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Biomedical subjects

P J Zilko

Publications and source records attributed to P J Zilko.

At least 19 recordsLinked to original sources
PubMed1995

Apolipoprotein E epsilon 4 in inclusion body myositis.

The genetic predisposition to inclusion body myositis (IBM) is probably multifactorial. The deposition of the beta-amyloid protein is a characteristic histological feature of both IBM and Alzheimer's disease (AD). The epsilon 4 allele of apolipoprotein E (APO E) has been strongly associated with familial and late-onset AD. We therefore compared the APO E allele frequencies in a group of 14 patients with IBM with those in a group of patients with other inflammatory muscle diseases and in the general population. The frequency of the epsilon 4 allele in IBM was increased (0.29) compared with that in patients with other inflammatory muscle diseases (0.15) and the general population (0.13) (p < 0.05). These data suggest that APO E genotype may be one of the factors involved in determining the predisposition to the development of IBM.

Adult↗
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↗
PubMed1986

Scleromyxedema and inflammatory myopathy: a clinicopathologic study of three patients.

Scleromyxedema (lichen myxedematosus) is a rare cutaneous manifestation in patients with idiopathic inflammatory myopathy. The clinical and histological findings in three patients with this association are presented. Two patients had a severe inflammatory polymyopathy which responded incompletely to corticosteroid therapy, while in the third, who developed esophageal carcinoma, the myopathy was relatively mild and the skin changes were the dominant feature. The occurrence of scleromyxedema in patients with inflammatory myopathy appears to carry a poor prognosis.

Adult↗
PubMed1986

Genetic studies in familial fibrosing alveolitis. Possible linkage with immunoglobulin allotypes (Gm).

A family containing 12 subjects spanning three generations and including six cases with clinical evidence of definite or probable fibrosing alveolitis has been investigated. Histologic confirmation was available for three cases. The subjects were between 15 and 54 years of age at diagnosis. Although the size of the sample is small, the mode of inheritance of fibrosing alveolitis within this family appeared to be dominant with incomplete penetrance. HLA typing showed that at least one of the affected siblings did not share any HLA haplotypes with other affected siblings in the third generation. This makes it unlikely that a disease gene would be in association with HLA genes on chromosome 6. In contrast, all affected siblings, as well as two as yet unaffected siblings, carried the immunoglobulin haplotype Gm 1. These studies indicate that familial fibrosing alveolitis in this family may be inherited by a dominantly inherited gene located on chromosome 14 close to the loci encoding for Gm.

Adolescent↗
PubMed1986

Genetic markers in rheumatoid arthritis relationship to toxicity from D-penicillamine.

In a 3-centre study involving 144 patients with rheumatoid arthritis (RA), a relationship between side effects from D-penicillamine and HLA antigens, allotypic markers of the IgG heavy chain (Gm) and allotypes of complement components Bf, C4A and C4B was sought. There was a significant association between proteinuria induced by D-penicillamine and the antigens DR3 and B8. However, the presence of DR2 seemed to protect against the development of proteinuria. Thrombocytopenia from D-penicillamine was significantly associated with HLA-A1 and DR4; 15 of 23 patients who possessed both antigens developed thrombocytopenia (p less than 0.001 uncorrected, approximate relative risk (RR) = 5.5). A null complement allele located at the C4B locus (C4BQO) was also associated with thrombocytopenia from D-penicillamine (p less than 0.005, RR = 17.3). Our study confirms the findings from other series which indicate that there is a genetic predisposition for the development of proteinuria from D-penicillamine in RA and suggests that this may also be the case in D-penicillamine induced thrombocytopenia.

Arthritis, Rheumatoid↗
PubMed1984

Thyrogastric autoimmunity and MHC associated alleles at the C4 locus in patients with type 1 (insulin-dependent) diabetes.

HLA antigens, complement allotypes, insulin antibodies and thyrogastric autoantibodies were determined in 69 patients with Type 1 (insulin-dependent) diabetes defined by a tendency to ketosis, non-obesity and insulin requirement within 2 years of diagnosis. Analysis of HLA and C4 allotypes suggested that Type 1 diabetes was associated with only certain DR3- and DR4-containing supratypes. Low antibody response to insulin was associated with all HLA-DR3, being present in 89% of those with DR3 compared with 48% of those without. Thyrogastric autoantibodies were associated with a null allele at the C4A locus, usually with HLA-B8-C4AQO-C4B1-BfS-DR3. These results indicate that, unlike Type 1 diabetes, low insulin antibody response was associated with all HLA-DR3. Thyrogastric autoantibodies, on the other hand, were associated with a null allele at the C4A locus. It is probable that while interaction between certain HLA-DR3 and DR4-containing supratypes is important in conferring susceptibility to Type 1 diabetes, other manifestations of autoimmunity are associated with supratypes containing C4AQ0, and in particular the diabetogenic supratype HLA-B8-C4AQ0-C4B1-BfS-DR3.

