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T J Vyse

Publications and source records attributed to T J Vyse.

31 records · Page 2Linked to original sources
PubMed1996

Effect of genetic background on the contribution of New Zealand black loci to autoimmune lupus nephritis.

Autoimmune diseases such as systemic lupus erythematosus are complex genetic traits with contributions from major histocompatibility complex (MHC) genes and multiple unknown non-MHC genes. Studies of animal models of lupus have provided important insight into the immunopathogenesis of disease, and genetic analyses of these models overcome certain obstacles encountered when studying human patients. Genome-wide scans of different genetic crosses have been used to map several disease-linked loci in New Zealand hybrid mice. Although some consensus exists among studies mapping the New Zealand Black (NZB) and New Zealand White (NZW) loci that contribute to lupus-like disease, considerable variability is also apparent. A variable in these studies is the genetic background of the non-autoimmune strain, which could influence genetic contributions from the affected strain. A direct examination of this question was undertaken in the present study by mapping NZB nephritis-linked loci in backcrosses involving different non-autoimmune backgrounds. In a backcross with MHC-congenic C57BL/6J mice, H2z appeared to be the strongest genetic determinant of severe lupus nephritis, whereas in a backcross with congenic BALB/cJ mice, H2z showed no influence on disease expression. NZB loci on chromosomes 1, 4, 11, and 14 appeared to segregate with disease in the BALB/cJ cross, but only the influence of the chromosome 1 locus spanned both crosses and showed linkage with disease when all mice were considered. Thus, the results indicate that contributions from disease-susceptibility loci, including MHC, may vary markedly depending on the non-autoimmune strain used in a backcross analysis. These studies provide insight into variables that affect genetic heterogeneity and add an important dimension of complexity for linkage analyses of human autoimmune disease.

Aging↗
PubMed1996

Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice.

F1 hybrids of New Zealand black (NZB) and New Zealand white (NZW) mice are a model of human systemic lupus erythematosus. These mice develop a severe immune com-plex-mediated nephritis, in which antinuclear autoantibodies are believed to play the major role. We used a genetic analysis of (NZB x NZW)F1 x NZW backcross mice to provide insight into whether different autoantibodies are subject to separate genetic influences and to determine which autoantibodies are most important in the development of lupus-like nephritis. The results showed one set of loci that coordinately regulated serum levels of IgG antibodies to double-stranded DNA, single-stranded DNA, total histones, and chromatin, which overlapped with loci that were linked to the production of autoantibodies to the viral glycoprotein, gp70. Loci linked with anti-gp70 compared with antinuclear antibodies demonstrated the strongest linkage with renal disease, suggesting that autoantibodies to gp70 are the major pathogenic antibodies in this model of lupus nephritis. Interestingly, a distal chromosome 4 locus, Nba1, was linked with nephritis but not with any of the autoantibodies measured, suggesting that it contributes to renal disease at a checkpoint distal to autoantibody production.

Alleles↗
PubMed1996

Backcross analysis of genes linked to autoantibody production in New Zealand White mice.

F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice are genetically predisposed to develop a lupus-like autoimmune disease characterized by IgG autoantibody production and an immune complex glomerulonephritis. Genes from both parental strains contribute to autoimmunity in the F1 animal. NZW mice produce mostly non-pathogenic autoantibodies to ssDNA and histones as their major autoimmune trait. We studied the genetics of this trait in order to gain insight into the NZW contribution to F1 disease. Genome-wide mapping of (NZW x BALB/c)F1 x NZW backcross mice showed that four NZW non-MHC loci on chromosomes 1, 11, 16, and 19 were linked with IgG autoantibody production. Another NZW locus on chromosome 14 appeared to be selectively linked with IgG anti-histone Abs. In this backcross, contributions from the nonautoimmune BALB/c strain were also apparent. Heterozygosity for the BALB/c MHC (H2d) was linked with IgG autoantibody production. This influence of H2d is therefore similar to that seen in (NZW x NZB)F1 mice, in which heterozygosity for H2d enhances autoantibody production and disease. Surprisingly, two non-MHC BALB/c loci were linked with IgM autoantibody levels, whereas no NZW loci had such an effect. Neither of these two loci have been previously linked with autoimmunity in lupus-prone mice. These data show that autoantibody production in NZW mice is a polygenic trait that is influenced by contributions from MHC and non-MHC genes. The results also support the hypothesis that NZW genes act to class-switch the autoantibody response, an effect that appears to contribute to disease in (NZB x NZW)F1 mice.

Animals↗
PubMed1996

The molecular basis of hereditary complement factor I deficiency.

