Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytochrome P450 IID6 is an autoantigen recognized by the sera of children affected with a subtype of autoimmune hepatitis. It was hypothesized that a mutation in the CYP2D6 gene could explain the autoimmune response in these patients. To examine this question, genomic DNA from peripheral lymphocytes (n = 9) and liver (n = 1) of 10 patients with anti-LKM-1 antibody was analysed by Southern blot for genetic association studies between a particular CYP2D6 haplotype and autoimmune hepatitis. In addition, a region of CYP2D6, from the same genomic DNA, was amplified by polymerase chain reaction (PCR) and digested by BstNI, in a search for the most prevalent 29B mutation, described in subjects who do not express the P450 IID6. Total RNA and proteins, prepared from the liver of an anti-LKM-1+ patient, were analysed by Northern and Western (immunoblot) blots respectively. Our results do not reveal any major structural change in the DNA of this patient at the CYP2D6 locus that could explain their autoimmune response. Corroborating this observation, no changes were noted either in P450 IID6 mRNA size or in the corresponding protein. However, these data do not exclude the possibility of subtle changes in the protein due to point mutations in critical regions that might trigger an autoimmune response.
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PMID:Study of CYP2D6 gene in children with autoimmune hepatitis and P450 IID6 autoantibodies. 134 12

Several hepatobiliary diseases appear to be mediated by the host immune response. They can be subdivided into those in which the immune reaction is against an infectious agent such as hepatitis viruses, those in which the immune reaction appears to be against an autoantigen expressed on hepatobiliary cells, and those due to alloimmunity. The existence of autoimmune liver diseases indicates a breakdown in the mechanisms responsible for self-tolerance. In HBV infection, the hepatocellular necrosis appears to be mediated by the host immune response against viral antigens expressed on the membranes of infected hepatocytes. Autoimmune chronic active hepatitis can be subdivided on the basis of differences in circulating autoantibodies. In classic type I autoimmune chronic hepatitis, autoantibodies are directed against non-organ- and non-species-specific antigens. Thus, they are unlikely to be involved in pathogenesis. In contrast, type II autoimmune chronic hepatitis is characterized by antibodies against specific cytochrome P-450 isoenzymes that appear to be expressed on the surface membrane of hepatocytes. Immunogenic cytochrome P-450 also can be induced by drug metabolism and haptenation. This indicates that environmental or medicinal xenobiotics may initiate autoimmune liver damage. Primary biliary cirrhosis is characterized by T-cell-mediated inflammation and destruction of interlobular and septal bile ducts and antibodies specific for epitopes of the 2-oxo-acid dehydrogenase multienzyme complex of mitochondria. The histopathologic lesion NSDC also is observed in alloimmune-mediated diseases such as CGVHD and rejection of liver allografts. PSC may be mediated by an immune response against endothelial cells of the peribiliary capillary plexus, with secondary reactions to bile duct epithelial cell antigens. The pathogenesis of alcoholic liver disease is multifactorial, but one component involves an immune response to acetaldehyde-protein adducts. Secondary sensitization of cell-mediated effector mechanisms, endothelial damage, and secretion of noxious cytokines appear to be involved in pathogenesis.
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PMID:Immune disorders of the liver and bile duct. 151 50

Using an autoimmune hepatitis model of A/J mice which was prepared with immunization by syngeneic crude liver proteins, various influences of neonatal thymectomy were studied by observations of histological liver changes, autoantibody to liver-specific membrane lipoprotein (LSP), delayed-type hypersensitivity (DTH) to LSP, and purified protein derivative (PPD), and suppressor activity to LSP. The liver changes in the thymectomized mice were more intense than those in the non-thymectomized controls. Production of the anti-LSP autoantibodies and positive DTH to syngeneic LSP could be recognized in both groups of the thymectomized mice and the non-thymectomized controls, but the levels of those were higher in the former. In the level of DTH to PPD the thymectomized mice were lower than the non-thymectomized controls. Adoptive transfer experiments showed that suppressor activity to LSP was reduced in the spleen cells of neonatally thymectomized mice. This experiment suggests that neonatal thymectomy is apt to abolish tolerance to LSP on account of depressed suppressor activity to autoantigen, and accordingly liver damage is increased.
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PMID:Effect of neonatal thymectomy on experimental autoimmune hepatitis in mice. 362 70

