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P Parham

Publications and source records attributed to P Parham.

At least 19 recordsLinked to original sources
PubMed1992

Serologic cross-reactivities poorly reflect allelic relationships in the HLA-B12 and HLA-B21 groups. Dominant epitopes of the alpha 2 helix.

Previous analysis has emphasized the correlation between primary structures of class I HLA molecules and their patterns of serologic cross-reactivity. Here we describe the structures of two serologic groups of HLA-B alleles for which this is not the case. HLA-B45, an allele associated with black populations, is serologically paired with B44 in the B12 group; its structure, however, is divergent from that of B44 but closely related to B50. The BN21 (B*4005) allele is associated with native Americans and is serologically grouped with B50 in the B21 group; its structure, however, is more closely related to alleles of the B40 group. The B44 and B45 serologically cross-reactive molecules differ at seven functional positions of the Ag recognition site; the B50 and BN21 molecules differ at four such residues. These differences are predicted to alter peptide presentation and be capable of eliciting strong alloreactive T cell responses. For these pairs of B12 and B21 Ag, serology appears dominated by epitopes formed by short sequences of the alpha 2 helix which have been shuffled by recombination between alleles. The implications of these results for HLA matching in transplantation are discussed.

Alleles↗
PubMed1992

Distinctive polymorphism at the HLA-C locus: implications for the expression of HLA-C.

The HLA-C locus remains an enigma. The serological polymorphism is poorly defined, HLA-C molecules are expressed at the cell surface at about 10% the levels of HLA-A and -B, and their importance for antigen presentation to either CD8-bearing T cells or natural killer cells is unclear. Our understanding of HLA-C polymorphism has also lagged behind that of HLA-A and -B. We have applied the polymerase chain reaction to the characterization of cDNA encoding HLA-C antigens. Combining the recent results with previously characterized HLA-C alleles gives a data base of 26 sequences, which was used to analyze the nature of HLA-C polymorphism and compare it to the variation seen in HLA-A and -B. The sequences form 10 families of alleles that correlate well with the patterns of serological crossreactivity, including the C blanks, and all major HLA-C allelic families appear to have been sampled. The families further divide into two groups of HLA-C alleles defined on the basis of linked substitutions in the 3' exons. In comparison with HLA-A and -B, HLA-C alleles are more closely related to each other, there being less variation in residues of the antigen recognition site and more variation at other positions. In particular, the helix of the alpha 1 domain of HLA-C molecules is unusually conserved. Despite the reduced diversity in the antigen recognition site, it is evident that HLA-C genes have been the target of past selection for polymorphism. Within the antigen recognition site, it is the alpha 1 domain that is most diagnostic of HLA-C, whereas the alpha 2 domain is similar to that of HLA-B, the locus to which HLA-C is most closely related. In particular, conserved motifs in the alpha 1 helix and the conserved glycine at the base of the B pocket (position 45) provide a combination of features that is uniquely found in HLA-C molecules. We hypothesize that these features restrict the peptides bound by HLA-C molecules and in this manner reduce the efficiency of HLA-C assembly and expression at the cell surface. The overall picture HLA-C polymorphism obtained from this sampling of HLA-C alleles is unlikely to change as further alleles are characterized.

Alleles↗
PubMed1992

HLA-J, a second inactivated class I HLA gene related to HLA-G and HLA-A. Implications for the evolution of the HLA-A-related genes.

Ragoussis and co-workers (Genomics 4:301) previously described a class I HLA gene (now designated HLA-J) that maps to within 50 kb of HLA-A. The nucleotide sequences of three HLA-J alleles are reported here. Comparison of the nucleotide sequences of HLA-J alleles shows this gene is more related to HLA-G, A, and H than to HLA-B, C, E, and F. All four alleles of HLA-J are pseudogenes because of deleterious mutations that produce translation termination either in exon 2 or exon 4. Apart from these mutations, the predicted proteins have structures similar to those of HLA-A, B, and C molecules. There is, however, little polymorphism at HLA-J and none at functional positions of the Ag-recognition site. The polymorphism is less than found for HLA-H another HLA-A-related pseudogene. HLA-J appears, like HLA-H, to be an inactivated gene that result from duplication of an Ag-presenting locus related to HLA-A. Nucleotide sequence comparisons show that the HLA-A, H, J, and G genes form a well defined group of "HLA-A-related" loci. Evolutionary relationships as assessed by construction of trees suggest the four modern loci: HLA-A, G, H, and J were formed by successive duplications from a common ancestral gene. In this scheme one intermediate locus gave rise to HLA-A and H, the other to HLA-G and J.

