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1.  Immunology of naturally transmissible tumours 
Immunology  2014;144(1):11-20.
Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution.
doi:10.1111/imm.12377
PMCID: PMC4264906  PMID: 25187312
cancer; comparative immunology/evolution; MHC; transplantation; tumour immunology
2.  Sequence of a Complete Chicken BG Haplotype Shows Dynamic Expansion and Contraction of Two Gene Lineages with Particular Expression Patterns 
PLoS Genetics  2014;10(6):e1004417.
Many genes important in immunity are found as multigene families. The butyrophilin genes are members of the B7 family, playing diverse roles in co-regulation and perhaps in antigen presentation. In humans, a fixed number of butyrophilin genes are found in and around the major histocompatibility complex (MHC), and show striking association with particular autoimmune diseases. In chickens, BG genes encode homologues with somewhat different domain organisation. Only a few BG genes have been characterised, one involved in actin-myosin interaction in the intestinal brush border, and another implicated in resistance to viral diseases. We characterise all BG genes in B12 chickens, finding a multigene family organised as tandem repeats in the BG region outside the MHC, a single gene in the MHC (the BF-BL region), and another single gene on a different chromosome. There is a precise cell and tissue expression for each gene, but overall there are two kinds, those expressed by haemopoietic cells and those expressed in tissues (presumably non-haemopoietic cells), correlating with two different kinds of promoters and 5′ untranslated regions (5′UTR). However, the multigene family in the BG region contains many hybrid genes, suggesting recombination and/or deletion as major evolutionary forces. We identify BG genes in the chicken whole genome shotgun sequence, as well as by comparison to other haplotypes by fibre fluorescence in situ hybridisation, confirming dynamic expansion and contraction within the BG region. Thus, the BG genes in chickens are undergoing much more rapid evolution compared to their homologues in mammals, for reasons yet to be understood.
Author Summary
Many immune genes are multigene families, presumably in response to pathogen variation. Some multigene families undergo expansion and contraction, leading to copy number variation (CNV), presumably due to more intense selection. Recently, the butyrophilin family in humans and other mammals has come under scrutiny, due to genetic associations with autoimmune diseases as well as roles in immune co-regulation and antigen presentation. Butyrophilin genes exhibit allelic polymorphism, but gene number appears stable within a species. We found that the BG homologues in chickens are very different, with great changes between haplotypes. We characterised one haplotype in detail, showing that there are two single BG genes, one on chromosome 2 and the other in the major histocompatibility complex (BF-BL region) on chromosome 16, and a family of BG genes in a tandem array in the BG region nearby. These genes have specific expression in cells and tissues, but overall are expressed in either haemopoietic cells or tissues. The two singletons have relatively stable evolutionary histories, but the BG region undergoes dynamic expansion and contraction, with the production of hybrid genes. Thus, chicken BG genes appear to evolve much more quickly than their closest homologs in mammals, presumably due to increased pressure from pathogens.
doi:10.1371/journal.pgen.1004417
PMCID: PMC4046983  PMID: 24901252
3.  Antigen processing and presentation: Evolution from a bird's eye view☆ 
Molecular Immunology  2013;55(2):159-161.
Highlights
► Single MHC molecules in chicken versus multiple MHC molecules in mammals. ► Single MHC molecules in chicken strongly determine immune response. ► Single chicken class I due to co-evolution with polymorphic antigen processing genes. ► Co-evolution in chicken MHC due to different genomic organisation. ► Chicken MHC like ancestral MHC, with inversion in lineage to mammals.
