The Cluster of BTN Genes in the Extended Major Histocompatibility Complex

Rhodes, David A.; Stammers, M.; Malcherek, Georg; Beck, Stephan; Trowsdale, John

doi:10.1006/geno.2000.6406

Cited by 124 publications

(122 citation statements)

References 43 publications

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“…PRSS16 encodes a thymus-specific serine protease that is highly expressed in cortical thymic epithelial cells, and believed to be involved in the regulation and/or positive selection of T cells. 19 The functions of the proteins encoded by the BTN cluster are not yet fully understood, but they are expressed on the cell surface in several immunological tissues like the spleen, lymph nodes and thymus and also in the pancreas, 30,31 and an immunological role has been implicated. The BTN genes have a strong domain similarity with other genes in the MHC, and with the B7.1 (CD80) and the B7.2 (CD86) costimulatory receptors on antigen-presenting cells.…”

Section: Discussionmentioning

confidence: 99%

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

et al. 2009

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The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1*0401-DQA1*03-DQB1*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.

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Section: Discussionmentioning

confidence: 99%

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

et al. 2009

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“…The butyrophilin in milk is now correctly specified as butyrophilin1A1, as it is the gene product of only one of the genes (BTN1A) that code for the family of proteins known as butyrophilins (Rhodes et al, 2001). The butyrophilins are part of the immunoglobulin superfamily and contain two folded immunoglobulin domains, a transmembrane domain and a C-terminal end that may include a large B30.2 domain.…”

Section: Caseinsmentioning

confidence: 99%

The evolution of milk secretion and its ancient origins

Oftedal

2012

Animal

187

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Lactation represents an important element of the life history strategies of all mammals, whether monotreme, marsupial, or eutherian. Milk originated as a glandular skin secretion in synapsids (the lineage ancestral to mammals), perhaps as early as the Pennsylvanian period, that is, approximately 310 million years ago (mya). Early synapsids laid eggs with parchment-like shells intolerant of desiccation and apparently dependent on glandular skin secretions for moisture. Mammary glands probably evolved from apocrine-like glands that combined multiple modes of secretion and developed in association with hair follicles. Comparative analyses of the evolutionary origin of milk constituents support a scenario in which these secretions evolved into a nutrient-rich milk long before mammals arose. A variety of antimicrobial and secretory constituents were co-opted into novel roles related to nutrition of the young. Secretory calcium-binding phosphoproteins may originally have had a role in calcium delivery to eggs; however, by evolving into large, complex casein micelles, they took on an important role in transport of amino acids, calcium and phosphorus. Several proteins involved in immunity, including an ancestral butyrophilin and xanthine oxidoreductase, were incorporated into a novel membrane-bound lipid droplet (the milk fat globule) that became a primary mode of energy transfer. An ancestral c-lysozyme lost its lytic functions in favor of a role as a-lactalbumin, which modifies a galactosyltransferase to recognize glucose as an acceptor, leading to the synthesis of novel milk sugars, of which free oligosaccharides may have predated free lactose. An ancestral lipocalin and an ancestral whey acidic protein four-disulphide core protein apparently lost their original transport and antimicrobial functions when they became the whey proteins b-lactoglobulin and whey acidic protein, which with a-lactalbumin provide limiting sulfur amino acids to the young. By the late Triassic period (ca 210 mya), mammaliaforms (mammalian ancestors) were endothermic (requiring fluid to replace incubatory water losses of eggs), very small in size (making large eggs impossible), and had rapid growth and limited tooth replacement (indicating delayed onset of feeding and reliance on milk). Thus, milk had already supplanted egg yolk as the primary nutrient source, and by the Jurassic period (ca 170 mya) vitellogenin genes were being lost. All primary milk constituents evolved before the appearance of mammals, and some constituents may have origins that predate the split of the synapsids from sauropsids (the lineage leading to 'reptiles' and birds). Thus, the modern dairy industry is built upon a very old foundation, the cornerstones of which were laid even before dinosaurs ruled the earth in the Jurassic and Cretaceous periods.Keywords: evolution, lactation, milk composition, casein, milk fat globule ImplicationsLactation has an evolutionary origin and biological context within which its secretory processes and milk constituents evolved. This revi...

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“…This unassuming molecule is a member of the butyrophilin/B7-like group of proteins belonging to the Ig superfamily that are found clustered at the extended end of the classical MHC I genes on human chromosome 6. 82 In a series of elegant experiments involving specific activating and inhibitory antibodies to CD277 as well as domain-swapping and knockdown experiments, the Scotet-Bonneville group shows convincing evidence that this widely expressed molecule provides the necessary support that pAgs need to awaken Vc9Vd2 T cell effector functions. 81 The fact that no functional orthologue of CD277 exists in rodents adds further credence to its purported role as the long-awaited missing link-or what may very well turn out to be a series of interconnected links.…”

Section: Vd2 T Cells: To Know the Complex Burden Of Being Humanmentioning

confidence: 99%

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

2012

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The elusive task of defining the character of cd T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the a and b T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, cd T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and ab T cells are particularly well equipped to respond to the 'missing self' and the 'dangerous non-self', respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the 'safe non-self' and dealing with the inevitable 'distressed self', and it is within this more complex realm cd T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human cd T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to life's many stresses. Keywords: antigen recognition; danger-associated molecular patterns; gamma delta T cell subsets; immune homeostasis; innate immunity; stress response PROLOGUE Since the time of their accidental discovery during the molecular characterization of the a and b T cell receptor (TCR) genes belonging to their relatively unambiguous brethren, 1 'enigmatic' is still one of the most commonly used adjectives to describe cd T cells. This can be attributed to the fact that these unconventional lymphocytes have thus far been remarkably successful in thwarting most attempts at definition. Much of what we know about T cell biology and function comes from what has been discerned through studies done on ab T cells; however, one thing that is certain is that the majority of the rules governing the lives of ab T cells are surprisingly irrelevant when it comes to understanding the elusive character of cd T cells. Table 1 highlights some of the major differences between these two T cell subsets in humans.Recognition by cd T cells is not typically in the context of classical major histocompatibility complex (MHC) class I or II molecules and neither is antigen processing required. 2,3 These observations are corroborated by the fact that the majority of cd T cells are CD8 and CD4 negative. Crystal structure analysis of the cd TCR determined that the length and conformation of cd TCR resemble immunoglobulins (Ig) more than the ab TCR, which was taken to suggest that antigen recognition by cd T cells may be more similar to the binding of antibody to antigen rather than the MHC/peptide complex recognized by ab T cells. 4 The very basis of foreign antigen rec...

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The Cluster of BTN Genes in the Extended Major Histocompatibility Complex

Cited by 124 publications

References 43 publications

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

The evolution of milk secretion and its ancient origins

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

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