Biomedical subjects
Publications and source records attributed to D Doniach.
Two haemagglutination tests using preserved turkey erythrocytes are described for the detection of thyroglobulin and microsomal antibodies, respectively. Comparative studies with the more traditional sheep cell techniques show good correlation of titres when testing sera from patients with autoimmune thyroid disorders.
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A previously unrecognized autoantibody, detected by immunofluorescence, reacted with all human organs but gave negative results on tissues from rat, mouse, rabbit, guinea-pig, calf and chicken. From its predilection for mitochondria-rich cells (oncocytes) and its selective absorption with human but not animal mitochondria, it was identified as an anti-human mitochondrial antibody and named AHMA. The antibody is found in about 1% of normal subjects and is mostly of IgG class and of low titres. Its prevalence is increased in primary biliary cirrhosis where it may be associated with the standard non-species-specific AMA used for the differential diagnosis of this disease. The importance of AHMA is mainly in possible confusion with organ-specific reactions in submaxillary duct, parathyroid oxyphil cells and in trying to identify new endocrine cells such as those producing pancreatic polypeptide (HPP) in human tissues. Animals immunized with human hormones develop reactions to human mitochondria and thus produce misleading immunofluorescence reactions when used in low dilutions.
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Determination of histocompatibility antigens in 63 patients with alcoholic liver disease showed that HLA-B8 was more prevalent in patients with cirrhosis than in controls, but among those with fatty liver and minimal fibrosis the prevalence of this antigen was normal. Another noticeable difference was the absence of HLAA28 in the cirrhotic group. In the total series of 219 patients the prevalence of antinuclear and smooth muscle antibodies was raised; they were especially prevalent in patients with cirrhosis. Raised serum IgA and IgG concentrations were also common (found in 50% and 37% respectively) and were again significantly associated with cirrhosis. In contrast, serum IgM levels, which were raised in 46% of cases, were not significantly related to the presence of cirrhosis but correlated significantly with the degree of portacaval shunting. These results support recent evidence suggesting that immune responses may be implicated in alcohol-induced liver damage, particularly in its progression to cirrhosis.
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Full clinical and laboratory details of 203 patients with postoperative jaundice were submitted to a panel of hepatologists. All patients whose jaundice may have had an identifiable cause were excluded, which left 76 patients with unexplained hepatitis following halothane anaesthesia (UHFH). Hepatitis in 95% of these cases followed multiple exposure to halothane, with repeated exposure within four weeks in 55% of cases. Twenty-nine patients were obese, 52 were aged 41-70, and 53 were women. Thirteen patients died in acute hepatic failure. Rapid onset of jaundice after anaesthesia, male sex, and obesity in either sex were poor prognostic signs. Of the clinical stigmata of hypersensitivity, only eosinophilia was impressive. The UHFH group had a much greater incidence of liver kidney microsomal (LKM) and thyroid antibodies and autoimmune complement fixation than those patients whose jaundice related to identifiable factors. Thirteen of the 19 patients with LKM antibodies also had thyroid antibodies. In six patients retested two to three years later LKM antibodies had disappeared, although thyroid antibodies persisted. Rapidly repeated exposure to halothane may cause hepatitis, but such a complication is probably rare. Possibly obese women with a tendency to organ-specific autoimmunity may be more at risk. Nevertheless, the comparative risks of rapidly repeated halothane or non-halothane anaesthesia cannot be determined from the present data. If alternative satisfactory agents are available halothane should be avoided in patients with unexplained hepatitis after previous exposure, although in three to five patients with UHFH who were re-exposed to halothane jaundice did not recur.
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Titres of antibodies to rubella, measles, smooth muscle, nuclei, and Escherichia coli were examined in relation to the presence of particular histocompatibility antigens in 57 patients with active chronic hepatitis, 8 of whom were HBsAg positive. With the exception of antibodies to E. Coli, the HBsAg-negative patients with HLA-B8 or HLA-B12 had higher titres than those with neither, and antibody titres were highest in the 7 cases with both these histocompatibility antigens. In contrast, E. coli antibody titres were not related to the presence of particular histocompatibility antigens but correlated closely with the degree of portosystemic shunting. None of the HBsAg-positive patients possessed HLA-B8, and titres of all the antibodies were significantly lower than in the HBsAg-negative cases. The increased antibody response in HBsAg-negative patients is likely to be due to a genetically determined increase in immunological responsiveness for which HLA-B8 and HLA-B12 are markers. The results obtained in healthy family members also suggest that this defect in immunoregulation is under polygenic control.
Three hundred and twelve sera containing antibodies to smooth muscle (SMA) wer analysed for the immunofluorescence patterns they produced in various tissues. A classification is described based on the three main appearances in rat kidney. Some sera, mainly of low titre, reacted only with vessel walls (SMA-V), some stained vessels and renal glomeruli (SMA-G) and high titre sera, mainly from patients with chronic active hepatitis stained vessels, glomeruli, and intracellular fibrils in renal tubules (SMA-T). Peripheral staining in hepatocytes or thyroid cells was not a regular feature. 41/43 polyclonal SMA-T and -G sera were absorbed out completely by actin, and this also removed the pericullular staining in liver and thyroid when present. High titre SMA-V antibodies could not be absorbed by actin, and the antigen remains to be identified.
DNA antoantibodies in serum will bind to antigen-coated polystyrene tubes and can be detected by radiolabelled anti-immunoglobulin. The method is quantitative, gives information on the antibody class and is not readily subject to interference by factors such as the size of the DNA, minor contamination of double-stranded with single-stranded DNA and the presence of materials which can combine "non-specifically" with the antigen. Double-stranded DNA gave good discrimination between SLE and rheumatoid arthritis but with single-stranded preparations approximately 40% of the RA patients showed elevated antibody values. Individual results obtained with the two antigens were compared and correlated with the Farr test and ANA titres. Surprisingly, a proportion of the SLE sera gave high background binding to tubes coated with gelatine.
(1) A new antibody has been found by immunofluorescence which reacts with cardiac conducting tissue using ox heart false tendons. It was detected in eight out of ninety-three cases of idiopathic heart block (8-6%), in one out of twenty-two cases of secondary heart block (4-5%) and in seven of 165 normal controls (4.2%), in titres varying from 1:10 to 1:40. Previous authors had indicated that this tissue might contain unique antigens. (2) Sera reacting with type I fibres in skeletal muscle (red zebra) were found to be of two varieties, one of which stained conducting fibres diffusely while it gave minimal staining of cardiac muscle; the other reacting with myofibrils in Purkinje cells and heart. (3) Some sera with high titre smooth muscle antibodies (SMA) reacted with conducting tissue together with skeletal and cardiac muscle, suggesting that the four tissues have at least one antigen in common. (4) Known non-organ specific antibodies behaved as expected on beef conducting fibres: striational fluorescence of myasthenia gravis sera reacted with the same patterns on Purkinje myofibrils; AMA and ANA produced IFL in expected locations; ribosomal antibodies reacted strongly, while LKM and reticulin antibodies showed no reactivity. (5) Although the incidence of specific Purkinje fibre antibodies was not significantly raised in idiopathic heart block, the clinical associations suggest that some cases might be related to autoimmunity possibly involving cell-mediated mechanisms as in polymyositis.