Alleles↗
PubMed1983

HLA and complement allotypes in Type 1 (insulin-dependent) diabetes.

A group of patients with Type 1 (insulin-dependent) diabetes mellitus was investigated for HLA-A, B and DR antigens as well as C4 and factor B polymorphism. A significant excess of DR3/DR4 heterozygotes was observed (27% versus 17% by Hardy-Weinberg expectation). The factor B allele BfF1 was present in 13% of patients with Type 1 diabetes (gene frequency of 0.08 versus 0.01 in control subjects). A rare C4 B allele, C4 B2.9, was found in 18% of patients with Type 1 diabetes (n = 63) compared with 1.1% of control subjects (n = 176). Total C4 deficiency at the C4 A locus (C4 AQ0,0) was present in 10% of patients with Type 1 diabetes compared with 0% of control subjects. Examination of HLA, C4 and Bf phenotypes in patients with Type 1 diabetes suggested that three high risk supratypes, HLA-A1 B8 BfS C4 AQ0 C4 B1 DR3; HLA-B18 BfF1 C4 A3 C4 BQ0 DR3; HLA-A2 CW3 BW62 BfS C4 A3 C4 B2.9 DR4 are markers for susceptibility alleles.

Adult↗
PubMed1983

Complement allotyping in SLE: association with C4A null.

Immunogenetic factors are important in systemic lupus erythematosus (SLE) and deficiency of a number of complement components is often associated with a lupus-like illness. The complement components Bf, C2 and C4 are encoded within the human major histocompatibility complex (MHC) and are polymorphic. A study of HLA and Bf and C4 polymorphism in 43 patients with SLE was undertaken firstly, to determine whether partial deficiency of C2 and C4 may predispose to disease and secondly, because it may allow the better definition of important supratypes associated with the disease and which may include the relevant disease gene(s). An increased frequency of C4A null alleles has been shown in SLE, with a minimal estimated C4A null gene frequency of 0.32 versus 0.20, but no case of partial C2 deficiency was identified. These results may indicate a direct role for partial C4 deficiency or that C4A null may be a marker for an important supratype which includes the relevant disease gene(s).

Complement C2↗
PubMed1983

Disease associations with complotypes, supratypes and haplotypes.

We have used the term supratype to describe combinations of alleles and have examined associations with disease. In RA and insulin-dependent diabetes one or more supratypes appear to be important but their functional significance remains obscure. In MG and SLE the HLA supratype may contain loci involved in immunoregulation, complement synthesis and hormone metabolism. MG induced by D-Pen is associated with Bw35/DR1 rather than A1, B8, DR3. In contrast there is no evidence of a supratype in AS. We have proposed a model for the pathogenesis of sacroiliitis and AS and have postulated two non-linked genes which act stepwise upon HLA-B27. There are cogent reasons for examining the functional effects of known loci within the MHC and particularly those involved in the expression of complement components.

Alleles↗
PubMed1980

Immunological status may predict clinical outcome in BCG treated melanoma.

Twenty-seven patients with surgically resected stage II or III malignant melanoma were treated with bacillus Calmette-Guérin (BCG) and followed prospectively to determine whether relapse could be predicted. Peripheral blood mononuclear (lymphocyte plus monocyte) counts (PBM), T and B cell counts, phytohaemagglutinin (PHA) cytotoxicity, PHA transformation, antibody-dependent cell-mediated cytotoxicity (ADCC) and serum immunoglobulin concentrations were studied before and during therapy. Patients ultimately classified as having a poor clinical outcome (inoperable recurrence) were compared with those with a more favourable outcome. Prior to therapy, poor outcome patients had lower PBM and T cell counts but there was some overlap. After three months, these differences were more pronounced. Low PHA cytotoxicity was also associated with poor outcome; again the differences were more apparent at 3 months than prior to therapy. These results suggest that PBM, T cell counts and PHA cytotoxicity may predict poor outcome some months before inoperable recurrence in apparent clinically.

Adult↗