BG1 has a major role in MHC-linked resistance to malignant lymphoma in the chicken

Department of Molecular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2009; 106(39):16740-5. DOI: 10.1073/pnas.0906776106
Source: PubMed


Pathogen selection is postulated to drive MHC allelic diversity at loci for antigen presentation. However, readily apparent MHC infectious disease associations are rare in most species. The strong link between MHC-B haplotype and the occurrence of virally induced tumors in the chicken provides a means for defining the relationship between pathogen selection and MHC polymorphism. Here, we verified a significant difference in resistance to gallid herpesvirus-2 (GaHV-2)-induced lymphomas (Marek's disease) conferred by two closely-related recombinant MHC-B haplotypes. We mapped the crossover breakpoints that distinguish these haplotypes to the highly polymorphic BG1 locus. BG1 encodes an Ig-superfamily type I transmembrane receptor-like protein that contains an immunoreceptor tyrosine-based inhibition motif (ITIM), which undergoes phosphorylation and is recognized by Src homology 2 domain-containing protein tyrosine phosphatase (SHP-2). The recombinant haplotypes are identical, except for differences within the BG1 3'-untranslated region (3'-UTR). The 3'-UTR of the BG1 allele associated with increased lymphoma contains a 225-bp insert of retroviral origin and showed greater inhibition of luciferase reporter gene translation compared to the other allele. These findings suggest that BG1 could affect the outcome of GaHV-2 infection through modulation of the lymphoid cell responsiveness to infection, a condition that is critical for GaHV-2 replication and in which the MHC-B haplotype has been previously implicated. This work provides a mechanism by which MHC-B region genetics contributes to the incidence of GaHV-2-induced malignant lymphoma in the chicken and invites consideration of the possibility that similar mechanisms might affect the incidence of lymphomas associated with other oncogenic viral infections.

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Available from: Marcia Madsen Miller
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    • "This VNTR is found in the central region of the B region, close to the gene BG1. This gene has been shown to be associated with resistance to Marek's disease in the chicken (Goto et al. 2009). Preliminary evidence of a correlation between LEI0258 alleles and MHC-B SNPs or sequences has been observed in White Leghorn lines (Chazara et al. 2008), White Leghorn, Rhode Island Red or Fayoumi animals (Chazara et al. 2011), and Brazilian chickens (Lima- Rosa et al. 2005). "
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    ABSTRACT: The chicken major histocompatibility complex (MHC) is located on the microchromosome 16 and is described as the most variable region in the genome. The genes of the MHC play a central role in the immune system. Particularly, genes encoding proteins involved in the antigen presentation to T cells. Therefore, describing the genetic polymorphism of this region is crucial in understanding host-pathogen interactions. The tandem repeat LEI0258 is located within the core area of the B region of the chicken MHC (MHC-B region) and its genotypes correlate with serology. This marker was used to provide a picture of the worldwide diversity of the chicken MHC-B region and to categorize chicken MHC haplotypes. More than 1,600 animals from 80 different populations or lines of chickens from Africa, Asia, and Europe, including wild fowl species, were genotyped at the LEI0258 locus. Fifty novel alleles were described after sequencing. The resulting 79 alleles were classified into 12 clusters, based on the SNPs and indels found within the sequences flanking the repeats. Furthermore, hypotheses were formulated on the evolutionary dynamics of the region. This study constitutes the largest variability report for the chicken MHC and establishes a framework for future diversity or association studies.
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    • "More researchers are designating their attention to the influence of pathogens on the evolution of the MHC polymorphism. Major histocompatibility complex polymorphism is thought to be subject to some form of balancing selection, most likely pathogen-mediated selection (Mona et al., 2008; Goto et al., 2009), and this selection is the birth-and-death model of evolution in the adaptive process (Gu and Nei, 1999). Lian et al. (2010) found that the human BTNL2 gene was linked to tuberculosis in the Chinese Han population. "
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    ABSTRACT: To better understand the major histocompatibility complex (MHC) genetic character of domestic birds, we sequenced and analyzed chicken MHC II (B-L) genes of 3 local chicken breeds, derived from 3 separate areas in China. We amplified cDNA sequences from 105 individuals, accounting for 35 alleles. Some of the same B-LB alleles with a high frequency were found in all samples. The putative B-L α-chain had few polymorphic sites, whereas the B-L β-chain had several polymorphic sites. Most of the mutation positions were located in the B-LB β1 domain encoded by exon 2, especially in the peptide-binding region. This indicated that the highly polymorphic peptide-binding region could potentiate binding diverse antigen epitopes. The comparison of 3-D molecule structures of chicken B-L and human HLA-DR1 revealed a distinctly structural similarity, but the chicken B-L molecule had more polymorphic sites than the human HLA-DR1 molecule, which presumably might be a mechanism to compensate for responding to a wider array of pathogens due to fewer loci for chicken. Moreover, some conserved sites in human and chicken MHC class II molecules reflected their common ancestry and similar functions. These results suggest that the chicken B-L gene showed more polymorphic sites and distinctly dominant trans-breed alleles, potentially to adapt to pathogens.
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    • "In the evolution process, mutation of the amino acid sequence occurs in the non-PBD, destroying PBD structure integrity which makes MHC molecules fail in binding antigen peptides, while some mutations within the PBD increase the potential of MHC binding antigen peptides. The polymorphic genes of MHC are regarded as essential genes for individual fitness under conditions of selection (Eizaguirre et al., 2009), and it is just these negative or positive selections that drive MHC allelic diversity at loci for antigen presentation (Goto et al., 2009). We all know that MHC gene descended from a common ancestry and came into being polymorphism under the environmental pressure. "
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    ABSTRACT: Major histocompatibility complex (MHC) is a highly polymorphic gene and plays an important role in immune system for vertebrate. To understand the polymorphism character of domestic, we cloned 32 cDNAs of MHC class I α genes of two local chicken breeds in different areas of China. There were 112 variable amino acid residues in all five domains (leader peptide, α1, α2, α3 and TM/CY domains) of the putative α chain, and 76 of them were located in α1 and α2 domains. There were 23 to 25 polymorphic sites with high mutation frequency in α1 and α2 domains. Comparison of chicken with duck, human and mouse revealed that the two domains were highly similar among different species, and some highly polymorphic sites were located at the sites 9, 111(114), 113 (116) and 153 (156). Analysis of the phylogenetic tree indicated no relationship between the breeds and polymorphic alleles. All these results therefore indicate that MHC I class molecule of domestic chickens was more influenced by the pressure of common pathogens rather than geographic differences.
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