Alleles↗
PubMed1992

Unusual HLA-B alleles in two tribes of Brazilian Indians.

The Kaingang and Guarani are culturally and linguistically distinct tribes of southern Brazil. Like all Amerindian groups they show limited HLA polymorphism, which probably reflects the small founder populations that colonized America by overland migration from Asia 11,000-40,000 years ago. We find the nucleotide sequences of HLA-B alleles from the Kaingang and Guarani to be distinct from those characterized in caucasian, oriental and other populations. By comparison, the HLA-A and C alleles are familiar. These results and those reported in the accompanying paper on the Waorani of Ecuador reveal that a marked evolution of HLA-B has occurred since humans first entered South America. New alleles have been formed through recombination between pre-existing alleles, not by point mutation, giving rise to distinctive diversification of HLA-B in different South American Indian tribes.

Alleles↗
PubMed1992

The HLA-A,B "negative" mutant cell line C1R expresses a novel HLA-B35 allele, which also has a point mutation in the translation initiation codon.

The HLA-A,B negative mutant cell line C1R is widely used as a transfection recipient in functional studies of class I MHC genes. It was derived from a normal B cell line, Hmy2, by three rounds of mutagenesis and immunoselection with anti-HLA mAb. Serology characterizes C1R to be negative for the HLA-A2, A3, B35, Bw62, and Cw3 Ag of the parental cell line while retaining expression of HLA-Cw4. We find, however, that CTL specific for HLA-B35 lyse C1R cells, suggesting that expression of HLA-B35 is also retained. To resolve this paradox we examined the expression of HLA-A,B,C genes and proteins in C1R cells. The results are consistent with deletion of the HLA-A3, Bw62, Cw3 haplotype and retention of the HLA-A2, B35, Cw4 haplotype in C1R. Although present, the HLA-A2 gene appears not to be transcribed. As expected, the HLA-Cw4 gene is transcribed and the protein expressed at normal levels. Transcription of the HLA-B35 gene is also normal and comparable to that of HLA-Cw4. However, expression of the HLA-B35 protein is reduced to a few percent of the parental level. Comparison of the nucleotide sequence of B35 alleles from C1R and Hmy2 revealed that reduced translation in C1R is caused by a point mutation (ATG to TTG) in the translation initiation codon. The HLA-B35 allele from C1R and Hmy2 represents a novel subtype, B*3503, differing from B*3501 by replacement of serine by phenylalanine at the peptide binding position 116. This study shows cell surface levels of a class I molecule which are insensitive to lysis by antibody and complement can be readily recognized by alloreactive T cells, further illustrating the relative sensitivity of Ag recognition by T cells.

Alleles↗
PubMed1992

Anchoring pockets in human histocompatibility complex leukocyte antigen (HLA) class I molecules: analysis of the conserved B ("45") pocket of HLA-B27.

Dissection of the peptide binding grooves of seven subtypes of human histocompatibility leukocyte antigen (HLA)-B27 into the six specificity pockets defined by the 2.6-A structure of HLA-A*0201 revealed just one pocket, the B ("45") pocket, that is conserved among all the HLA-B27 subtypes. Functional studies of mutant HLA-B*2705 molecules with point substitutions in residues of the B pocket show that this structure, and the glutamine residue at position 45 in particular, plays a critical role in cell surface expression, peptide binding, and in the presentation of both exogenous and endogenous peptides by HLA-B*2705. We predict that the B pocket of HLA-B*2705 interacts with an amino acid side chain that anchors peptides in the binding groove, and that this peptide motif is present in most endogenously processed peptides that bind to all seven subtypes of HLA-B27.