Most detailed knowledge of the MHC outside of mammals has come from studies of chickens, originally due to the economic importance of the poultry industry. We have used our discoveries about the chicken MHC to develop a framework for understanding the evolution of the MHC, based on the importance of genomic organisation for gene co-evolution. In humans, MHC class I molecules are polymorphic and determine the specificity of peptide presentation, while the molecules involved in antigen processing are functionally monomorphic. The genes for tapasin, transporters associated with antigen presentation (TAPs) and inducible proteasome components (LMPs) are located in and beyond the class II region, far away from the class I genes in the class I region. In contrast, chickens express only one class I locus at high levels, which can result in strong MHC associations with resistance to particular infectious pathogens. The chicken TAP and tapasin genes are located very close to the class I genes, and have high levels of allelic polymorphism and moderate sequence diversity, co-evolving their specificities to work optimally with the dominantly expressed class I molecule. The salient features of the chicken MHC are found in many if not most non-mammalian species examined, and are likely to represent the ancestral organisation of the MHC. Comparison with the MHC organisation of humans and typical mammals suggests that a large inversion brought the class III region into the middle of the MHC, separating the antigen processing genes from the class I gene, breaking the co-evolutionary relationships and allowing a multigene family of well-expressed class I genes. Such co-evolution in the primordial MHC was likely responsible for the appearance of the antigen presentation pathways and receptor–ligand interactions at the birth of the adaptive immune system. Of course, much further work is required to understand this evolutionary framework in more detail.
doi:10.1016/j.molimm.2012.10.030
PMCID: PMC3878743  PMID: 23182425
Antigen processing; Antigen presentation; Major histocompatibility complex; MHC; Class I; Transporters associated with antigen presentation; TAP; Tapasin; Bird; Chicken; Non-mammalian; Vertebrate; Evolution, Adaptive immunity
4.  A tale of two tumours: Comparison of the immune escape strategies of contagious cancers☆ 
Molecular Immunology  2013;55(2):190-193.
Highlights
► There are two naturally occurring contagious cancers, Devil Facial Tumour Disease (DFTD) and Canine Transmissible Venereal Tumour (CTVT). ► Both contagious cancers share mechanisms of immune evasion. ► These mechanisms of immune evasion provide insights into how contagious cancers can emerge.
The adaptive immune system should prevent cancer cells passing from one individual to another, in much the same way that it protects against pathogens. However, in rare cases cancer cells do not die within a single individual, but successfully pass between individuals, escaping the adaptive immune response and becoming a contagious cancer. There are two naturally occurring contagious cancers, Devil Facial Tumour Disease (DFTD), found in Tasmanian devils, and Canine Transmissible Venereal Tumour (CTVT), found in dogs. Despite sharing an ability to pass as allografts, these cancers have a very different impact on their hosts. While DFTD causes 100% mortality among infected devils and has had a devastating impact on the devil population, CTVT co-exists with its host in a manner that does not usually cause death of the dog. Although immune evasion strategies for CTVT have been defined, why DFTD is not rejected as an allograft is not understood. We have made progress in revealing mechanisms of immune evasion for DFTD both in vitro and in vivo, and here we compare how DFTD and CTVT interact with their respective hosts and avoid rejection. Our findings highlight factors that may be important for the evolution of contagious cancers and cancer more generally. Perhaps most importantly, this work has opened up important areas for future research, including the effect of epigenetic factors on immune escape mechanisms and the basis of a vaccine strategy that may protect Tasmanian devils against DFTD.
doi:10.1016/j.molimm.2012.10.017
PMCID: PMC3878782  PMID: 23200636
Contagious cancer; Immune evasion; MHC; Tasmanian devil; Devil facial tumour disease; Canine transmissible venereal tumour; Cancer
5.  How the devil facial tumor disease escapes host immune responses 
Oncoimmunology  2013;2(8):e25235.
The devil facial tumor disease (DFTD) is a contagious cancer that has recently emerged among Tasmanian devils, rapidly decimating the population. We have recently discovered that DFTD cells lose the expression MHC molecules on the cell surface, explaining how this tumor avoids recognition by host CD8+ T cells.
doi:10.4161/onci.25235
PMCID: PMC3782528  PMID: 24083079
contagious cancer; transmissible tumor; Tasmanian devil; DFTD; CTVT; MHC; epigenetics; interferon; extinction; conservation
6.  The peptide motif of the single dominantly expressed class I molecule of the chicken MHC can explain the response to a molecular defined vaccine of infectious bursal disease virus (IBDV) 
Immunogenetics  2013;65(8):609-618.
