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Biomedical subjects

W Ollier

Publications and source records attributed to W Ollier.

At least 55 records · Page 3Linked to original sources
PubMed1994

HLA associations with inclusion body myositis.

Inclusion body myositis (IBM) is defined clinically by a characteristic pattern of progressive proximal and distal limb muscle weakness and resistance to steroid therapy, and histologically by the presence of distinctive rimmed vacuoles and filamentous inclusions as well as a mononuclear infiltrate in which CD8+ T cells are predominant. Muscle damage is believed to be mediated by autoimmune mechanisms, but very little information is available on the immunogenic features of IBM. MHC class I and DR antigens were typed on 13 caucasoid patients with IBM using standard serological techniques or by allele-specific oligonucleotide typing. Complement components C4 and properdin factor B (Bf) were typed by immunofixation after electrophoresis. Restriction fragment length polymorphisms (RFLP) in the class III region were analysed using cDNA probes for C4 and 21-hydroxylase (CYP21) after Taq 1 digestion. IBM was associated with DR3 (92%), DR52 (100%) and HLA B8 (75%). The phenotype data were examined for likely haplotypes by considering together the alleles at the class I, DR and complement loci along with the C4 and CYP21 RFLP. Ten of the DR3+ subjects had a 6.4-kb C4-hybridizing fragment characteristic of a deletion of C4A and CYP21-A. These patients probably carried all, or at least the class II and III regions, of the extended haplotype marked by B8/C4A*Q0/C4B1/BfS/DR3/DR52, which has been associated with several autoimmune diseases and is present in 11% of the healthy caucasoid population. Of the remaining subjects, two had evidence of the extended haplotype marked by B18/C4A3/C4BW*0/BfF1/DR3, which is present in less than 5% of the healthy population and has been associated with insulin-dependent diabetes mellitus. These data provide support for an autoimmune etiology for, and genetic predisposition to, IBM.

Adult↗
PubMed1994

Increased frequency of TAP2B in early onset pauciarticular juvenile chronic arthritis.

OBJECTIVES: To determine whether polymorphisms of the TAP genes, which lie within the major histocompatibility complex (MHC), are associated with juvenile chronic arthritis (JCA). METHODS: Eighty five JCA patients and 166 white controls were typed for the TAP gene alleles using ARMS-PCR. The same populations were analysed for DRB1 and DPB1 alleles using PCR-SSO typing. RESULTS: TAP2B was increased in early onset pauciarticular JCA (EOPA-JCA) compared with controls (62% v 44% Odds ratio (OR) 2.1, 95% CI 0.9-4.7). After allowing for the known linkage disequilibrium between TAP2B and DR1 the association of TAP2B and EOPA-JCA was maintained (OR 3.5, 95% CI 1.3-9.7). HLA-DRB1*04 and TAP2D were found to be in linkage disequilibrium in both the control (delta 0.018 p < 0.05) and JCA patient groups (delta 0.021 p < 0.05). No linkage disequilibrium was found between the TAP and DPB1 alleles. CONCLUSIONS: The association between TAP2B and EOPA-JCA is a further indication of the heterogeneity which exists in this clinically defined subgroup of patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

X chromosome inactivation patterns correlate with fetal-placental anatomy in monozygotic twin pairs: implications for immune relatedness and concordance for autoimmunity.

