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Biomedical subjects

P Sinnott

Publications and source records attributed to P Sinnott.

17 recordsLinked to original sources
PubMed2005

An unusual form of autoimmune hepatitis in young Somalian men.

BACKGROUND: Significant diversity in disease severity has been identified for autoimmune disorders among different ethnic groups. Current knowledge of both the natural history and management of autoimmune hepatitis (AIH) has been derived from European or Japanese patients, and there is limited information about the disease in patients from other ethnic groups. AIMS: To assess the clinical, histological and immunological features of AIH in patients from Somalia and to determine their response to therapy. METHODS: Retrospective review of a cohort of young Somalian men with atypical AIH compared with a control group of European patients. RESULTS: The six Somalian men were younger at presentation (median age 37 (range 24-59) years) than the seven female and three male European controls (55 (34-54) years, P = 0.06). The Somalians had slightly more severe disease at presentation-median modified Ishak stage of 2.5 compared with 2 in Europeans (P = 0.61) and four (66%) had features of cholestasis compared with only one (10%) European patient (P = 0.04). Therapy with prednisolone and azathioprine was completely effective for eight of 10 Europeans but only one of seven Somalians (P = 0.04). Analysis of human leucocyte antigen types revealed differences between the Somalian and European patients, although these differences did not reach statistical significance. CONCLUSIONS: Somalian men with AIH present with cholestatic features and respond poorly to standard immunosuppressive regimes.

Adult↗
PubMed2004

Presence of HLA antibodies in single-donor-derived fresh frozen plasma compared with pooled, solvent detergent-treated plasma (Octaplas).

Adverse reactions to plasma transfusion are well documented. One of the most serious hazards of transfusion, transfusion-related acute lung injury (TRALI), has nearly as high an incidence of mortality and major morbidity as that reported for the transfusion of incorrect blood components. The specific mechanisms of plasma component-induced adverse reactions remain unclear, but a major contribution may be related to the presence of alloantibodies. In this study, a laboratory analysis was undertaken to determine the presence of HLA antibodies in leucodepleted single-donor-derived fresh frozen plasma (FFP). A comparison was made with a pooled plasma product that has undergone solvent detergent treatment. In total, 58 plasma samples from single-donor units of leucodepleted FFP were tested along with samples from 12 units (three for each ABO blood group) of the pooled plasma (Octaplas); Octapharma Ltd, Coventry, UK), for the presence of HLA antibodies. HLA-specific enzyme-linked immunosorbent assay (ELISA) methods were used to screen for their presence, and complement-dependent cytotoxicity and flow cytometry analyses were used to further define their presence, specificity and class [immunoglobulin G (IgG)/IgM]. In the study groups, HLA antibodies were found to be present in five of the single-donor units (9%) while the pooled plasma samples tested negative.

Antibodies↗
PubMed2001

Familial steroid-responsive nephrotic syndrome and HLA antigens in Bengali children.

We investigated the major histocompatibility complex class I and II loci in three Bengali families with nine children affected with steroid-sensitive nephrotic syndrome (SSNS). A sequence-specific primer (SSP) of DNA typing method was used to detect human leukocyte antigens (HLA). The unaffected siblings and their parents were also studied. Similar to previous reports, there was a high frequency of HLA-DR7.1 (DRB1*0701), DR53 (DR B4*01011-0104) and DQ2 (DQB2*0201-3) antigens in the affected children. However, there was a similar finding in the unaffected children and their parents. HLA-DR7.1 probably was not a causative factor, since it had no predictive value for the occurrence or the severity of SSNS in the affected families. Siblings with identical HLA typing behaved differently (they either had or did not have SSNS). In these families there was no correlation between predisposition to the nephrotic syndrome and the genetic determinant responsible for HLA.

Adolescent↗
PubMed2000

Benign monoclonal expansion of CD8+ lymphocytes in HIV infection.

