PubMed Health⌕ Search

Biomedical subjects

P E Harris

Publications and source records attributed to P E Harris.

At least 19 recordsLinked to original sources
PubMed1998

Peptides bound to major histocompatibility complex molecules.

Peptides are the means by which immune effector T cells recognize and defend against the foreign proteins of pathogens. T cell recognition of these molecules, however, is strictly dependent on peptide binding to the receptor-like molecules of the major histocompatibility complex (MHC) locus. The basic unit of recognition is a trimolecular complex consisting of the T cell antigen receptor, the MHC molecule, and the MHC-bound peptide ligand. The multistep process that culminates in MHC presentation of peptides to T cells begins in the last phases of protein catabolism. While the individual roles of many key molecules involved in peptide presentation have recently been defined, there still remain many questions regarding processing of proteins into MHC-bound peptides. This review summarizes the recent developments in peptide antigen processing for MHC molecules, with focus on how proteins are believed to be sampled and selected for degradation into peptides.

Animals↗
PubMed1998

Ligation of HLA class I molecules on smooth muscle cells with anti-HLA antibodies induces tyrosine phosphorylation, fibroblast growth factor receptor expression and cell proliferation.

The development of transplant atherosclerosis, a manifestation of chronic rejection, is the major obstacle to long-term survival of cardiac and renal allografts. The incidence of transplant atherosclerosis is increased in transplant recipients producing antidonor HLA antibodies following transplantation, suggesting that anti-HLA antibodies play a role in the pathogenesis of the disease. We have postulated that anti-HLA antibodies mediate the development of transplant atherosclerosis by binding to class I molecules on the endothelium and smooth muscle of the graft and transducing signals which stimulate cell proliferation. In this report we demonstrate that anti-HLA class I antibodies transduce signals in smooth muscle cells stimulating increased tyrosine phosphorylation of intracellular proteins and up-regulation of fibroblast growth factor (FGF) receptors. Antibody binding to class I molecules on smooth muscle cells is also accompanied by increased responsiveness to basic FGF and augmented cell proliferation. These findings may explain the increased occurrence of transplant atherosclerosis in recipients producing anti-donor HLA antibodies.

Antibodies↗
PubMed1998

Intramolecular and intermolecular spreading during the course of organ allograft rejection.

There are two distinct pathways by which T cells may recognize MHC alloantigens. The direct pathway involves T-cell recognition of intact MHC molecules expressed by donor antigen-presenting cells (APCs). The second, or indirect, pathway describes T-cell recognition of peptides derived from the processing and presentation of allogeneic MHC molecules on self APCs. Recent data demonstrates that indirect recognition plays a central role in both acute and chronic rejection of human organ allografts. Our studies have shown that, at the onset of primary acute rejection, recipient T-cell responses to donor HLA-DR alloantigens are limited to a single dominant determinant present on one of the disparate alloantigens and restricted by one of the responder's HLA-DR molecules. In allograft recipients with recurring episodes of rejection, and/or at the onset of chronic rejection, recipient T-cell reactivity may spread to other epitopes within the allogeneic MHC molecule as well as to other alloantigens expressed by graft tissue. Both quantitative and qualitative alterations in T-cell allopeptide reactivity are associated with increased risk of cellular and/or humoral rejection. These studies provide a basis for the design of new therapeutic strategies and for immunologic monitoring of transplant recipients.

Graft Rejection↗
PubMed1997

Naturally processed tissue- and differentiation stage-specific autologous peptides bound by HLA class I and II molecules of chronic myeloid leukemia blasts.

Structural analysis of naturally processed peptides bound to the HLA class I and class II molecules of chronic myeloid leukemia (CML) blast cells was performed to characterize the antigen processing and autoantigen repertoire in this hematopoietic malignancy. Self-peptides derived from the carboxy-terminal end of the breakpoint cluster region (bcr) protein, as well as several differentiation stage- and tissue-specific self-antigens characteristic of early stages of myeloid differentiation, such as c-fes, c-pim, granulocyte-macrophage colony-stimulating factor receptor alpha chain, proteinase 3, and cathepsin G, were identified. A common characteristic of several of the high copy-number self-peptides identified in this study is the participation of their parent proteins in signal transduction or myeloid effector function. Because bcr-abl junctional peptides bind to a limited number of major histocompatibility complex (MHC) class I alleles, an effective peptide-based immunotherapy strategy for CML requires identification of further tumor-associated or tissue-specific peptide antigens binding to common MHC alleles such as HLA-A2. The differentiation stage- and tissue-specific MHC-bound peptides found in this study, as well as the naturally processed proteins from which they are derived, may represent autoantigens towards which T-cell responses may potentially be developed for immunotherapy of hematopoietic malignancies such as CML.

