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D Faustman

Publications and source records attributed to D Faustman.

At least 19 recordsLinked to original sources
PubMed2001

Bayesian analysis of case control polygenic etiology studies with missing data.

Many genetic studies are based on analysing multiple DNA regions of cases and controls. Usually each is tested separately for association with disease. However, some diseases may require interacting polymorphisms at several regions, and most disease susceptibility is polygenic. In this paper, we develop new methods for determining combinations of polymorphisms that affect the risk of disease. For example, two different genes might produce normal proteins, but these proteins improperly function when they occur together. We consider a Bayesian approach to analyse studies where DNA data from cases and controls have been analysed for polymorphisms at multiple regions and a polygenic etiology is suspected. The method of Gibbs sampling is used to incorporate data from individuals who have not had every region analysed at the DNA sequence or amino acid level. The Gibbs sampling algorithm alternatively generates a sample from the posterior distribution of the sequence of combinations of polymorphisms in cases and controls and then uses this sample to impute the data that are missing. After convergence the algorithm is used to generate a sample from the posterior distribution for the probability of each combination in order to identify groups of polymorphisms that best discriminate cases from controls. We apply the methods to a genetic study of type I diabetes. The protein encoded by the TAP2 gene is important in T cell function, and thus may affect the development of autoimmune diseases such as insulin dependent diabetes mellitus (IDDM). We determine pairs of polymorphisms of genetic fragments in the coding regions of linked HLA genes that may impact the risk of IDDM.

Journal Article↗
PubMed2000

Essential role of human leukocyte antigen-encoded proteasome subunits in NF-kappaB activation and prevention of tumor necrosis factor-alpha-induced apoptosis.

The multisubunit proteasome complex is the principal mediator of nonlysosomal protein degradation. The proteasome subunit varies minimally between cells with the exception of LMP2, LMP7, and LMP10 subunits in rodent and human cells. LMP2 and LMP7 subunits are encoded by the human lymphocyte antigen region, and they optimize proteolytic mediated antigen presentation. The proteasome is also important for the function of transcription factor nuclear factor-kappaB (NF-kappaB). It is required for NF-kappaB subunits p50 and p52 generation and catalyzes degradation of phosphorylated IkappaBalpha. These proteasome-mediated reactions have now been shown to be defective in T2 cells, a human lymphocyte cell line that lacks both LMP2 and LMP7. Although T2 cells contain normal expression of p100 and p105, the abundance of p50 and p52 was greatly reduced. Tumor necrosis factor-alpha (TNF-alpha) induced normal phosphorylation of IkappaBalpha but failed to induce degradation of phosphorylated IkappaBalpha. Both DNA binding assays and luciferase assays revealed that TNF-alpha-induced NF-kappaB activation is defective in T2 cells. Unlike parental cells, T2 cells were susceptible to TNF-alpha-induced apoptosis. These data indicate human leukocyte antigen-linked proteasome subunits are essential for NF-kappaB activation and protection of cells from TNF-alpha-induced apoptosis.

Animals↗
PubMed2000

Defective function of the proteasome in autoimmunity: involvement of impaired NF-kappaB activation.

Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The nonobese patient with diabetes (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse in select lymphocytic and monocytic lineages that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor-alpha (TNF-alpha). The novel role of the proteasome in dysfunction in autoimmunity is presented and documented to be both tissue and developmental stage specific. We propose a role of the proteasome as a step in disease pathogenesis and tissue targeting.

Animals↗
PubMed2000

Identification of premature ovarian failure patients with underlying autoimmunity.

