Biomedical subjects
M Walport
Publications and source records attributed to M Walport.
Grand rounds--Hammersmith Hospital. Persistent fever in pulmonary tuberculosis.
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Genetic analysis of TAP2 in systemic lupus erythematosus patients from two ethnic groups.
The aim of this study was to determine whether the TAP2 (Transporter associated with Antigen Processing 2) locus is involved in susceptibility to systemic lupus erythematosus (SLE). We adopted the interethnic approach to overcome problems in the analysis resulting from linkage disequilibrium. The TAP2 gene polymorphisms of the codons corresponding to amino acid positions 379, 565 and 665 were investigated by amplification refractory mutation system polymerase chain reaction (ARMS-PCR) in 186 patients (151 white Europeans, 35 Afrocaribbeans) and 183 controls (79 white Europeans, 104 Afrocaribbeans). In the European SLE patients, the frequency of the TAP2 type V-A-TA was marginally lower compared with the control group (31% vs 42%), with negative linkage disequilibrium between this TAP2 type and DR3 probably accounting for the difference. For the European SLE patients, we confirmed a significant association of DR3 with disease status [odds ratio = 4.16, 95% confidence interval (CI), 2.08-8.39] and in the patients with DR3 there was a significantly high frequency of the TAP2 type V-A-T-. In the Afrocaribbean SLE patients, any associations of disease status with TAP2 phenotype were the inverse of those in the European patients. Thus, in these patients the frequency of V-A-TA was higher than in controls (46% vs 26%, OR = 2.4, 95% CI 1.01-5.74), while the frequency of V-A-T- was lower (26% vs 40%, not significant). Despite possible sampling error, the lack of a difference in TAP2 status between cases and controls within ethnic groups and, if anything, an inverse association across ethnic groups, makes it unlikely that the TAP2 polymorphism studied here is of primary relevance to SLE susceptibility.
Late presentation of Kartagener's syndrome. Consequences of ciliary dysfunction.
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Clearance of 131I-labeled murine monoclonal antibody from patients' blood by intravenous human anti-murine immunoglobulin antibody.
Five patients treated with intraperitoneal 131I-labeled mouse monoclonal antibody for ovarian cancer also received i.v. exogenous polyclonal human anti-murine immunoglobulin antibody. The pharmacokinetics of 131I-labeled monoclonal antibody in these patients were compared with those of 28 other patients receiving i.p.-radiolabeled monoclonal antibody for the first time without exogenous human anti-murine immunoglobulin, and who had no preexisting endogenous human anti-murine immunoglobulin antibody. Patients receiving i.v. human anti-murine immunoglobulin antibody demonstrated a rapid clearance of 131I-labeled monoclonal antibody from their circulation. The (mean) maximum 131I blood content was 11.4% of the injected activity in patients receiving human anti-murine immunoglobulin antibody compared to 23.3% in patients not given human anti-murine immunoglobulin antibody. Intravenous human anti-murine immunoglobulin antibody decreased the radiation dose to bone marrow (from 131I-labeled monoclonal antibody in the vascular compartment) 4-fold. Following the injection of human anti-murine immunoglobulin antibody, 131I-monoclonal/human anti-murine immunoglobulin antibody immune complexes were rapidly transported to the liver. Antibody dehalogenation in the liver was rapid, with 87% of the injected 131I excreted in 5 days. Despite the efficient hepatic uptake of immune complexes, dehalogenation of monoclonal antibody was so rapid that the radiation dose to liver parenchyma from circulating 131I was decreased 4-fold rather than increased. All patients developed endogenous human anti-murine immunoglobulin antibody 2 to 3 weeks after treatment.
Progressive systemic sclerosis: autoimmune arteriopathy.
In a case of progressive systemic sclerosis (PSS), widespread deposition of IgM was found in the media and internal elastic lamina of small muscular arteries. IgA and C3 were also found in some vessels. Antibody eluted from the kidney bound to smooth muscle and elastica of small arteries. These findings suggest that PSS is a vasculopathy which is mediated by complement-fixing antibodies.
The identification of autoantigens, autoantibodies and their idiotypes.
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Erythrocytes transfused into patients with SLE and haemolytic anaemia lose complement receptor type 1 from their cell surface.
Erythrocyte complement receptor type 1 (CR1) shows a numerical deficiency in patients with SLE and with haemolytic anaemias. This receptor is a cofactor for the enzymatic degradation of C3b and is believed to play a role in the transport of immune complexes from the circulation to the reticulo-endothelial system. Erythrocyte CR1 was enumerated on cells which had been transfused into patients with SLE and haemolytic anaemias. In three patients with active disease up to 60% of CR1 was lost from erythrocytes during 5 days after blood transfusion and up to 410 molecules of C3 were deposited on these cells. These are the first in vivo data showing that CR1 may be lost from circulating erythrocytes. This acquired deficiency of CR1 on erythrocytes may have pathological consequences in patients with SLE.
High incidence of anticardiolipin antibodies in relatives of patients with systemic lupus erythematosus.
Anticardiolipin antibodies (aCL) were measured in the serum of 22 patients with systemic lupus erythematosus (SLE) and 101 of their first degree relatives. Four patients' sera (18%) were positive. Eight sera from relatives were strongly positive (7.9%). All 8 relatives came from different families, and only 3 of them were related to a positive positive proband. All 8 had clinical and/or other serological abnormalities, compared with only 30% of the aCL negative relatives (p less than 0.05). There were no reports or evidence of thrombosis, thrombocytopenia or spontaneous abortion among the aCL positive relatives. Our data indicate a strikingly higher incidence of aCL among relatives of lupus patients compared with controls. This may be associated with an increased incidence of abnormal clinical or serological findings in these individuals, and constitute a feature of a genetic predisposition to SLE.
Detection of cross-reactive anti-DNA antibody idiotypes in the serum of systemic lupus erythematosus patients and of their relatives.
Two common cross-reacting anti-DNA antibody idiotypes designated 16/6 and 32/15, previously identified in the serum of patients who have systemic lupus erythematosus, were found in 24% and 7%, respectively, of 147 first-degree relatives. These findings imply that high-frequency germ-line genes exist among lupus relatives, as well as patients. These dominant or public anti-DNA antibody idiotypes are not likely to be pathogenic factors, but are probably a genetically associated phenomenon.
C3 receptors, complement deficiency and SLE.
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