Biomedical subjects
P Parham
Publications and source records attributed to P Parham.
Killer cell receptors: keeping pace with MHC class I evolution.
NK cells express receptors that bind to polymorphic determinants of MHC class I heavy chains. MHC ligands vary greatly between mammalian species, and the use of distinct molecular families of NK cell receptors by humans and mice suggests that the receptors too can be evolving rapidly. The KIR (killer cell inhibitory receptor) family of receptors are found in primates and recognize class I epitopes that are of relatively recent origin in primate evolution. Therefore, KIR molecules have probably evolved class I receptor function more recently than C-type lectins, which are represented in both humans and mice. Individual humans express NK cell receptors for which they have no class I ligand, demonstrating a looseness in the coupling of expression between the receptors and their ligands. However, study of a single donor suggests that every NK cell expresses at least one inhibitory receptor for a self-HLA class I allotype, consistent with the missing self hypothesis. Thus the NK-cell receptor-class I interaction appears to control the NK-cell repertoire during ontogeny of the individual and has the potential to be a selective factor influencing both MHC class I and NK cell receptor diversity in the evolution of populations and species.
Assignment of TCF1, TGM1, CALM1, CKB, THBS1, B2M, and FES in Ateles paniscus chamek (Platyrrhini, Primates).
Regional assignment of five markers to chromosome 2 of Ateles paniscus chamek (APC) confirmed a syntenic association similar to human (HSA) 12q + 14q + 15q. TCF1 was allocated to a shortest region of overlap (SRO) in APC 2p and found to be syntenic to PEPB, while TGM1, CALM1, THBS1, and B2M were assigned to APC 2q, being syntenic to NP, HEXA, and MPI. Conversely, markers close to HSA 14qter (CKB) and HSA 15qter (FES-IDH2) were relocated to other Ateles syntenic groups. Karyotypic comparisons showed an evident homoeology between APC 2p and HSA 12q, whereas APC 2q was similar to an HSA 14qter::HSA 15qter fusion product.
Nomenclature for factors of the HLA system, 1996.
Explore the source record for details and available documents.
Nomenclature for factors of the HLA system, 1996.
Explore the source record for details and available documents.
Natural killer cells, HLA class I molecules, and marrow transplantation.
Explore the source record for details and available documents.
Mismatches for two major and one minor histocompatibility antigen correlate with a patient's rejection of a bone marrow graft from a serologically HLA-identical sibling.
We describe the case of a patient with chronic myeloid leukemia who rejected a bone marrow (BM) graft from a sibling donor believed to be HLA identical. Sequencing of the HLA genes showed the mother to be heterozygous for two closely related HLA haplotypes that could not be resolved by serological typing. The donor and the recipient had each inherited a different maternal haplotype resulting in allelic mismatches for the HLA-B35 and the HLA-DR11 genes. T cell cytotoxicity directed towards the donor's B35 allele was detected in the patient, in addition to CTL specificity for an HLA-B7-restricted minor histocompatibility antigen carried by the donor, resulting in three histocompatibility mismatches between the BM donor and the recipient.
Killer cell inhibitory receptor recognition of human leukocyte antigen (HLA) class I blocks formation of a pp36/PLC-gamma signaling complex in human natural killer (NK) cells.
The killer cell inhibitory receptors (KIR) of human natural killer (NK) cells recognize human leukocyte antigen class I molecules and inhibit NK cell cytotoxicity through their interaction with protein tyrosine phosphatases (PTP). Here, we report that KIR recognition of class I ligands inhibits distal signaling events and ultimately NK cell cytotoxicity by blocking the association of an adaptor protein (pp36) with phospholipase C-gamma in NK cells. In addition, we demonstrate that pp36 can serve as a substrate in vitro for the KIR-associated PTP, PTP-1C (also called SHP-1), and that recognition of class I partially disrupts tyrosine phosphorylation of NK cell proteins, providing evidence for KIR-induced phosphatase activity.
The inter-locus recombinant HLA-B*4601 has high selectivity in peptide binding and functions characteristic of HLA-C.