BACKGROUND: A transient expansion of the CD8+ T cell pool normally occurs in the early phase of HIV infection. Persistent expansion of this pool is observed in two related settings: diffuse infiltrative lymphocytosis syndrome (DILS) and HIV associated CD8+ lymphocytosis syndrome. AIM: To investigate a group of HIV infected patients with CD8+ lymphocytosis syndrome with particular emphasis on whether monoclonality was present. METHODS: A group of 18 patients with HIV-1 infection and persistent circulating CD8+ lymphocytosis was compared with 21 HIV positive controls. Serum samples were tested for antinuclear antibodies, antibodies to extractable nuclear antigens, immunoglobulin levels, paraproteins, human T lymphotropic virus type 1 (HTLV-1), Epstein-Barr virus, and cytomegalovirus serology. Lymphocyte phenotyping and HLA-DR typing was performed, and T cell receptor (TCR) gene rearrangement studies used to identify monoclonal populations of T cells. CD4+ and CD8+ subsets of peripheral blood lymphocytes were purified to determine whether CD8+ populations inhibited HIV replication in autologous CD4+ cells. RESULTS: A subgroup of patients with HIV-1 infection was found to have expanded populations of CD8+ T cell large granular lymphocytes persisting for 6 to 30 months. The consensus immunophenotype was CD4- CD8+ DRhigh CD11a+ CD11c+ CD16- CD28+/- CD56- CD57+, consistent with typical T cell large granular lymphocytes expressing cellular activation markers. Despite the finding of monoclonal TCR gene usage in five of 18 patients, there is evidence that the CD8+ expansions are reactive populations capable of mediating non-cytotoxic inhibition of HIV replication. CONCLUSIONS: A subgroup of HIV positive patients has CD8+ lymphocytosis, but despite the frequent occurrence of monoclonal TCR gene usage there is evidence that this represents an immune response to viral infection rather than a malignant disorder.

Adult↗
PubMed1999

Interleukin-10 (IL10) promoter polymorphisms and multiple sclerosis.

Interleukin-10 (IL10) is an anti-inflammatory cytokine which may modulate disease expression in multiple sclerosis (MS). Three dimorphic polymorphisms within the IL10 promoter region at positions - 1082, -819 and -519 have previously been identified. The - 1082*A allele has been associated with low and the - 1082*G allele with high in vitro IL10 production. We have genotyped 185 Caucasian MS patients and 211 ethnically matched controls for each of these three dimorphisms. MS patients were stratified for severity of disease outcome. No associations were found for any IL10 promoter polymorphisms when the MS cases were compared with controls or with disease outcome with regards to disability. IL10 polymorphism does not appear to be associated with MS or to influence disease progression.

Adult↗
PubMed1998

HPV 16 infection and progression of cervical intra-epithelial neoplasia: analysis of HLA polymorphism and HPV 16 E6 sequence variants.

High-risk human papillomavirus (HPV) infection plays an important role in cervical intra-epithelial neoplasia (CIN), but HPV infection alone is not sufficient for progression to cervical cancer. Several lines of evidence suggest that cellular immune surveillance is important in the control of HPV infection and the development of CIN. The presentation to T cells of target viral peptides in the context of HLA molecules is influenced by the genetic polymorphisms of both HPV and HLA and thereby influences the host immune response and clinical outcome of HPV infection. HLA class I and II polymorphism in susceptibility for HPV 16 infection, development and progression of CIN was analyzed in a group of 118 patients participating in a prospective study of women with initial abnormal cytology. Patients were stratified according to HPV status and course of the disease. HLA-B*44 frequency was increased in the small group of patients with a lesion that showed clinical progression during follow-up [OR = 9.0 (4.6-17.5), p = 0.007]. HLA-DRB1*07 frequency was increased among HPV 16-positive patients compared with patients who were negative for all HPV types [OR = 5.9 (3.0-11.3), p = 0.02]. Our results are consistent with the immunogenetic factors associated with disease progression being different from those associated with susceptibility to HPV 16 infection. Sequencing of the HPV 16 E6 and E7 open reading frames of a subset of these patients (n = 40) showed the frequency of HPV 16 variants to be similar to other studies. However, there was no significant correlation between variant incidence and disease progression or viral persistence and no significant correlation with any HLA allele. It appears that multiple HLA types can influence HPV 16-associated cervical dysplasia but the role of HPV 16 variants in disease progression and susceptibility in relation to HLA polymorphism remains unclear.