In contrast to typical mammals, the chicken MHC (the BF-BL region of the B locus) has strong genetic associations with resistance and susceptibility to infectious pathogens as well as responses to vaccines. We have shown that the chicken MHC encodes a single dominantly expressed class I molecule whose peptide-binding motifs can determine resistance to viral pathogens, such as Rous sarcoma virus and Marek’s disease virus. In this report, we examine the response to a molecular defined vaccine, fp-IBD1, which consists of a fowlpox virus vector carrying the VP2 gene of infectious bursal disease virus (IBDV) fused with β-galactosidase. We vaccinated parental lines and two backcross families with fp-IBD1, challenged with the virulent IBDV strain F52/70, and measured damage to the bursa. We found that the MHC haplotype B15 from line 15I confers no protection, whereas B2 from line 61 and B12 from line C determine protection, although another locus from line 61 was also important. Using our peptide motifs, we found that many more peptides from VP2 were predicted to bind to the dominantly expressed class I molecule BF2*1201 than BF2*1501. Moreover, most of the peptides predicted to bind BF2*1201 did in fact bind, while none bound BF2*1501. Using peptide vaccination, we identified one B12 peptide that conferred protection to challenge, as assessed by bursal damage and viremia. Thus, we show the strong genetic association of the chicken MHC to a T cell vaccine can be explained by peptide presentation by the single dominantly expressed class I molecule.
doi:10.1007/s00251-013-0705-x
PMCID: PMC3710569  PMID: 23644721
Gumboro disease; Avian MHC; T cell epitope; Fowlpox virus vaccine
7.  The tammar wallaby major histocompatibility complex shows evidence of past genomic instability 
BMC Genomics  2011;12:421.
Background
The major histocompatibility complex (MHC) is a group of genes with a variety of roles in the innate and adaptive immune responses. MHC genes form a genetically linked cluster in eutherian mammals, an organization that is thought to confer functional and evolutionary advantages to the immune system. The tammar wallaby (Macropus eugenii), an Australian marsupial, provides a unique model for understanding MHC gene evolution, as many of its antigen presenting genes are not linked to the MHC, but are scattered around the genome.
Results
Here we describe the 'core' tammar wallaby MHC region on chromosome 2q by ordering and sequencing 33 BAC clones, covering over 4.5 MB and containing 129 genes. When compared to the MHC region of the South American opossum, eutherian mammals and non-mammals, the wallaby MHC has a novel gene organization. The wallaby has undergone an expansion of MHC class II genes, which are separated into two clusters by the class III genes. The antigen processing genes have undergone duplication, resulting in two copies of TAP1 and three copies of TAP2. Notably, Kangaroo Endogenous Retroviral Elements are present within the region and may have contributed to the genomic instability.
Conclusions
The wallaby MHC has been extensively remodeled since the American and Australian marsupials last shared a common ancestor. The instability is characterized by the movement of antigen presenting genes away from the core MHC, most likely via the presence and activity of retroviral elements. We propose that the movement of class II genes away from the ancestral class II region has allowed this gene family to expand and diversify in the wallaby. The duplication of TAP genes in the wallaby MHC makes this species a unique model organism for studying the relationship between MHC gene organization and function.
doi:10.1186/1471-2164-12-421
PMCID: PMC3179965  PMID: 21854592
8.  Detection of weak receptor–ligand interactions using IgM and J-chain-based fusion proteins 
European Journal of Immunology  2012;42(5):1354-1356.
doi:10.1002/eji.201142151
PMCID: PMC3437510  PMID: 22539303
IgM; Immunoglobulin fusion protein; J-chain; Receptor-ligand
9.  Immunology of naturally transmissible tumours 
Immunology  2014;144(1):11-20.
Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution.
doi:10.1111/imm.12377
PMCID: PMC4264906  PMID: 25187312
cancer; comparative immunology/evolution; MHC; transplantation; tumour immunology

Results 1-9 (9)