BACKGROUND: Monozygotic (MZ) twinning is a poorly understood phenomenon that may result in subtle biologic differences between twins, despite their identical inheritance. These differences may in part account for discordant expression of disease in MZ twin pairs. Due to their stochastic nature, differences in X chromosome inactivation patterns are one source of such variation in female MZ twins. MATERIALS AND METHODS: We investigated X chromosome inactivation patterns in the blood of 41 MZ twin pairs based on methylation of the androgen receptor gene using a Hpa II-PCR assay. Twenty-six female MZ twin pairs with autoimmune disease (rheumatoid arthritis or multiple sclerosis) were studied. In addition, we studied 15 newborn female MZ twin pairs who were characterized at birth with respect to the anatomy of chorionic membranes (dichorionic versus monochorionic). RESULTS: We found a strong correlation between dichorionic fetal anatomy and differences in X chromosome inactivation patterns between members of an MZ twin pair. In contrast, all monochorionic twin pairs had closely correlated patterns of X chromosome inactivation. X chromosome inactivation patterns did not distinguish between MZ twin pairs who were concordant or discordant for autoimmune disease. CONCLUSIONS: The highly similar patterns of X chromosome inactivation among monochorionic twin pairs may result from their shared placental blood supply during intrauterine life. Alternatively, these patterns may indicate that X chromosome inactivation occurs before the twinning event in this anatomic subgroup of MZ twins. The data further suggest that these factors do not make a major contribution to the high discordance rates for autoimmune disease in MZ twin pairs.

Autoimmune Diseases↗
PubMed1993

A shared HLA-DRB1 sequence confers RA susceptibility in Greeks.

Previous serological studies of Greek rheumatoid arthritis (RA) patients have failed to demonstrate an association with DR4. Using sequence specific oligonucleotide typing we have identified the DRB1 alleles in panels of Greek RA patients and controls. When patient and control HLA-DRB1 frequencies were compared, significantly higher frequencies of DRB1*0101 (23.3% vs. 7.0%, odds ratio [OR] 4.0, 95% confidence intervals [CI] 1.4-12.0) and DRB1*1001 (20.9% vs. 5.8%, OR 4.3, 95% CI 1.3-13.7) were found in RA patients compared with controls. No association of DRB1*04 with RA was observed (20.9% vs. 14.0% in controls) confirming earlier reports. However DRB1*04 subtyping demonstrated a small but significant increase of DRB1*0405 in patients (14.0% vs. 3.5%, OR 4.5, 95% CI 1.1-18.9). When the frequency of individuals carrying the shared RA susceptibility epitope was compared between patients and controls it was found to be significantly higher in RA patients (60.5% vs. 22.1%, OR 5.4, 95% CI 2.4-12.0). We conclude that the shared epitope is significantly associated with RA in this population, but that it is predominantly accounted for by DRB1*0101 and DRB1*1001. Previous studies of UK RA patients have demonstrated a negative association of DR2 with disease and articular erosions. HLA-DR2 variants, DRB1*1501 and *1502 are not at reduced frequency in Greek RA patients (DRB1*1501, 14.0% in patients vs. 7.0% in controls; DRB1*1502, 7.0% in patients vs. 7.0% in controls). Genes conferring RA resistance may be in linkage disequilibrium with DR2 in UK patients. This does not appear to be the case in Greek RA patients. No association was seen between RA and HLA-DPB1 type.

Alleles↗
PubMed1993

Absence of an association between HLA-DRB1*04 and rheumatoid arthritis in newly diagnosed cases from the community.

OBJECTIVES: To determine HLA-DR4 and DR1 allele frequencies in a series of patients with newly diagnosed early inflammatory arthritis. METHODS: HLA-DR1 and DR4 frequencies were determined by oligonucleotide typing of 208 patients classified as having either rheumatoid arthritis (RA) or undifferentiated inflammatory polyarthritis. RESULTS: The frequency of occurrence of DR4 in these patients with RA did not differ significantly from that in controls in the United Kingdom (42 v 37%). HLA-DR1 was increased in the group with inflammatory polyarthritis (25 v 18%). CONCLUSIONS: The frequency of DR4 is not increased in newly diagnosed community based patients with RA. This supports the hypothesis that DR4 is less important as a marker for susceptibility to RA than it is for disease persistence or severity.

Arthritis, Rheumatoid↗
PubMed1993

Variations in serum sCD23 in conditions with either enhanced humoral or cell-mediated immunity.