The vast majority of new human HLA class I alleles are formed by conversions between existing alleles of the same locus. A notable exception to this rule is HLA-B*4601 formed by replacement of residues 66-76 of the alpha 1 helix of B*1501 by the homologous segment of Cw*0102. This inter-locus recombination, which brings together characteristic elements of HLA-B and HLA-C structure, is shown here to influence function dramatically. Naturally processed peptides bound by B*4601 are distinct from those of its parental allotypes B*1501 and Cw*0102 and dominated by three high abundance peptides. Such increased peptide selectivity by B*4601 is unique among HLA-A,B,C allotypes. For other aspects of function, presence of the small segment of HLA-C-derived sequence in an otherwise HLA-B framework converts B*4601 to an HLA-C-like molecule. Alloreactive cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and cellular glycosidases all recognize B*4601 as though it were an HLA-C allotype. These unusual properties are those of an allotype which has frequencies as high as 20% in south east Asian populations and is associated with predisposition to autoimmune diseases and nasopharyngeal carcinoma.
Immunology: keeping mother at bay.
Like its better-known polymorphic relatives, HLA-G, a relatively unpolymorphic class I MHC molecule expressed by fostal trophoblast cells, binds short peptides with a defined sequence motif; HLA-G may play an important role in maternal tolerance to a fostus.
Unusual uniformity of the N-linked oligosaccharides of HLA-A, -B, and -C glycoproteins.
MHC class I glycoproteins possess an invariant site for N-linked oligosaccharide addition at position 86 of the heavy chain. For human HLA-A, -B, and -C class I glycoproteins, position 86 is the only site of N-linked glycosylation. Comparison of the size and relative abundance of oligosaccharides associated with nine HLA-A, -B, or -C allotypes isolated from EBV-transformed B cell lines and mixtures of HLA-A, -B, and -C allotypes isolated from pooled PBLs revealed a very restricted set of structures. Allotypes encoded by the HLA-A and -B loci have two predominant glycan structures that were almost exclusively di-sialylated. In contrast, HLA-C allotypes have four glycan structures, comprising those associated with HLA-A and -B and two additional glycans. Identical oligosaccharides were present on different allotypes of a class I HLA locus, and in particular, HLA-C allotypes defining two inhibitory specificities for NK cells were shown to possess the same set of oligosaccharides. The uniformity of oligosaccharide structure associated with different HLA-A, -B, and -C products and the relative lack of heterogeneity for any given allotype are unusual features for a mammalian glycoprotein. Particularly striking is that such conserved oligosaccharide structures juxtapose the major regions of amino acid sequence variation within the Ag recognition site, including the polymorphisms of the alpha 1 helix that determine the inhibitory ligands for human NK cells.
Population biology of antigen presentation by MHC class I molecules.
In principle, the function of major histocompatibility complex (MHC) molecules is simple: to bind a peptide and engage a T cell. In practice, placing this function within the context of the immune response begs questions of population biology; How does the immune response emerge from the interactions among populations of peptides, T cells and MHC molecules? Within a population of vertebrates, how does MHC polymorphism stamp individuality on the response? Does polymorphism confer differential advantages in responding to parasites? How are the pressures on the MHC reflected in turnover of alleles? The role of mutation, recombination, selection, and drift in the generation and maintenance of MHC class 1 polymorphism are considered.
Unexpected beta2-microglobulin sequence diversity in individual rainbow trout.
For mammals beta2-microglobulin (beta2m), the light chain of major histocompatibility complex (MHC) class I molecules, is invariant (or highly conserved) and is encoded by a single gene unlinked to the MHC. We find that beta2m of a salmonid fish, the rainbow trout (Oncorhynchus mykiss), does not conform to the mammalian paradigm. Ten of 12 randomly selected beta2m cDNA clones from an individual fish have different nucleotide sequences. A complex restriction fragment length polymorphism pattern is observed with rainbow trout, suggesting multiple beta2m genes in the genome, in excess of the two genes expected from the ancestral salmonid tetraploidy. Additional duplication and diversification of the beta2m genes might have occurred subsequently. Variation in the beta2m cDNA sequences is mainly at sites that do not perturb the structure of the mature beta2m protein, showing that the observed diversity of the trout beta2m genes is not primarily a result of pathogen selection.
Patr-A and B, the orthologues of HLA-A and B, present hepatitis C virus epitopes to CD8+ cytotoxic T cells from two chronically infected chimpanzees.
