in the human MHC with conserved structures are indicated by green bars and text. Sequences not present in the corresponding human class I region are indicated by red bars and text. Other non-class I genes are colored in blue.
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Segments of the sequence with significant similarity indicative of duplication events are indicated with similar hatching bounded by solid lines. The scale below is in base pairs. B Dot matrix analysis of the mamu-A region against itself to provide a visualization of the repetitive nature of this segment.
The minmatch score was set at 30 and masklevel was set at Tick marks on the vertical indicate the scale in kb segments and on the horizontal in kb segments. The locations of the class I genes are indicated in relative positions at top and to the left. C Phylogenetic analysis of the mamu-A region genes and pseudogenes.
Included in this analysis are all mamu class I-like genes contained in this segment Table 1. The reconstructed amino acid sequences were aligned using ClustalW with default parameters. Phylogenetic reconstruction was generated using the Neighbor-Joining algorithm Saitou and Nei , and tested using rounds of bootstrap analysis. The tree is unrooted. Segmental duplication has also occurred in the mamu-B region in one of the most remarkable findings of this work. This increase has resulted from a complex series of segmental duplications and a single transposition of some 43 kb of sequences from the mamu-A region including mamua3.
In the complete haplotype 1 sequence presented in Figure 3 , 19 mamu-B -like genes were found arrayed in a tandem arrangement. Similar to the mamu-A region, the mamu-B region can be grossly subdivided into two segments. The telomeric portion extending from mamu-B1 , interrupted by the mamu-A transposed segment, and continuing to mamu-B10 has arisen in part from six tandem duplications of a segment some 60 kb in length, whereas the centromeric portion from mamu-B11 to mamu-B19 has arisen in part from a single larger tandem duplication of about kb Fig.
Such a historical relationship between mamu-B1 through mamu-B10 and the mamu-B11 to mamu-B19 genes is reflected in the evolutionary distances among them Fig. Analysis of a complete mamu class I B region haplotype. A Comparison of human and mamu-B region segments. Immediately beneath is depicted the mamu-B region extending 1. Segments of similarity between rhesus and human are bounded by lines connecting the two cartoons.
The positions of homologs to human genes and pseudogenes are indicated with bars and symbols that are explained in the top, left box. Orthologous genes with conserved functional structure are indicated by green bars and text. Segments with significant similarity indicative of past duplication events are indicated with similar hatching bounded by solid lines.
The placement of bars above or below the line indicates direction of transcription according to convention. B Dot matrix analysis of the mamu-B region haplotype 2 against itself. The minmatch score was set at 30 and the masklevel was set at Tick marks indicate the scale in kb segments on the vertical and 50 kb on the horizontal. Similarity among segments is indicated by similar coloring within the bar on the top and further bounded by vertical lines within the box. C Phylogenetic analysis of all mamu-B -like genes in the region based on 5-kb of genomic sequence surrounding each gene.
Included in this analysis are all of those genes from haplotype 1 listed in Table 2. A multiple alignment of the repeat-masked genomic sequences was performed using ClustalW with default parameters. Phylogenetic reconstruction was generated using the Neighbor-Joining algorithm Saitou and Nei and tested using rounds of bootstrap analysis. Although this finding is fascinating evolutionarily, another important issue raised is whether the expansion in gene number could significantly alter the progress or development of an acquired or innate immune response of the rhesus macaque relative to human.
To answer this first question requires knowledge of which of these genes are transcribed and translated into functional class I products.
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Of the 19 B-like genes on haplotype 1, seven have identical matches to cDNAs derived from macaque peripheral blood , and seven have typical class I protein-encoding capacity, including apparently functional exons and highly similar promoter regions. Of the remaining five genes, four have stop codons within exons 2—4, presumably inactivating the gene, and a single gene encodes a protein without a leader peptide Table 2. One unique and relevant feature of mamu-B genes may be the structure of exon 1 and the placement of the ATG start codon.
A second arrangement contains only the downstream ATG yielding a signal peptide with 21 amino acids. All three types are transcribed as examples of representative cDNAs that have been found for each. In addition, peptide-binding motifs and SIV cytotoxic T-lymphocyte epitopes have been deciphered for each type Evans et al. Thus, there may be as many as 28 functional mamu-B antigen-presenting molecules expressed in an individual macaque. Our initial attempts to unravel the mamu-B region encountered difficulty because it was not possible to assign a BAC to one haplotype unambiguously, due to the underlying complex repetitive structure of the mamu-B sequences.
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Further, the complex arrangement of genes heightened interest in a comparison of the sequence from both haplotypes. Therefore, we combined the sequence from haplotype 1 with data from over half of haplotype 2, the latter including nine additional mamu-B genes. Of these, three had identical matches to cDNA sequences and five genes were structurally intact with a typical class I coding capacity Table 2. One gene appeared to be an allele of mamu-B19 , but contained several in frame stop codons not found in the allelic sequence.
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However, despite having anchors at the ends, it was apparent that any notion of alleles between mamu-B genes at corresponding positions between the two sequences was ambiguous. Thus, mamu-h2B5 was more closely related to mamu-B6 , whereas mamu-h2B6 and mamu-h2B7 aligned most significantly with mamu-B3 and mamu-B4 , respectively. Further, mamu-h2B17 and mamu-h2B18 both appeared to be allelic to mamu-B18 and only distantly related to mamu-B17 Fig.
Comparison of two mamu-B haplotype sequences. A Two segments from haplotype 2 spanning and kb from the telomeric and centromeric ends of the region, respectively, are aligned above the corresponding complete haplotype 1 segment. Genes and other sequences are indicated as described in the legend to Figure 3. Lines between the top and bottom mamu-B genes indicate the most closely related sequences between the two haplotypes alleles. B Dot matrix similarity between the segments from haplotype 2 containing h2-B2 though h2-B7 and the B2 though B8 segment from haplotype 1.
Red lines enclose and connect the matrix at positions that have the highest percent similarity between loci from the respective haplotypes. Tick marks indicate the scale in kb segments on the vertical and 20 kb on the horizontal. The locations of the class I genes from haplotype 2 are indicated in relative positions at top and to the left. C Phylogenetic analysis of all mamu-B -like genes, based on 5 kb of genomic sequence surrounding each gene.
Included in this analysis are all B genes listed in Table 2. D Reconstruction of the evolution of haplotype 1 blue and haplotype 2 red from the ancestral sequence yellow , by way of a kb duplication between the blue boxes , followed by deletions on both sides black horizontal lines. Dashed gray lines indicate yet unavailable sequence. Red lines connect alleles of mamu-B genes; x deleted alleles. To begin to unravel the complex relationships between the two mamu-B haplotypes, we took advantage of the presence within the repeat units of large numbers of retroposed elements Alus , LINEs, etc.
The simplest reconstruction of the events that might have occurred to generate these divergent haplotype structures is depicted in Figure 4D. The pivotal event in this reconstruction is the duplication of kb of ancestral sequence, including genes B4, B5 , and B6. Haplotype 1 evolved from the ancestral, unduplicated sequence by a series of deletions, one of which erased the allele of h2B2.
Haplotype 2 evolved, after the kb duplication, by deleting the alleles of B4 and B5 , and by a further duplication that generated h2B17 and h2B Thirteen additional mamu-B genes are predicted to be located in the yet-unsequenced regions of this haplotype, but some may have also been lost by deletions. In rhesus, this region is organized similarly. Haplotype 2 contains two genes that appear structurally intact and match cDNA sequences consistent with functionality.