Soluble CD23 (sCD23) is increased by interleukin-4 (IL-4) and decreased by interferon-gamma (IFN-gamma). On the basis of cytokine profiles T-helper (Th) cells may be functionally divided into IL-2- and IFN-gamma-secreting Th1 cells, which are involved in cell-mediated immunity (CMI), and IL-4- and IL-5-producing Th2 cells, which are involved in humoral immunity. Compared with sex-matched controls (median 8.5) we found significantly elevated levels of serum sCD23 in patients with rheumatoid arthritis (median 22.7, P < 0.0002), with the highest levels detected in patients fulfilling an increasing number of the American Association revised criteria for rheumatoid arthritis. Soluble CD23 levels were also significantly raised in autoimmune thyroiditis (median 11.7, P < 0.02) and myasthenia gravis (median 10.4, P < 0.05). In contrast patients with either coeliac (median 6.5) or Crohn's disease (median 5.8) had reduced levels of sCD23 compared to appropriate controls (median 11.8), in both cases significant at P < 0.01. Variations in sCD23 may, therefore, reflect enhanced Th1 activity in the two later conditions in contrast to heightened Th2 activity within the three classical autoimmune conditions.

Antibody Formation↗
PubMed1993

Absence of rheumatoid arthritis in a rural Nigerian population.

A 2-stage population screening survey of 2,000 inhabitants of 2 rural townships in southern Nigeria was undertaken. No case of rheumatoid arthritis (RA) was discovered in those responding, although 3 cases of inflammatory polyarthritis were found. One of these individuals satisfied the modification of the American College of Rheumatology classification tree criteria that allows for missing radiographic data. Simultaneous monitoring, during a 4-month period, of the local health clinic serving the townships also failed to reveal a case of RA. Three (5.5%) of 55 individuals tested were positive for rheumatoid factor, a rate lower than in previous surveys of rural West African populations. Further immunogenetic investigation of that subsample from this population, using HLA oligonucleotide typing, suggested that HLA-DR4 was rare (1/55). Further, although HLA-DR1 was present in 7 (13%), 6 had the DRB1*0102 variant seen in black populations and not thought to be associated with RA. Our study confirmed the findings of others that rural African groups have extremely low rates of RA. In addition HLA genes containing the RA associated "shared epitope" are also relatively infrequent and might explain this reduction in RA prevalence.

Adolescent↗
PubMed1992

Effects of C4 null alleles and homoduplications on quantitative expression of C4A and C4B.

The availability of MoAbs now allows the accurate quantification of the individual C4 isotypes, C4A and C4B. Using a sensitive two-site immunoradiometric technique to measure serum levels of C4A and C4B, we studied the relationship between genotype and phenotype and physiological factors affecting C4 expression in 129 fully genotyped healthy subjects. Our results confirm that there is extensive phenotypic overlap between genotypic groups and it was not possible to determine the presence of single null alleles from total serum C4. Of the factors which may influence C4 expression, we found that age contributes a very small influence but that gender has no effect and there was no evidence for the presence of feedback of null alleles on the expression of remaining genes. Potential problems in quantifying C4 arising from the complex relationship between isotypic identity and serotypic recognition were highlighted by the finding of reversed antigenic expression of a C4B*5 molecule which was recognized as C4A by the anti-Rg:1 monoclonal used in these studies. We also confirmed that the extended MHC haplotype associated with Felty's syndrome, HLA-B44, C4A*3, C4BQ*O, HLA-DR4, encodes an expressed, duplicated, C4A gene.

Adult↗
PubMed1992

Population genetics of rheumatoid arthritis.

A major component of genetic susceptibility to rheumatoid arthritis (RA) appears to be explained by inheritance of HLA-DRB1 alleles, which have a conserved sequence of amino acids in the third hyper-variable region of the molecule. This "shared epitope" is found on various DR4, DR1, and DR6 variants, as well as on DR10. The evidence for this "shared epitope" in RA is examined at the population level, including how it fits in with the available epidemiologic data and RA disease severity.

Alleles↗
PubMed1991

Immunogenetic heterogeneity in rheumatoid disease as illustrated by different MHC associations (DQ, Dw and C4) in articular and extra-articular subsets.