Common chimpanzees (Pan troglodytes) infected with hepatitis C virus (HCV) show a disease progression similar to that observed for human patients. Although most infected animals develop a chronic hepatitis, virus persistence is associated with an ongoing immune response, for which the beneficial or detrimental effects are uncertain. Lines of virus-specific cytotoxic CD8+ T lymphocytes (CTL) have been previously established from liver biopsies of two common chimpanzees chronically infected with HCV-1. The viral epitopes recognized by six lines of CTL have been defined using synthetic peptides and shown to consist of 8 to 9-residue peptides derived from various viral proteins. Five of the epitopes derive from sequences that vary among strains of HCV. The majority of the corresponding variant epitopes from different HCV strains were either recognized less efficiently or not at all by the CTL, suggesting their response may have limited potential for controlling replication of HCV variants. Complementary DNAs encoding class I alleles of the two common chimpanzees, Patr-A, -B, and -C were cloned, sequenced, and transfected individually into a class I-deficient human cell line. Analysis of peptide presentation by the class I transfectants to CTL identified the Patr class I allotypes that present the six epitopes defined here and an additional epitope defined previously. The assignment of epitopes to class I allotypes based upon analysis of the transfected cells correlates precisely with the segregation of antigen-presenting function within a panel of common chimpanzee cell lines and the expression of class I heavy chains as defined by isoelectric focusing. Five of the HCV-1 epitopes are presented by Patr-B allotypes, two epitopes are presented by a Patr-A allotype, and none is presented by Patr-C allotypes.
Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype.
Natural killer (NK) cells that express the NKB1 receptor are inhibited from killing target cells that possess human histocompatibility leukocyte antigen (HLA) B molecules bearing the Bw4 serological epitope. To investigate whether NKB1 expression is affected by HLA type, peripheral blood lymphocytes of 203 HLA-typed donors were examined. Most donors had a single population of NKB1+ cells, but some had two populations expressing different cell surface levels of NKB1, and others had no detectable NKB1+ cells. Among the donors expressing NKB1, both the relative abundance of NKB1+ NK cells and their level of cell surface expression varied substantially. The percentage of NKB1+ NK cells ranged from 0 to >75% (mean 14.7%), and the mean fluorescence of the positive population varied over three orders of magnitude. For each donor, the small percentage of T cells expressing NKB1 (usually <2%), had a pattern of expression mirroring that of the NK cells. NKB1 expression by NK and T cells remained stable over the 2-yr period that five donors were tested. Patterns of NKB1 expression were not associated with Bw4 or Bw6 serotype of the donor or with the presence of any individual HLA-A or -B antigens. Cells expressing NKB1 are often found in donors who do not possess an appropriate class I ligand, and can be absent in those who express Bw4+ HLA-B antigens. Family studies further suggested that the phenotype of NKB1 expression is inherited but not HLA linked. Whereas identical twins show matching patterns of NKB1 expression, HLA-identical siblings can differ in NKB1 expression, and conversely, HLA-disparate siblings can be similar. Thus NKB1 expression phenotypes are tightly regulated and extremely heterogeneous, but not correlated with HLA type.
The presentation of a hepatitis C viral peptide by distinct major histocompatibility complex class I allotypes from two chimpanzee species.
A cytotoxic T lymphocyte (CTL) line, derived from the liver of a common chimpanzee (Pan troglodytes) with hepatitis C, specifically recognized a hepatitis C viral 9-mer peptide (KHP-DATYSR in single-letter amino acid code) bound by the major histocompatibility complex (MHC) class I molecule, Patr-A04. This same CTL line also recognized the identical peptide bound by a structurally different class I molecule, Papa-A06, derived from the separate chimpanzee species, Pan paniscus or pygmy chimpanzee. These class I allotypes differ by six amino acids but, in spite of the structural differences, share the same antigen-presenting function. This is the first observation of antigen presentation to a given T cell receptor by different MHC class I allotypes from separate species.
B27 polymorphism and peptide repertoire.
Over 130 HLA-B alleles have been defined at the level of nucleotide sequence. Nine of these are subtypes of HLA-B27. To understand how HLA-B27 predisposes towards arthritis it is important to determine which B27 subtypes are associated with disease susceptibility and which are not. A characteristic of HLAB27 is the binding of peptides having arginine at position 2. However, HLA-B*7301, a rare and unusual allele of European populations, has an identical "B" subpocket to B*27 and also binds peptides with arginine at position 2. The association of the Bw4 public epitope with inhibition of certain NK cells raises the possibility that NK cell responses may contribute to HLA-B27-associated disease.