The chicken B locus is a minimal essential major histocompatibility complex.

Here we report the sequence of the region that determines rapid allograft rejection in chickens, the chicken major histocompatibility complex (MHC). This 92-kilobase region of the B locus contains only 19 genes, making the chicken MHC roughly 20-fold smaller than the human MHC. Virtually all the genes have counterparts in the human MHC, defining a minimal essential set of MHC genes conserved over 200 million years of divergence between birds and mammals. They are organized differently, with the class III region genes located outside the class II and class I region genes. The absence of proteasome genes is unexpected and might explain unusual peptide-binding specificities of chicken class I molecules. The presence of putative natural killer receptor gene(s) is unprecedented and might explain the importance of the B locus in the response to the herpes virus responsible for Marek's diseases. The small size and simplicity of the chicken MHC allows co-evolution of genes as haplotypes over considerable periods of time, and makes it possible to study the striking MHC-determined pathogen-specific disease resistance at the molecular level.     

Isolation and characterization of a protochordate histocompatibility locus

Histocompatibility--the ability of an organism to distinguish its own cells and tissue from those of another--is a universal phenomenon in the Metazoa. In vertebrates, histocompatibility is a function of the immune system controlled by a highly polymorphic major histocompatibility complex (MHC), which encodes proteins that target foreign molecules for immune cell recognition. The association of the MHC and immune function suggests an evolutionary relationship between metazoan histocompatibility and the origins of vertebrate immunity. However, the MHC of vertebrates is the only functionally characterized histocompatibility system; the mechanisms underlying this process in non-vertebrates are unknown. A primitive chordate, the ascidian Botryllus schlosseri, also undergoes a histocompatibility reaction controlled by a highly polymorphic locus. Here we describe the isolation of a candidate gene encoding an immunoglobulin superfamily member that, by itself, predicts the outcome of histocompatibility reactions. This is the first non-vertebrate histocompatibility gene described, and may provide insights into the evolution of vertebrate adaptive immunity.     

Presentation of viral antigen controlled by a gene in the major histocompatibility complex

We describe a mutant human cell line (LBL 721.174) that has lost a function required for presentation of intracellular viral antigens with class I molecules of the major histocompatibility complex (MHC), but retains the capacity to present defined epitopes as extracellular peptides. The cell also has a defect in the assembly and expression of class I MHC molecules, which we show can be restored by exposure of the cells to a peptide epitope. This phenotype suggests a defect in the association of intracellular antigen with class I molecules similar to that described for the murine mutant RMA-S (ref. 5), but in the present case the genetic defect can be mapped within the MHC locus on human chromosome 6.     

Experimental evidence for the existence of iron-rich metal in the Earth's lower mantle

The oxidation state recorded by rocks from the Earth's upper mantle can be calculated from measurements of the distribution of Fe3+ and Fe2+ between the constituent minerals. The capacity for minerals to incorporate Fe3+ may also be a significant factor controlling the oxidation state of the mantle, and high-pressure experimental measurements of this property might provide important insights into the redox state of the more inaccessible deeper mantle. Here we show experimentally that the Fe3+ content of aluminous silicate perovskite, the dominant lower-mantle mineral, is independent of oxygen fugacity. High levels of Fe3+ are present in perovskite even when it is in chemical equilibrium with metallic iron. Silicate perovskite in the lower mantle will, therefore, have an Fe3+/total Fe ratio of at least 0.6, resulting in a whole-rock ratio of over ten times that of the upper mantle. Consequently, the lower mantle must either be enriched in Fe3+ or Fe3+ must form by the disproportionation of Fe2+ to produce Fe3+ plus iron metal. We argue that the lower mantle contains approximately 1 wt% of a metallic iron-rich alloy. The mantle's oxidation state and siderophile element budget have probably been influenced by the presence of this alloy.     

Essential requirement for major histocompatibility complex recognition in T-cell tolerance induction

The induction of T-cell responses involves the recognition of extrinsic antigen in association with antigens of the major histocompatibility complex (MHC), in mice and man, with different T cells recognizing antigen in association with either class I (H-2K/D, HLA-A, B, C) or class II (Ia, HLA-D/DR) MHC antigens. However, the requirement of MHC recognition in the induction of immunological tolerance remains ill defined. With human T helper clones recognizing synthetic peptides of influenza haemagglutinin (HA-1), we have investigated the nature of antigen-induced stimulation, and antigen-induced antigen-specific unresponsiveness, immunological tolerance. Tolerance is not due to cell death, as the cells remain responsive to interleukin-2 and is associated with the loss of T3 antigen from the cell surface. Using monoclonal antibodies to the non-polymorphic regions of human class II antigens to inhibit the induction of T-cell tolerance we report here that induction of tolerance requires the recognition of MHC antigens.     

Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex

In mice the product of the Mlsa locus is an unusual antigen capable of interaction with certain products of the major histocompatibility locus (MHC) to form a ligand for a large portion of the T-cell alpha/beta receptor repertoire, including nearly all receptors that use V beta 8.1. The presence of Mlsa/MHC during T-cell development results in the deletion of T cells that express V beta 8.1, documenting the importance of clonal deletion in establishing tolerance to self antigens.     

Molecular evidence for new mutation at the hprt locus in Lesch-Nyhan patients

Hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC2.4.2.8), which functions in the metabolic salvage of purines, is encoded by an X-linked gene in man. Partial HPRT deficiencies are associated with gouty arthritis, while absence of activity results in Lesch-Nyhan syndrome (L-N). L-N patients fail to reproduce and the heterozygous state appears to confer no selective advantage. Thus, Haldane's principle predicts that new mutations at the hprt locus must occur frequently in order for L-N syndrome to be maintained in the population. This constant introduction of new mutations would be expected to result in a heterogeneous collection of genetic lesions, some of which may be novel. As we report here, the mutations in the hprt gene of seven L-N patients, selected from an initial survey of 28 patients, have been characterized and all were found to be distinctly different, as predicted. The origin of one unusual mutation has been identified by analysis of DNA from four generations of family members. Further molecular analysis of the origin of new mutations at the hprt locus should aid in resolving the issue of an apparent difference in the frequency of hprt mutations in males and females.     

Progress in crystallization of major histocompatibility complex class I in vertebrates

The major histocompatibility complex(MHC)of proteins that exists in all vertebrates is encoded by a cluster of genes associated with the immune response and related functions.MHC is divided into MHC I,II,and III;MHC I is involved in antigenic presentation,binding T cell receptors,and leading ultimately to specific cellular immune responses.The complicated functions of MHC I are determined by the nature of the complex.The crystal structure of MHC I has been solved for many animals,revealing the relationship between spatial structure and function.MHC I consists of an a heavy chain and a b2m light chain,both ligated non-covalently to a complex when a peptide is bound to the antigenic-binding groove.The a heavy chain is divided into an extracellular domain,a transmembrane domain,and an intracellular domain.The extracellular domain consists of sub-regions a1,a2,and a3.The a1 and a2 together form the antigenic-binding groove and bind antigenic peptides with 8–10 amino acid residues.MHC I can form a stable spatial structure;however,it should be noted that there are differences in the structure of MHC I among animal species,including anchored amino acids in binding peptides,binding sites,molecular distance,crystallization conditions,etc.Here,progress in determination of the crystal structure of human,mouse,chicken,non-human primate,and swine MHC I is described in detail.     

Differential function of major histocompatibility complex antigens in T-lymphocyte activation.

We have emphasised the functional dichotomy of MHC LD and LD antigens as well as the differences in cellular responses to these antigens. Perhaps in so doing we have failed to stress adequately the similarities that exist. But while the similarities (for example skin graft rejection associated with both K and I region differences) are so very clear, the differences have best allowed our progressive understanding of MHC induced cellular responses from the perspective stressed in this article. Of greatest importance to our understanding of these transplantation antigens are the potentially differential roles for the LD and SD antigens in the complex series of events that are collectively referred to as the "allograft reaction". It has been suggested that these differences may be "merely quantitative". This possibility has been discussed repeatedly in our previous reports on the distinction of LD and SD. In fact, the great bulk of biological phenomena can be reduced to quantitative differences. It would seem to us that sufficient evidence for such differential activity exists to make the LD-SD dichotomy model an heuristically valuable one for purposes of designing future experiments. We have discussed the clinical relevance of this model elsewhere. Many authors have speculated and evidence has been gathered to suggest, that cell surface antigens associated with the MHC are important in developmental and other cell interactions. Some studies have directly addressed the question of the need for MHC compatibility to allow cell interaction to proceed optimally. It thus seems most appropriate that the genetic complex with which we are dealing has been termed the major histocompatibility complex; allowing for the literal interpretation of this term this may be the genetic region that by its influence on "tissue compatibility" may control critical cellular interactions in addition to those observed in allograft reactions. It is the simple good fortune for those whose attention was focused on this complex by transplantation problems to find themselves with a panorama of biological phenomena that require extensive experimental probing and integration, hopefully ultimately leading to an understanding of the MHC in a broader context than has to date been possible.