Amino Acid Sequence↗
PubMed1992

HLA-Bw22: a family of molecules with identity to HLA-B7 in the alpha 1-helix.

Various HLA-B molecules exhibit serologic cross-reactions with HLA-B7, including HLA-B27, B40, Bw42, and Bw22. Of this group, primary structures for the three serologic subdivisions of HLA-Bw22, HLA-Bw54, Bw55, and Bw56, have yet to be determined. Here, we describe the nucleotide sequences of five distinctive HLA-Bw22 alleles isolated from cells of different ethnic origins typed either for Bw54, Bw55, or Bw56. Heterogeneity in molecules typed as Bw55 and Bw56 was defined. The five HLA-Bw22 alleles form a closely related family that appears to have evolved by a series of simple gene conversion events, all of which alter the antigen recognition site of the encoded proteins. Of note, HLA-Bw54 is the product of a gene conversion between HLA-B and C alleles. All the Bw22 alleles encode an alpha 1-helix identical in amino acid sequence to that of HLA-B7 and Bw42, a feature almost certainly responsible for the serologic cross-reactivity of these molecules. Shared substitutions in the alpha 1-helix can also explain the cross-reactivity of Bw22 and B7 with B27. Patterns of amino acid substitution in the alpha 2-domain of Bw22 heavy chains correlate with certain antibody and T cell cross-reactivities, thereby implicating particular amino acids in their target epitopes.

Alleles↗
PubMed1992

Molecular definition of an elusive third HLA-A9 molecule: HLA-A9.3.

The HLA-A9 family has been characterized as possessing two well defined specificities; HLA-A23 and A24. Serological studies have suggested the presence of a third member of this family HLA-A9.3, however there is doubt surrounding the existence of this specificity. HLA-A23, A24, and the putative A9.3 proteins were analyzed biochemically by immunoprecipitation and isoelectric focusing. Both HLA-A24 and A9.3 have identical isoelectric points whereas A23 is different. We have sequenced cDNA encoding HLA-A23, A24, and A9.3. From the observed protein sequences, we found A9.3 to differ from A24 by two amino acid substitutions located in the alpha 2 helix of the class I molecule. These substitutions are expected to significantly change the shape of the peptide binding cleft.

Alleles↗
PubMed1992

Reptilian class I major histocompatibility complex genes reveal conserved elements in class I structure.

The polymerase chain reaction was used to isolate clones with class I major histocompatibility complex sequences from fish (carp), amphibian (axolotl), and two species of reptile (lizard and snake). The lizard and snake clones were used to isolate class I cDNA clones. All the sequences showed the expected evolutionary relatedness. The carp and axolotl clones and one lizard cDNA clone lacked the first cysteine in the alpha 3 domain which in other class I heavy chains forms an intradomain disulfide bond. A small number of amino acid residues are conserved in the class I heavy chain sequences from all five classes of vertebrates. In the first two domains they are symmetrically clustered and contribute to intra- and interdomain contacts. None of these invariant residues are at peptide-binding, T-cell receptor-interacting, or CD8-binding positions.

Amino Acid Sequence↗
PubMed1992

HLA class I nucleotide sequences, 1992.

The HLA class I sequences included in this compilation are taken from articles listed in the literature: "Nomenclature for Factors of the HLA System, 1991" [1], "Nomenclature for Factors of the HLA System, 1990" [2], and "Nomenclature for Factors of the HLA System, 1989" [3]. Because of the increased number of sequences, we have only included sequences for exons 2-4 in this compilation. Where discrepancies have arisen between reported sequences, the original authors have been contacted where possible, and necessary amendments to published sequences have been incorporated into this alignment. Future sequencing may identify errors in this list, and we would welcome any evidence that helps to maintain the accuracy of this compilation. In the sequence alignments, identity between nucleotides is indicated by a hyphen (-). An unavailable sequence is indicated by a period (.). Gaps in the sequence are inserted to maintain the alignment between different alleles showing variation in amino acid number.

Base Sequence↗