The molecular basis of hereditary complement factor I deficiency is described in two pedigrees. In one pedigree, there were two factor I-deficient siblings, one of whom was asymptomatic and the other suffered from recurrent pyogenic infections. Their factor I mRNA was analyzed by reverse transcription of fibroblast RNA followed by amplification using the polymerase chain reaction. Both siblings were homozygous for the same transversion (adenine to thymine) at nucleotide 1282 in the cDNA. This mutation causes histidine-400 to be replaced by leucine. The altered histidine is a semi-conserved residue within the serine proteinase family, although no function has been ascribed to it. The proband of the second pedigree studied was found to be a compound heterozygote. One allele had the same mutation as the first family, the second allele had a donor splice site mutation that resulted in the deletion of the mRNA encoded in the fifth exon (a low-density lipoprotein receptor domain) from its transcript.

Alleles↗
PubMed1996

Genetic basis of systemic lupus erythematosus.

Recent studies have emphasized that systemic lupus erythematosus is a complex genetic trait with contributions from the MHC and multiple non-MHC genes. Genome-wide linkage studies in murine models of lupus have mapped the positions of a number of non-MHC loci, but the contributing genes have not yet been identified. Recent studies in human systemic lupus erythematosus have found an association with a particular FCGR2A allele. Although susceptibility genes in lupus are unlikely to involve mutations with severe functional consequences, murine knockout models that develop lupus-like features may provide insight into the pathogenetic mechanisms and contributing genes in the human disease.

Animals↗
PubMed1994

The organization of the human complement factor I gene (IF): a member of the serine protease gene family.

The human complement factor I gene (IF) was cloned from a flow-sorted cosmid library. The gene spans 63 kb and comprises 13 exons. The first exon, which encodes the leader sequence and 5' untranslated region, is separated from the body of the gene by a large intron of 36 kb. Factor I is a mosaic protein, and there is a correlation between the genomic organization and the modular structure of the protein. The second exon encodes a module found only in complement C6 and C7 (FI/C6/C7); the third and fourth exons encode a single CD5 domain; and the fifth and sixth exons each encode a low-density lipoprotein receptor module. Two very small exons, 21 and 36 bp, then separate the first six exons from the last five that encode the serine protease domain of factor I. Within the serine protease gene family factor I has a unique genomic structure, but it bears a much closer resemblance to trypsin than it does to the other complement system serine proteases, factor B, C2, and C1r/C1s.

Base Sequence↗
PubMed1994

Hereditary complement factor I deficiency.

We describe four cases (from three families) of hereditary factor I deficiency, bringing the total number of cases now reported to 23. In one family there are two affected siblings: one has suffered recurrent pyogenic infections; the other is asymptomatic. In the second family, the patient had recurrent pyogenic infections and a self-limiting vasculitic illness; in the third family, the patient suffered recurrent pyogenic and neisserial infections. All four patients had markedly reduced concentrations of C3 in the serum (family 1 propositus: 28%; family 1 asymptomatic sibling: 15%; family 2: 31%; and family 3: 31% normal human serum) which was in the form of C3b. Low IgG2 levels may occur in primary C3 deficiency, and a reduction in IgG2 concentration to 1.14 g/l (normal: 1.30-5.90 g/l) was found in the patient from family 2. Using radioligand binding assays, we demonstrated increased binding of C3b to erythrocytes in a patient with factor I deficiency. This C3b could not be cleaved by autologous serum but could be cleaved by normal serum or purified factor I. We review and compare the published cases of C3, factor H and factor I deficiency.

Adolescent↗
PubMedDate not supplied

The genetics of systemic lupus erythematosus.

BACKGROUND: There is a genetic predisposition to human systemic lupus erythematosus (SLE). The genes that contribute to susceptibility are, for the most part, unknown. The introduction of new gene mapping techniques has opened the way to explore lupus genetics on a genome-wide basis. METHODS: Microsatellites are simple sequence repeats widely distributed throughout eukaryotic genomes. They exhibit length variation. This polymorphism can be exploited to provide a panoply of genome-wide markers. Thereby, loci linked with lupus have been mapped in lupus-prone mouse strains and in recently published studies in multi-case human families. RESULTS: More than 20 non-MHC (major histocompatibility complex) loci have now been linked with murine lupus. Nine non-MHC loci have been corroborated in human SLE. Some of the mouse intervals are syntenic with human loci raising the tantalizing possibility of common susceptibility genes. Although we await the results of formal gene identification, functional studies in back-cross and congenic analyses indicate that, in the mouse at least, disease genes act at multiple levels in disease development. CONCLUSIONS: A large number of genes are involved in the pathogenesis of SLE. The data also suggest that even the MHC contribution is multiple. Having mapped disease loci, geneticists now face the task of closing down on the actual aetiological alleles and demonstrating how they might operate. This undertaking will add significantly to our understanding of disease development.

Animals↗
PubMedDate not supplied

Connective tissue diseases: advances in diagnosis and management.

Connective tissue diseases encompass a group of multisystem inflammatory syndromes whose pathogenesis is thought to be autoimmune. They are all associated with the production of autoantibodies that bind to predominantly intracellular antigens. We will describe recent advances that have led to improved classification and more accurate prognosis.

Autoantibodies↗