Adult↗
PubMed1998

Two novel biallelic polymorphisms in the IL-2 gene.

We have detected two novel single nucleotide polymorphisms in the IL-2 gene, at positions -330 and +166 relative to the transcription start site. The +166 change occurs within the leader peptide and does not affect amino acid sequence. The -330 polymorphism has two common alleles, making it an ideal marker for genetic association studies.

5' Untranslated Regions↗
PubMed1998

IL-10 gene promoter polymorphisms in rheumatoid arthritis.

IL-10 is an anti-inflammatory cytokine which may modulate disease expression in RA. Three dimorphic polymorphisms within the IL-10 gene promoter have recently been identified and appear to influence regulation of its expression. The 1082*A allele has been associated with low and the 1082*G allele with high in vitro IL-10 production. We have analysed 117 unrelated Caucasoid RA patients and 119 ethnically matched controls. No significant differences in the allele frequencies of the three polymorphisms were found between controls and RA patients. In contrast, a significant association between the 1082*A allele and the (-1082*A/-819*C/-592*C) haplotype and IgA RF+ve/IgG RF-ve patients was observed. The association of genotypes encoding low IL-10 production with IgA RF in RA is incompatible with its suggested role in antibody isotype switching. IgA RF has been associated with severe RA and may thus be indirectly correlated with a genotype encoding low IL-10 production.

Alleles↗
PubMed1997

Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus.

OBJECTIVE: To investigate interleukin 10 (IL-10) gene promoter polymorphisms in systemic lupus erythematosus (SLE) and its clinical subsets. METHODS: DNA from 76 Caucasian patients with SLE and 119 controls as genotyped for 3 defined dimorphic polymorphisms (G or A at position -1082, C or T at position -819, C or A at position -592) in the promoter region of the IL-10 gene, using the polymerase chain reaction to amplify the IL-10 gene promoter and oligonucleotide probes specific for each allelic sequence. The frequency of genotypes was compared between patients with SLE and controls, and between clinical subsets of patients with the disease. RESULTS: There was no significant change in the allele frequency of the three IL-10 gene promoter dimorphic polymorphisms in the SLE group compared with controls. However, when subgrouped according to autoantibody status and clinical features, IL-10 -1082*G, -819*C, and -592*C alleles were increased in patients possessing Ro autoantibodies and those with renal involvement. These alleles are in preferential allelic association, namely GCC, ACC, and ATA haplotypes, and the GCC haplotype was increased in these patient subgroups. CONCLUSION: Polymorphisms within the IL-10 gene promoter that are associated with high IL-10 levels may be important in the development of certain clinical features in SLE.

Adolescent↗
PubMed1996

Immunogenetic factors in HPV-associated cervical cancer: influence on disease progression.

No HLA allele or specificity was significantly different in frequency between a group of 150 cervical cancer patients from north-west England and controls (corrected P values). HLA-DRB1*1501/DQB1*0602 was non-significantly increased, particularly among patients with HPV16-positive tumours. HLA-B7-positive patients had a significantly poorer clinical outcome than HLA-B7-negative patients. A significant component of the genotypic effect is down-regulation of HLA-B7 expression by the tumour cells.

Adult↗
PubMed1995

Histocompatibility testing for kidney transplantation: an update.

Histocompatibility testing prior to kidney transplantation is an established necessity. Recipient sensitization to HLA specificities affects the efficacy of the lymphocytotoxic cross-match and influences the achievable HLA mismatch. Within Europe most cadaver donor kidneys are allocated on the basis of minimum histocompatibility mismatch contrasting with the North American system which allows for exchange of kidneys only where there is no detectable donor/recipient mismatch. There is also a contrast between the immunosuppression protocols used in these continents with, in general, more aggressive regimens used in North America. In the 1990s there has been considerable refinement in the techniques available to histocompatibility laboratories for definition of HLA phenotypes and genotypes and some obstacles to successful transplantation have been overcome. We review some of these changes with particular reference to our own experience.