Genetic variants at DRB1 (Dw subtypes), DQB, and C4 loci were compared in rheumatoid disease subjects with or without the extra-articular feature of Felty's syndrome or major vasculitis. DR4 positive subjects with rheumatoid arthritis alone showed no preferential associations with DQB or Dw variants or with C4 null alleles. Felty's subjects showed associations with the DQB encoded DQw7 allele and with the C4B null allele but no preferential associations with any Dw subtype of DR4. By contrast DR4 +ve rheumatoid-vasculitic subjects showed associations with the Dw14 as well as with DQw7 and the C4A null allele. These different MHC associations in different clinical disease subsets show that rheumatoid disease is immunogenetically heterogeneous and suggest that MHC genes outside the DRB1 locus may also influence susceptibility or modify expression of the rheumatoid disease process.

Alleles↗
PubMed1991

Ig CH and D14S1 variants in rheumatoid arthritis--linkage and association studies.

We have looked for an effect of 14th chromosomal genes linked to immunoglobulin heavy chain (IgCH) or D14S1 regions on susceptibility to rheumatoid arthritis (RA) by both linkage (sibling pair analysis) and association studies. There was no overall linkage between RA and either IgCH or D14S1. However, Gm haplotype similarity in affected siblings appeared greater in either DR4-positive as compared to DR4-negative sibships or in sibships without clinical or serological evidence of autoimmune thyroid disease when compared to sibships with such evidence. In association studies there were no associations at the D14S1 locus. Within the Ig CH region there were no overall associations. However, within the RA population G1m (z) and G3m (g) both appeared less frequent in DR4-negative RA versus both DR4-positive RA and versus control groups. Analysis of DNA variants at Ig CH loci showed differences at the gamma 4 locus with a 9.0 kb fragment appearing less frequently in DR4-positive RA versus DR4-negative RA and control groups. The results suggest a weak or HLA-DR dependent effect of genes linked to the Ig CH region on susceptibility to RA.

Arthritis, Rheumatoid↗
PubMed1990

Heterogeneity of HLA-DR4 in Greeks including a unique DR4-DQw2 association.

It has been shown that Greek RA patients do not show an increased frequency of HLA-DR4 compared with Greek controls. As only the Dw4 and Dw14 subtypes of DR4 are implicated in RA, we have characterised DR4-positive Greek RA patients and controls using serology, MLC typing and RFLP analysis to see whether the distribution of DR4 subtypes or other HLA antigens associated with DR4 could account for these findings. In the 10 patients and 12 controls studied, Dw10 was common, being present in almost half the controls. Dw4 was not detected in the controls, but was present in three of the RA patients, indicating that there may be some relationship between Dw4 and RA in this population; Dw13 and Dw14 were also found, Dw15 was not detected. Eight of the subjects did not type as any of the HLA-D antigens mentioned. Three controls had unusual DR4-DQ associations, two having DR4-DQw2 and one possessing DR4-DQw4. Analysis of the TaqI DRB RFLP of the subjects showed that one control did not have the 6.1 kb band characteristic of DR4s. All these results indicate that DR4 is a heterogeneous antigen in this population and that several as yet undescribed variants of DR4 may be present.

Arthritis, Rheumatoid↗
PubMed1990

Association of DR4 related RFLP bands and RA in Greeks.

Using the Taq1 restriction enzyme and DR beta, DQ alpha probes, the DNAs of Greek RA patients and controls were characterised for RFLP's associated with DR4. Three DR beta bands, 14.8kb, 6.1kb and 5.4kb were observed at significantly higher frequency in the patients compared with controls. By using a DQ alpha probe, the 2.6kb band (associated with DR1, DRw10, DRBR and DRw14 (Dw9)) was at a significantly raised frequency in the patients. The DQ alpha 5.3kb band associated with DR4, DR7 and DR9 was also raised in the RA patients although this increase did not reach statistical significance. In view of the previously documented lack of association between DR4 (and other DR antigens) and RA in Greeks, the results suggest that some degree of HLA class II association exists with RA in this population at the DNA level which may not be overtly reflected serologically.

Adult↗
PubMed1989

Analysis of HLA antigens on germ cells in human semen.