Although known causes of premature ovarian failure (POF) include X chromosome deletions, radiation and chemotherapy, and genetic defects of the gonadotropin hormones or receptors, at least one third to one half of cases remain idiopathic. A significant proportion of patients with apparently idiopathic POF have some evidence for an autoimmune etiology. However, the only gold standard for detecting autoimmune causes of immune ovarian destruction has been invasive ovarian biopsy. Serum antibodies to ovarian and other self-tissue have been described in up to one third of women with POF, but the tests are not well standardized, not well correlated with ovarian histology, and highly variable. Recently, specific defects of expression of cell surface markers on peripheral blood lymphocytes have been shown to identify, in population-based studies, individuals destined to develop autoimmune pancreatic destruction and type I diabetes mellitus, even before any other evidence of autoimmunity. We, therefore, sought to test the ability of cell surface marker expression in women with POF to identify autoimmune defects. Seventeen women with POF, 11 of whom had positive antibody titers to ovary, thyroid, or antinuclear antibody, were studied on at least two occasions and compared in blinded fashion with normal controls and patients with autoimmune type I diabetes mellitus. The most useful marker for identifying autoimmunity was the surface density of conformationally correct HLA class I molecules on macrophages, a structure essential for T cell education. Using this marker, 7 of the 9 patients with autoantibodies and 3 of the 8 patients without autoantibodies were identified as having evidence of a defect in self-antigen presentation similar to that of type I diabetics (chi-square, p = 0.03). Subsequent testing identified antismooth muscle antibodies in 1 of the women with a defect of HLA class I molecules but no previously identified autoimmunity. In addition, there were increased numbers of CD8 T cells in both autoimmune POF and insulin-dependent diabetes mellitus (IDDM) patients. Exclusive to POF patients was a statistically significant increase in CD8 density on T cells. This was most prominent in POF patients with an underlying autoimmune etiology. These data further support a role for autoimmunity in POF patients and suggest that the further development of cell surface markers in combination with other diagnostic tests could result in diagnosis before the development of complete ovarian failure. The possibility for disease-specific therapy to prevent further autoimmune ovarian damage in selected POF patients is also envisioned.

Adult↗
PubMed2000

A role for NF-kappaB and the proteasome in autoimmunity.

Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The non-obese diabetic (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse lymphocytes that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect both prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor kappaB (NF-kappaB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor alpha (TNF-alpha). The proteasome dysfunction is both tissue and developmental stage specific and likely contributes to disease pathogenesis and tissue targeting.

Animals↗
PubMed1999

Novel splicing of the human MHC-encoded peptide transporter confers unique properties.

Presentation of intracellularly derived antigenic peptides to T cells requires their assembly together with MHC class I molecules in the endoplasmic reticulum (ER). Such peptides are delivered to the ER by an MHC-encoded transporter composed of TAP1 and TAP2 protein delivery. Here, the first alternative splicing of Tap2 is described. The human splice variant, termed Tap2iso, lacks exon 11 and original 3' untranslated region and contains a newly identified exon 12 and 3' untranslated region. The full-length Tap2iso cDNA (2496 bp) predicts a protein of 653 amino acids. Tap2iso mRNA was normally coexpressed with Tap2 mRNA in all human lymphocyte cell lines examined. Function of TAP2iso was evaluated at multilevel in TAP1/2iso and TAP1/2 cotransfected T2 cells, a mutant cell line deplete of endogenous Tap gene products. The TAP1-TAP2iso transporter facilitated the maturation of MHC class I molecules in the ER and restored surface expression of class I. Importantly, TAP1-TAP2iso transporters expressed in T2 cells exhibited distinct and opposing influences on peptide selectivities, at times exceeding 30-fold differences in competition experiments and attributable to diversity in the 3'-COOH tail. The common coexpression of an alternative splice product of the Tap2 gene may contribute to broaden immune diversity, a mechanism previously described to occur predominantly at the level of the TCR and MHC class I gene products.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

NOD mice are defective in proteasome production and activation of NF-kappaB.

The nonobese diabetic (NOD) mouse is an animal model of human type I diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) of the genome. We have identified in NOD lymphocytes a specific proteasome defect that results from the lack of the LMP2 subunit. The pronounced proteasome defect results in defective production and activation of the transcription factor NF-kappaB, which plays an important role in immune and inflammatory responses as well as in preventing apoptosis induced by tumor necrosis factor alpha. The defect in proteasome function in NOD mouse splenocytes was evident from impaired NF-kappaB subunit p50 and p52 generation by proteolytic processing and impaired degradation of the NF-kappaB-inhibitory protein IkappaBalpha. An obligatory role of MHC-linked proteasome subunits in transcription factor processing and activation has been established in a spontaneous-disease model and mutant cells similarly lacking the MHC-encoded subunit. These data suggest that NOD proteasome dysfunction is due to a tissue- and developmental-stage-specific defect in expression of the MHC-linked Lmp2 gene, resulting in altered transcription factor NF-kappaB activity, and that this defect contributes to pathogenesis in NOD mice. These observations are consistent with the diverse symptomatology of type I diabetes and demonstrate clear sex-, tissue-, and age-specific differences in the expression of this error which parallel the initiation and disease course of insulin-dependent (type I) diabetes mellitus.

Animals↗
PubMed1998

Antigen processing and autoimmunity. Evaluation of mRNA abundance and function of HLA-linked genes.