Amino Acid Sequence↗
PubMed1997

Induction of high affinity fibroblast growth factor receptor expression and proliferation in human endothelial cells by anti-HLA antibodies: a possible mechanism for transplant atherosclerosis.

The major limitation to long term survival of organ allografts is chronic rejection, which is manifested as atherosclerosis of the vessels of the transplanted organ. There is a significant association between transplant atherosclerosis and the development of Abs to the disparate HLA Ags present on the graft vasculature. We have investigated the effect of anti-HLA Abs on endothelial cells (EC) and smooth muscle cells cultured in vitro. Ab ligation of class I molecules on ECs results in increased high affinity fibroblast growth factor receptor mRNA expression, and enhanced basic fibroblast growth factor ligand binding. Ab binding to class I molecules on EC and smooth muscle cells is also accompanied by augmented cell proliferation. These results suggest that the intimal thickening observed in transplant atherosclerosis is the result of the proliferative effects of anti-HLA Abs.

Antibodies↗
PubMed1997

Polymorphism in the 5' terminal region of the mRNA of HLA-DQA1 gene: identification of four groups of transcripts and their association with polymorphism in the alpha 1 domain.

Relative to other loci in the MHC, the HLA-DQ locus exhibits an exceptional degree of polymorphism of both A1 and B1 genes, particularly in the region coding for alpha and beta chains. Diversification of the association between different alpha and beta molecules either in cis or in trans contributes to the structural diversity of the repertoire of cell-surface class II protein's in the population. In addition, structural allelic polymorphisms in the 5' regulatory region of both DQB1 and DQA1 shows several linkage groups with respect to the allelic coding sequence of the respective genes. We describe here the allelic polymorphism in the DQA1 mRNA structure located at the 5' untranslated terminal region. This portion of the mRNA molecule represents, in many genes, a cis-acting regulatory sequence playing a role in the posttranscriptional mechanisms by which gene expression can be modulated. Based on detailed transcriptional analysis, we have been able to define at least four groups of transcripts in DQA1. The mRNA variability was associated with the polymorphism of the second exon of the DQA1 gene, coding for the alpha 1 domain and not with the DNA polymorphism in the 5' regulatory region.

B-Lymphocytes↗
PubMed1997

Allopeptide-specific T cell reactivity altered by peptide analogs.

Recent evidence indicates that indirect allorecognition plays a key role in initiating and sustaining graft rejection. This self-restricted T cell response is generally limited to a restricted set of dominant immunogenic peptides derived from allogeneic HLA molecules. Here, we have examined whether peptide analogues of the dominant determinant of HLA-DRbeta1*0101 molecule (peptide DR1/22-35), recognized in the context of HLA-DRbeta1*1101 protein, are able to modulate the T cell response against the wild-type peptide Ag. The peptide analogues were generated by introducing single amino acid substitutions at putative MHC and TCR contact positions. Two analogues, 25R/A and 28E/Q, which bound to soluble DR11 protein, but did not stimulate an anti-DR1-specific T cell clone, inhibited the response of the clone to the wild-type peptide by TCR antagonism. Analogs 25R/A and 28E/Q were also able to inhibit the differentiation of Th precursors specific for peptide DR1/22-35. Two other peptides, 26L/I and 27L/V, acted as powerful TCR agonists, inducing a higher proliferative response of the DR1-specific T cell clone, compared with the wild-type peptide. At high concentrations, these peptides induced hyporesponsiveness of TCC-ZL36 in a manner similar to the wild-type peptide. Taken together, the results of this study indicate that specific suppression of indirect allorecognition can be achieved by using structural variants of the dominant allodeterminant.

Amino Acids↗
PubMed1997

Differential expression of insulin-dependent diabetes mellitus-associated HLA-DQA1 alleles in vivo.