Drug-induced autoimmune diseases have two immunological peculiarities. Firstly, some autoantibodies are present, which are virtually never seen in spontaneous human diseases and may be regarded as specific. This applies to antimitochondria antibody type 3 (anti M3) in the lupus-like syndrome caused by Venocuran, to antimitochondria antibody type 6 (anti M6) in iproniazide-induced hepatitis, to anti-insulin antibody found after treatment with methimazole, and to anti liver/kidney microsome antibody type 2 (anti LKM2) associated with hepatitis induced by tielinic acid. Secondly, a search for other autoantibodies shows that the immune disorder is much more limited than in spontaneous autoimmune diseases. Thus, contrary to myasthenia and idiopathic autoimmune haemolytic anaemia, we never found autoantibodies specifically directed against the thyroid, the stomach or the adrenal gland during treatment with D-penicillamine and alpha-methyldopa. Only some hypotheses may account for these peculiarities. Cross-reaction between drug and autoantigen may occur, but the fact that the antigen-antibody reaction is not inhibited by the drug or its metabolites does not support this explanation. Much more attractive is the "T-cell bypass" theory, according to which autoreacting suppressor T-cells are circumvented by helper T-cells stimulated by the drug-modified autoantigen. In this case, the autoimmune reaction would indicate to which body substance the drug is bound, thus making it immunostimulant, and not a structural similarity between the drug and the autoantigen.
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PMID:[Autoimmunity induced by drugs. Immunological characteristics and etiopathogenic hypotheses]. 624 48

Acetaldehyde in non-toxic doses (15.6 micrograms per start) causes in the inhibition test of the migration of leucocytes an inhibition of the migration in 6/13 of the patients with alcoholic hepatitis, a stimulation of the migration in 6/11 of alcohol cirrhoses. Healthy (n = 16) persons, patients with alcoholic fatty degeneration of the liver (n = 3) as well as non-alcoholic liver diseases (chronic persisting hepatitis, n = 11; chronic active hepatitis, n = 8, cirrhosis, n = 7) did not show this cellular immune reagibility. The inhibition of the migration and the stimulation of the migration, respectively, might develop by hapten autoantigen complexes (altered cytoskeleton?) with release of the factors of inhibition of migration and stimulation of migration, in which case the role of a hapten belongs to acetaldehyde. The results of the tests did not correlate with functional and histological findings of the liver, with the actual consumption of alcohol and also not with haptoglobin phaenotypes. When it is postulated that by acetaldehyde also the release of further lymphokines is mediated, origin and progression of alcoholic hepatitis and alcoholic cirrhosis might be explained immunopathogenetically.
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PMID:[Acetaldehyde-induced leukocyte migration inhibition in alcoholic liver diseases]. 712 38

An immunogenetic study of autoimmune chronic active hepatitis (CAH) showed the relative risk (RR) for this disease was 11.6 for patients who were HLA-B8, 11.7 for patients who were DR3 and 2.3 for patients who were Gma+x+. Moreover, the Gm haplotype Gma+x+ was present in 18 of 40 (45%) patients with HLA-B8, but in none of 10 patients negative for HLA-B8, whereas in 180 healthy controls Gma+x+ was evenly distributed among those positive (24%) and negative (18%) for HLA-B8. The RR was lowest in patients lacking HLA-B8 but positive for Gma+x+. Relative to this low-risk group, the risk was increased 39 times in subjects with both HLA-B8 and Gma+x+, 15 times in subjects with HLA-B8 who were not Gma+x+ and twice in subjects who were neither HLA-B8 nor Gma+x+. Statistical analysis indicated that the three-factor effect (disease risk affected by non-additive effects of HLA-B8 and Gma+x+) was significant (P less than 0.01), as were the main effects of HLA-B8 (P less than 0.001) and Gma+x+ (P less than 0.02). Thus in the presence of HLA-B8, genes linked to Gma+x+, an immunoglobulin CH allotype, may contribute to the development of autoimmune chronic active hepatitis; in the absence of HLA-B8 these same genes appear to be inactive. This may indicate interactions between MHC gene products and VH gene products in the presentation and recognition of autoantigen(s) in autoimmune hepatitis.
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PMID:Interaction of HLA and Gm in autoimmune chronic active hepatitis. 724 97