Nucleated cells other than sperm (NCOS) were isolated from human semen by centrifugation on a Ficoll density gradient. Using tissue-specific monoclonal antibodies (mAb) greater than 99% of the NCOS were found to be sperm cell precursors (SpP). These cells were tested for the expression of class I and II (DR, DP and DQ) HLA antigens by using specific mAb. The anti-HLA class I and II and anti-beta 2-microglobulin mAb reacted with less than 1% of the NCOS. This was demonstrated by indirect immunofluorescence microscopy and fluorescence-activated cell sorter analysis. These results were similar to those obtained from testing germ cells in frozen sections of normal adult testis using the same panel of mAb. In mixed lymphocyte-NCOS cultures, the SpP failed to stimulate allogeneic lymphocytes even when different concentrations of cells were used. These results indicate little or no expression of HLA class I and II including the HLA-D (T cell-defined) determinant on the SpP, a phenomenon which could be of biological importance.

Antibodies, Monoclonal↗
PubMed1989

Free and serum testosterone levels in 276 males: a comparative study of rheumatoid arthritis, ankylosing spondylitis and healthy controls.

A cross-sectional study of testosterone levels in 276 males was undertaken. Of these 87 were RA patients, 48 males with AS and 141 were healthy controls. Free and serum testosterone levels were significantly lower in the RA males than in either the AS group or the healthy controls (p less than 0.001). This difference was unaffected by age. No differences were seen in testosterone levels between DR1 or DR4 RA patients compared to those without these antigens. No evidence of hyperandrogenicity was seen in the AS group. The finding that males with RA have lower androgen levels than both normal controls and a disease group with inflammatory spondarthritis supports the hypothesis that male sex hormones may be a protective factor against the development of RA.

Adult↗
PubMed1989

HLA class III haplotypes in multicase rheumatoid arthritis families.

The class III complement proteins (C2, BF, C4A, and C4B) were studied in 57 multicase rheumatoid arthritis (RA) families. When the gene frequencies for RA probands were compared to a normal control panel (162 haplotypes), a significantly higher frequency of the rare variant C4B*3 was observed (p less than 0.05). No significant differences were seen for the other C2, BF, C4A, or C4B alleles. The most common haplotype found in the probands was HLA-Cw5,B44,C2*C,BF*S,C4A*3,C4B*3,DR4, occurring with a frequency of 0.088. Haplotypes containing HLA-DR4 and Bw62 were found to carry either C4A*3,C4B*3; C4A*3,C4B*1; or C4A*4,C4B*2. When only haplotypes containing DR4 were compared between probands and controls, the frequency of the C4B*3-bearing haplotype remained higher in the probands. It is concluded that Bw62,C4A*3,C4B*3DR4 is a haplotype which is especially associated with RA. The low frequency in the RA population of this haplotype indicates that C4B*3 has a minor role in overall RA susceptibility.

Alleles↗
PubMed1989

Co-segregation of HLA and rheumatoid arthritis in multicase families.

Inheritance of parental HLA haplotypes was examined in the offspring of 95 multicase rheumatoid arthritis (RA) families. Overall, in these families there was no evidence of preferential transmission of one parental haplotype, although this might have been expected given the loading of these families with RA cases. However, there was a difference in inheritance when the affected and non-affected offspring were compared. A co-segregation analysis showed that the inheritance of parental HLA haplotypes was different between the affected and the unaffected offspring. Unlike a previous report, no difference was demonstrated in this study between the offspring of affected and non-affected parents. Similarly, the affected offspring of HLA DR4 heterozygote parents were more likely to inherit HLA DR4 than the non-affected offspring. It is concluded first that linkage studies of RA using the affected sib-pair method are not invalidated, which would have been the case in the presence of preferential transmission of HLA to all offspring. Secondly, HLA and specifically HLA-DR4 does co-segregate with RA, and, finally, parental RA status, independent of DR4, has little influence in explaining the genetic susceptibility to RA.

Arthritis, Rheumatoid↗