Quantitative defects in the density of conformationally correct human lymphocyte antigen (HLA) class I complexes on the surface of lymphocytes are apparent in patients with diverse HLA-linked autoimmune diseases, including Type I diabetes and Sjögren's syndrome. First, HLA class I expression was investigated in individuals with two rare and genetically divergent polyglandular autoimmune diseases. Polyglandular failure patients whose disease showed HLA linkage, but not those whose disease was not HLA linked, exhibited decreased HLA class I expression on the surface of their lymphocytes as well as a reduced abundance of transcripts of the HLA-linked genes Tap1 and Tap2, both of which encode proteins that contribute to HLA class I processing. Second, lymphocytes from patients with insulin-dependent diabetes mellitus (IDDM), Sjögren's syndrome, Graves' disease, and Hashimoto's disease showed varying degrees of decreased abundance of mRNAs that encode Tap1, Tap2, Lmp2, or Lmp7 (the latter two proteins also contribute to HLA class I processing). Third, in twins discordant for IDDM, reduced transcript abundance was preferential to diabetic subjects. Fourth, functional assays of isolated diabetic proteasomes, the peptide cutting complex containing LMP2 and LMP7 proteins, revealed altered peptidase activity. These data suggest that defective transcription of HLA class I-processing genes could contribute to the quantitative defect in cell-surface expression in autoimmune lymphocytes of HLA-controlled disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Evaluation of TAP1 polymorphisms with insulin dependent diabetes mellitus in Finnish diabetic patients. The Childhood Diabetes in Finland (DiMe) Study Group.

Insulin dependent diabetes mellitus (IDDM) is an autoimmune disease with a strong association between disease and the HLA class II region. Because abnormal antigen processing, in part characterized by altered class I processing, has been identified in patients with IDDM, the TAP (transporter associated with antigen processing) genes located in the HLA class II region make attractive candidate genes for IDDM. Five coding region variants of TAP1 were typed in a cohort of well characterized Finnish patients with diabetes (n = 119) and compared to racially marched control subjects (n = 92). We found that although no single TAP1 polymorphism was associated with IDDM, a genotypic combination of Ile/Val at codon 333 with Asp/Asp at codon 637 was found more frequently in subjects with IDDM (9.4%) compared to controls (1.2%; p = 0.025). This could not be accounted for by an association with any particular haplotype defined by class I or class II serology.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Human TAP1 polymorphisms detected by denaturing gradient gel electrophoresis.

Presentation of endogenous peptides by major histocompatibility complex class I (MHC) molecules is controlled, in part, by the Tap1 and Tap2 genes in the MHC class II region that encode a heterodimeric peptide transporter. Polymorphisms of human Tap1 in normal individuals have now been investigated systematically by denaturing gradient gel electrophoresis (DGGE) analysis of fragments of genomic DNA generated by the polymerase chain reaction. Polymorphisms identified by distinctive DGGE band patterns were confirmed by DNA sequencing. In addition to four previously described polymorphisms in the open reading frame, DGGE detected three new polymorphisms: a G-->T substitution in the promoter region, a 10-bp insert in intron 9, and a G-->T substitution 80-bp downstream of the translation termination codon.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

New monoclonal antibody diagnostic reagents for type I diabetes: differential lymphocyte surface antigen expression related to disease.

New cellular-based reagents are needed to diagnose type I diabetes as well as to monitor the outcomes of clinical trials at early time points. Four new monoclonal antibodies (mAbs) have been shown to demonstrate reduced binding to lymphocytes from identical twins with long-term type I diabetes relative to that observed with lymphocytes from their twin partners without diabetes or from control subjects. Biochemical analysis revealed mAb 3G12EG recognized an unidentified 45-kDa protein, whereas mAb 2E8F1 and 5B6E11 did not appear to precipitate specific proteins as detected by SDS-PAGE. Electrophoresis under reducing and nonreducing conditions and peptide mapping revealed that mAb 8F410 recognizes a novel dimeric form of HLA class I molecule. Predictions from crystallography studies suggested previously this class I dimer as the optimal activation of a single CD8 T-cell. In B-cells from both normal and diabetic individuals, the class I dimer was minimally associated with beta2-microglobulin rapidly formed in the endoplasmic reticulum. These new reagents appear to be able to identify new lymphocyte surface phenotypes associated with diabetes expression in both fresh blood samples and Epstein-Barr virus-established cell lines.

Adult↗
PubMed1995

Strategies for circumventing transplant rejection: modification of cells, tissues and organs.