Antibodies↗
PubMed1993

Lack of association of HLA polymorphisms with human papillomavirus-related cervical cancer.

An association of HLA-DQ3 with SCC of the cervix has been reported by researchers in Germany and Norway. This article documents a similar-sized study with patients and controls from northwest England. We report in detail on serologically determined HLA polymorphism in SCC patients with respect to HPV 16 infection, MHC class II expression within the tumor, serologic response to HPV, and other relevant clinical variables. We have also extended our studies to include DNA-based analysis using PCR and SSO probes for HLA-DQ. No significant association of any HLA-A, -B, -C, -DR, or -DQ antigen with SCC patients was found. While a possible explanation of the differences among studies could be a reflection of disease heterogeneity, the several tumor and clinical factors examined do not account for the observed differences from previous reports. Further studies are needed for a greater understanding of the interaction of HPV and HLA type in the development of cervical neoplasia.

Adult↗
PubMed1993

A de novo pathological point mutation at the 21-hydroxylase locus: implications for gene conversion in the human genome.

More than two hundred characterized 21-hydroxylase deficiency alleles appear to result exclusively from sequence exchanges involving the 21-hydroxylase gene (CYP21B) and a closely related pseudogene (CYP21A). Gene conversion-like events have also been reported in many other human gene clusters, but in the absence of a de novo mutation, the alternative explanation of a multiple recombination is possible. We now report a de novo pathological mutation at the 21-hydroxylase locus. DNA sequence analysis suggests that the mutation arose by a microconversion event involving exchange of up to 390 nucleotides between maternal CYP21A and CYP21B genes. This putative de novo gene conversion event appears to be the first characterized in humans.

Adrenal Hyperplasia, Congenital↗
PubMed1993

HLA allele detection using molecular techniques.

There are now many molecular biological techniques available to define HLA class I and class II alleles. Some of these are also applicable to other human polymorphic genes, in particular to those non-HLA genes encoded within the Mhc. The range of techniques available allows laboratories to choose those most suited to their purpose. The routine laboratory supporting solid organ transplants will need to type large numbers of potential recipients over a period of time, probably using PCR-SSOP while donors will be typed singly and rapidly using PCR-SSP with HLA allele compatibility determined by heteroduplex analysis. Laboratories supporting bone marrow transplantation, where time is less pressing, can choose from the whole range of techniques to determine accurately donor recipient Mhc compatibility. For disease studies, techniques defining precise HLA allele sequence polymorphisms are needed and high sample numbers have to be accommodated. When an association is established allele sequencing has to be used. In the near future, the precise role of HLA alleles in transplantation and disease susceptibility is likely to be established unambiguously.

Alleles↗
PubMed1990

Genesis by meiotic unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency.

The HLA-linked human steroid 21-hydroxylase gene CYP21B and its closely homologous pseudogene CYP21A are each normally located centromeric to a fourth component of complement (C4) gene, C4B and C4A, respectively, in an organization suggesting tandem duplication of a ca. 30-kilobase DNA unit containing a CYP21 gene and a C4 gene. Such an organization has been considered to facilitate gene deletion and addition events by unequal crossover between the tandem repeats. We have identified a steroid 21-hydroxylase [steroid, hydrogen-donor:oxygen oxidoreductase (21-hydroxylating), EC 1.14.99.10] deficiency patient who has a maternally inherited disease haplotype that carries a de novo deletion of a ca. 30-kilobase repeat unit including the CYP21B gene and associated C4B gene. This disease haplotype appears to have been generated as a result of meiotic unequal crossover between maternal homologous chromosomes. One of the maternal haplotypes is the frequently occurring HLA-DR3, B8, A1 haplotype that normally carries a deletion of a ca. 30-kilobase unit including the CYP21A gene and C4A gene. Haplotypes of this type may possibly act as premutations, increasing the susceptibility of developing a 21-hydroxylase deficiency mutation by facilitating unequal chromosome pairing.

Adrenal Hyperplasia, Congenital↗