Trifluoroacetylated (CF3CO-) proteins, elicited upon exposure of animals or humans to halothane, were recognized by anti-CF3CO antibody, monospecific for the hapten derivative N6-trifluoroacetyl-L-lysine. Anti-CF3CO antibodies cross-reacted with the dihydrolipoamide acetyltransferase (E2 subunit) of pyruvate dehydrogenase, indicating that epitopes on the E2 subunit of pyruvate dehydrogenase molecularly mimic those on CF3CO-proteins. Lipoic acid, the prosthetic group of the E2 subunit of pyruvate dehydrogenase was essential in this process, in that only the lipoylated form of the recombinantly expressed inner lipoyl domain of the human E2 subunit of pyruvate dehydrogenase, but not the unlipolyated form, was recognized by anti-CF3CO antibody. Furthermore, based on a high degree of structural relatedness, both CF3CO-Lys and (6RS)-lipoic acid, as well as the lipoylated peptide ETDK(lipoyl)ATIG specifically inhibited the recognition by anti-CF3CO antibody of the E2 subunit of pyruvate dehydrogenase, of trifluoroacetylated rabbit serum albumin and of human liver CF3CO-proteins. In sera of patients with halothane hepatitis, autoantibodies with properties identical to those of anti-CF3CO antibody were identified which could not discriminate between CF3CO-proteins and the E2 subunit of pyruvate dehydrogenase. These data suggest that the E2 subunit pyruvate of dehydrogenase is an autoantigen in halothane hepatitis and that molecular mimicry of CF3CO-proteins by the E2 subunit of pyruvate dehydrogenase is due to the similar structures of CF3CO-Lys and lipoic acid.
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PMID:Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis. Molecular mimicry of trifluoroacetyl-lysine by lipoic acid. 751 86

During follow-up of healthy relatives of 13 patients with autoimmune hepatitis, seven cases of infectious mononucleosis due to Epstein-Barr virus (EBV) occurred. In two of these seven, before EBV infection, there was a defect in suppressor-inducer T lymphocytes specifically controlling immune responses to the asialoglycoprotein receptor, an antigen expressed on the hepatocyte surface. In these two, antibodies to this autoantigen persisted and increased after infectious mononucleosis, and autoimmune hepatitis developed within 4 months. In susceptible individuals, EBV is a trigger for autoimmune hepatitis.
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PMID:Epstein-Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. 756 12

In certain subjects medicinal drugs or toxic agents may induce organ-specific or systemic diseases. The mechanisms of this induction vary according to the type of toxic agent involved. The modification of autoantigens by a toxic agent might be the cause of autoimmune disorders. Thus, certain drugs metabolized by enzymes are known to bind on these enzymes in a covalent manner, thereby making the enzyme immunogenic. The immune reaction thus induced could be responsible for hepatitis. If the modified autoantigen is a molecule, such as the class II molecules of the major histocompatibility complex, which plays an important role in communication between the immune system cells, the autoimmune reaction could result in polyclonal lymphocyte B activation and in a lupus-like autoimmune disease. It is also possible that a drug interferes with one of the element which control the advent of autoreactive T cells and in this way becomes responsible for autoimmune systemic manifestations.
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PMID:[Autoimmunity and toxic agents]. 817 65

IgG antibodies reacting with the GM3-comigrating band extracted from pooled AIDS lymphocytes were detected in 33.3% of AIDS patients sera, in 8% of asymptomatic anti-HIV-positive subjects, in none of the sera obtained from asymptomatic anti-HIV-negative drug abusers, from patients with acute B and chronic C hepatitis, and from healthy donors. All positive sera reacted selectively with the GM3-comigrating band obtained from AIDS lymphocytes but not with the corresponding band from normal lymphocytes. The lymphocytic ganglioside autoantigen was revealed as GM3. In addition, two main data were shown: (a) AIDS lymphocytes have an increased concentration of GM3 and (b) the ceramide of AIDS lymphocytic GM3 has a different percentual composition of fatty acids in contrast to control cells. It is suggested that these quantitative and qualitative changes might be responsible for the appearance of circulating anti-lymphocytic GM3 antibodies.
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PMID:GM3 as a target of anti-lymphocytic ganglioside antibodies in AIDS patients. 850 Feb 69


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