New technologies may permit the therapeutic use of transplanted cells or whole organs to be extended to the treatment of a wider range of diseases and a greater number of individuals. At present, the replacement of failing organs or the treatment of disease by transplantation is restricted by the need for co-administration of toxic immunosuppressive drugs to prevent rejection, and the limited availability of donor organs. Recent advances, however, suggest that genetically engineered or immunologically modified donor organs or cells can eliminate the need for host immunosuppression and can allow organ and cell survival across species. Transplantation could thus become a widespread therapeutic approach in the next century.

Antilymphocyte Serum↗
PubMed1994

Abnormal class I assembly and peptide presentation in the nonobese diabetic mouse.

Presentation of self-antigens by major histocompatibility complex (MHC) class I molecules requires the function of the MHC class II-linked genes Tap-1 and Tap-2. Evidence suggests that interruption of self-peptide presentation results in reduced cell surface expression of MHC class I molecules and the interruption correlates with progression to diabetic autoimmunity in nonobese diabetic (NOD) mice and humans. NOD mice possess a rare Tap-1 allele (Tap-1b); this is associated with reduced Tap-1 mRNA abundance in lymphocytes from diabetes-prone females and decreased conformationally correct class I molecules on the cell surface. In this study, we demonstrate that, similar to lymphoma cell lines with mutations in Tap-1 or Tap-2, the reduced expression of class I molecules on the surface of lymphocytes from diabetes-prone female NOD mice was normalized by incubation at low temperatures or by exposure to class I allele-specific peptides. As would be expected for cells that express surface class I molecules not associated with peptide, female NOD lymphocytes were resistant to lysis by class I-restricted, peptide-specific cytotoxic T lymphocytes. Furthermore, the rate of class I exit from the endoplasmic reticulum of lymphocytes from female NOD mice was delayed as demonstrated by delayed glycosylation. Male NOD mice, which are not prone to diabetes, lacked these functional defects in class I assembly and had near-normal levels of Tap-1 mRNA and exhibited normal density of class I epitopes that were peptide filled. These results are consistent with the possibility that the rare Tap-1b allele is associated with a quantitative defect in Tap-1 expression that influences disease course.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Mechanisms of autoimmunity in type I diabetes.

The work presented in this review suggests that in human and murine type I diabetes, defective MHC class I expression on APC is linked to autoimmunity. The defect in self-antigen presentation is present on prediabetic and diabetic APC, and this presumably delivers abnormal or lack of signals to T cells to allow self tolerance. Since most autoimmune diseases have strong genetic linkage to MHC class II region, our recent results additionally demonstrating low MHC class I expression on lymphoid cells in a diversity of autoimmune diseases (hypothyroidism, rheumatoid arthritis, lupus, etc.) suggest that this pathway of abnormal class I presentation of self epitopes may be important for tolerance to many tissue-specific antigens (40). Certainly, the unanswered genetic questions will address the role of the specific genes controlling self-antigen presentation through MHC class I followed by T-cell education to self.

Animals↗
PubMed1993

Use of donor beta 2-microglobulin-deficient transgenic mouse liver cells for isografts, allografts, and xenografts.

Donor graft major histocompatibility complex class I antigens are targets for both allogeneic and xenogeneic rejection. Mice homozygous for beta 2-microglobulin gene disruption express reduced amounts of surface MHC class I antigens. Liver cells from such mutant mice were transplanted into isogeneic, allogeneic, and xenogeneic recipients to evaluate the potential of these animals as transplant donors. The survival of allografts of transgenic 129 mouse liver cells in 15 immunocompetent and histoincompatible mouse recipients (BALB/c, D1.C) was only slightly improved 30 days after transplantation relative to normal 129 mouse allografts. These results could be attributable: (1) to host natural killer cell-mediated lysis of donor MHC class I antigen-deficient cells; (2) to donor liver cell MHC class I determinants that are reduced but not eliminated serving as rejection targets; (3) to the plentiful host supply of serum beta 2-microglobulin reconstituting the graft and restoring donor MHC class I. Culture studies confirmed the ability of exogenous human and bovine beta 2-microglobulin to restore rapidly MHC class I antigen expression on transgenic cells. Because cell surface exchange of beta 2-microglobulin is less efficient between species with divergent beta 2-microglobulin sequences, the survival of transgenic 129 mouse liver cells in guinea pig (60% beta 2-microglobulin identity) and Xenopus (34% beta 2-microglobulin identity) hosts was investigated. Significant prolongation of MHC class I antigen-deficient liver cell xenografts was apparently only in Xenopus hosts. Furthermore, transplants of transgenic 129 mouse liver cells into isogeneic normal 129 mouse recipients showed evidence of rejection in seven of nine recipients, suggesting that transgenic donor cells also may be susceptible to lysis by host natural killer cells.

Animals↗