The strong association of HLA-DQ genes with insulin-dependent diabetes mellitus (IDDM) susceptibility is persuasive evidence of their central role in the etiology of this autoimmune disease. Among other possibilities, it has been proposed that an unbalanced expression of IDDM-associated DQA, and/or DQB alleles may lead to alterations in the composition of alpha beta heterodimers and preferential expression of a particular heterodimer on the antigen-presenting cell surface, leading to self-recognition. In this report, we demonstrate the differential expression of DQA1 alleles in vivo, in particular of the two diabetogenic alleles DQA1*0301 and DQA1*0501. Family studies suggest that unequal HLA-DQA1 allele expression in heterozygous individuals is not associated in cis with the HLA-DQA1 gene, but may be affected by trans-acting determinant(s). We also discuss the segregation of this phenotype in IDDM-affected members. Furthermore, we examined historical samples of PBL from an IDDM-affected individual and an HLA-identical unaffected sibling acting in a kidney transplant program as donor and recipient, respectively. This analysis allowed us to establish that unbalanced expression of DQA1*0301 and DQA1*0501 can be induced by microenvironmental conditions. Inducible differential expression of HLA-DQA1 alleles may account for the discordance in the outcome of autoimmune disease in monozygotic twins and HLA-identical siblings.

Alleles↗
PubMed1997

Anti-HLA antibody ligation to HLA class I molecules expressed by endothelial cells stimulates tyrosine phosphorylation, inositol phosphate generation, and proliferation.

The major threat to long-term survival of solid organ allografts is chronic rejection. Progressive narrowing and ultimate luminal occlusion of the arteries and arterioles of the transplanted organ are the hallmarks of the disease. The mechanism of chronic rejection is poorly understood, but it is suspected that the associated vascular changes are a result of anti-HLA antibody-mediated injury to the endothelium. We have postulated that anti-HLA antibodies initiate chronic rejection by binding to class I molecules on the endothelium and transducing signals that result in endothelial cell activation and proliferation. Our data demonstrate that anti-HLA class I antibodies transduce signals in endothelial cells stimulating increased tyrosine phosphorylation of intracellular proteins. Antibody binding to class I antigens also leads to the generation of inositol phosphate and endothelial cell proliferation. These results indicate that anti-HLA antibodies can deliver functionally important signals to endothelial cells, a finding that may be fundamental to an understanding of the mechanisms of chronic rejection.

Antibodies, Monoclonal↗
PubMed1997

MHC class I antigen processing pathways.

The multistep process that culminates in major histocompatibility complex (MHC) class I presentation of foreign of self-peptides begins in the last phases of protein catabolism. Although the individual roles of many key molecules-such as proteasomes, the transporter associated with antigen processing, and various endoplasmic reticulum chaperones-have recently been elucidated, there still remain many questions regarding processing of proteins into MHC class I bound peptides. This review summarizes the recent developments in antigen processing for MHC class I molecules, with a focus on how proteins are believed to be sampled and selected for degradation.

Antigen Presentation↗
PubMed1997

Corticosteroid therapy in Riedel's thyroiditis.

We report a case of Riedel's thyroiditis presenting with a systemic illness, life-threatening stridor and a stony hard goitre. Diagnosis was confirmed by open thyroid biopsy. Treatment with corticosteroid resulted in a dramatic improvement. A possible autoimmune mechanism in the pathogenesis of Riedel's thyroiditis is discussed.

Autoimmune Diseases↗
PubMed1997

G protein and thyrotropin receptor mutations in thyroid neoplasia.

The cAMP pathway plays a central role in thyroid follicular cell growth and function. Mutations of the TSH receptor (TSHR) or G proteins (gsp) that activate adenylyl cyclase have been identified in autonomously functioning thyroid nodules. Gsp mutations have been identified also in other forms of thyroid neoplasia, but their reported prevalence has been extremely variable. We have studied the prevalence of gsp mutations and activating mutations of Gi2 alpha (gip) in a series of 66 benign and 34 malignant thyroid tumors. Thirty-six tumors were from Boston and 64 from the UK. In addition, we examined the 64 UK tumors for mutations of the TSHR gene. DNA extracted from fresh-frozen or paraffin-embedded tissue was amplified by PCR and examined for mutations using oligonucleotide-specific hybridization and single-strand conformation polymorphism analysis. No G protein gene mutations were identified in the Boston tumors. One gsp mutation, R201C, in a Hürthle cell adenoma and 1 gip mutation, R179C, in a follicular adenoma were demonstrated in tumors from the UK. Oligonucleotide-specific hybridization and single-strand conformation polymorphism analysis of the UK tumors did not demonstrate any mutations of the TSHR gene. Eleven normal thyroid tissue samples were wild-type for Gs alpha, Gi2 alpha, and the TSHR gene.

