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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    • "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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    Immunogenetics 03/2013; 65(6). DOI:10.1007/s00251-013-0697-6 · 2.23 Impact Factor
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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: In chickens infected with virulent (v) or very virulent (vv) Marek's disease (MD) virus (MDV) strains, small to moderate increases in plasma nitric oxide (NO) levels are seen, respectively, whereas very virulent plus (vv+) strains induce very high levels in vivo. The data presented in this report show that chickens presenting with clinical neurological disease following infection with the vv+ RK-1 strain have significantly higher in vivo NO levels compared to RK-1-infected non-symptomatic chickens. Using quantitative real-time PCR (qPCR) assays, DNA was used to measure MDV copy numbers in the spleen and brain of P2a (MD-susceptible) and N2a (MD-resistant) chickens following infection with the JM-16 (v) or RK-1 (vv+) strains. RNA was used to measure inducible NO synthase (iNOS), interferon-gamma (IFN-gamma), interleukin (IL)-1beta, IL-6, and IL-8 mRNA levels, in addition to MDV-specific mRNA expression using quantitative RT-PCR (qRT-PCR) assays. Viral DNA loads were found to be considerably higher in RK-1-infected chickens than JM-16-infected chickens at most time points in both organs, with viral copy numbers being two to four logs lower in the brain. Large increases in iNOS, IFN-alpha, IL-1beta, IL-6, and IL-8 were seen in the brains of RK-1-infected chickens. These data strongly support the hypothesis that pro-inflammatory responses, including high levels of iNOS/NO, IFN-alpha, and pro-inflammatory cytokine expression in the chicken brain, may play a major role in the neurological diseases associated with vv+MDV strains.
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