Amino Acid Sequence↗
PubMed1997

Metastatic prolactinoma: effect of octreotide, cabergoline, carboplatin and etoposide; immunocytochemical analysis of proto-oncogene expression.

A 49-yr-old woman presented with an extensive prolactinoma (serum PRL > 10,000 mU/L, normal range < 450 mU/L). Over a 5-yr period following transsphenoidal surgery and pituitary irradiation, she became increasingly resistant to high doses of bromocriptine and underwent transfrontal surgery followed by stereotactic radiotherapy. In spite of these treatments, serum prolactin estimations rose progressively to > 100,000 mU/L. Magnetic resonance imaging scanning demonstrated a massive cystic tumor invading the temporal lobes, extending into the cervical and thoracic spine, with metastases to cervical lymph nodes. High-dose cabergoline administration resulted in a 30% decrease in serum PRL. Octreotide was administered as a continuous sc infusion with a profound analgesic effect on facial pain but with no effect on tumor progression. She was treated with a course of chemotherapy consisting of carboplatin and etoposide without any noticeable effect. The patient died 6 months following chemotherapy. Immunocytochemical analysis demonstrated positive nuclear staining for WAF-1, Rb protein, c-myc, and p53 both in the original and metastatic tumors. The metastases but not the primary tumor stained for c-jun. Metastatic prolactinoma remains a therapeutic challenge. It is associated with a variable proto-oncogene expression, which may be coincidental or causal. Cabergoline had no advantage over bromocriptine. Octreotide relieved facial pain but did not alter tumor progression. An effective therapy for metastatic prolactinoma remains to be identified.

Antineoplastic Agents, Hormonal↗
PubMed1996

Predominant HLA-class II bound self-peptides of a hematopoietic progenitor cell line are derived from intracellular proteins.

Human myeloid progenitor cells temporarily express HLA class II molecules during the differentiation pathway to granulocytes and macrophages. The significance of major histocompatibility complex (MHC) class II molecules at this stage of development is unknown. As a first stop of inquiry into their function, we have characterized the profile of major self-peptides bound to the HLA-DR molecules expressed by KG-1 cells, a line that shares many of the phenotypic characteristics of colony-forming unit-granulocyte-macrophage progenitors. Searches of protein data bases showed that all matching peptides bound to the HLA-DR molecules of KG-1 cells corresponded to intracellular, rather than exogenous or transmembrane, precursor proteins. Because the absence of a conventional self-peptide repertoire could be related to altered trafficking of class II molecules, the biosynthesis of HLA-DR and the invariant chain proteins was determined. The MHC class II associated invariant chain protein is synthesized normally in KG-1 cells, but processed fragments of invariant chain, class II-associated invariant chain peptides (CLIPs), occupy the antigen-binding groove of KG-1 class II molecules at a much lower frequency compared with that of mature antigen-presenting cells. Low CLIP occupancy of HLA-DR is a characteristic shared by KG-1 cells, normal CD34+ progenitor cells, and HLA-DR+ breast carcinoma cells. The unusual profile of MHC class II bound peptides and the low level of CLIP bound to HLA-DR suggest that the antigen-processing pathway of KG-1 is different from that characterized in professional antigen-presenting cells and that exogenous antigen-processing may be a developmentally acquired characteristic in the myeloid lineage.

Amino Acid Sequence↗
PubMed1996

Monitoring of soluble HLA alloantigens and anti-HLA antibodies identifies heart allograft recipients at risk of transplant-associated coronary artery disease.

The development of accelerated transplant-related coronary artery disease (T-CAD) is the major obstacle to long-term survival of cardiac allografts. We have investigated the role of various demographic and immunologic parameters as prognostic indicators of T-CAD in a population of 274 heart allograft recipients. Our data demonstrate that patients who experience more than 1 episode of acute rejection per year and/or develop antidonor HLA antibodies are at increased risk of developing T-CAD. Using HLA-A2 as a marker for the release of soluble HLA antigens from the donor, we established that recipients displaying circulating donor alloantigens for more than 26 weeks following transplantation are at increased risk of developing T-CAD (P=0.008). This association suggests that the release of alloantigens from the allograft is indicative of chronic injury and/or that it stimulates chronic rejection via the indirect allorecognition pathway. Our findings indicate that patients at risk of developing T-CAD can be identified by monitoring the release of donor alloantigens and production of antidonor HLA antibodies following transplantation.

Adolescent↗