DOI Page / Citation link:
https://doi.org/10.11588/diglit.48120#0066
48 Molecular and Cell Biology of Autoantibodies and Autoimmunity
rhosis (PBC) [1] and a microsomal antigen (LKM-1) in autoimmune hepatitis [2],
Antimitochondrial antibodies (AMA) in PBC react with subunits of the pyruvate
dehydrogenase complex while LKM 1 antibodies react with human cytochrome
P450 dbl. LKM-1 autoantibodies characterize a subgroup of autoimmune type
chronic active hepatitis which can be distinguished serologically from classical
autoimmune type “lupoid” hepatitis associated with antinuclear antibodies
(ANA) and a third subgroup associated with antibodies to a soluble liver antigen
(SLA) [3]. LKM-1 autoantibodies affinity purified from LKM-l-cDNA derived
fusion protein recognize a 50 kD protein of liver as well as kidney microsomes.
LKM-1 antibodies against P450 db 1 are almost exclusively of subclass IgGl. A
sensitive and specific diagnostic test based on LKM-l-cDNA derived fusion pro-
tein was developed for differential diagnosis of chronic hepatitis, namely to dis-
tinguish LKM-1 associated autoimmune hepatitis from virus induced liver dis-
eases. In contrast to virus induced liver diseases autoimmune hepatitis profits
from immunosuppression. LKM-1 specifically inhibit the function of P450 dbl
in vitro [4]. P450 db 1 is known to metabolize several drugs, such as debrisoquin,
bufuralol and sparteine. Due to a genetic polymorphism, 10% of the normal
Caucasian population are deficient for this protein and are phenotypically slow
metabolizers. Patients with LKM 1 antibody positive liver disease express db 1
protein in their liver, their sera inhibit the enzyme function in vitro but not P450
db 1 catalysed drug metabolism in vivo. Thus autoantibodies reacting with the ac-
tive site of an enzyme inhibit its function in vitro without affecting its drug
metabolism in vivo. Possibly these findings serve as a model for other autoim-
mune disorders. The availability of specific cDNA’s allows now a precise iden-
tification of the autoepitopes and facilitates new possibilities to study T-cell
response.
References
1. Gershwin, N.E., Mackay, I.R., Sturgess, A. et al. (1987): Identification and
specificity of a cDNA encoding the 70 kD mitochondrial antigen recognized in prima-
ry biliary cirrhosis. J. Immunol. 138, 3525
2. Manns, M., Johnson, E. F., Griffin, I.C. J., Tan, E.M., Sullivan, K. F. (1989): The
major target of liver kidney microsomal autoantibodies in idiopathic autoimmune
hepatitis is cytochrome P450 dbl. J. Clin. Invest. 83, 1066-1972
3. Manns, M., Gerken, G., Kyriatsoulis, A., Staritz, M., Meyer Zum
Buschenfelde, K.-H. (1987): Characterisation of a new subgroup of autoimmune
chronic active hepatitis by autoantibodies against a soluble liver antigen. Lancet 1,
292-294
4. Zanger, U.M., Hauri, H.P., Loeper, J., Homberg, J.-C., Meyer, U.A. (1988): An-
tibodies against human cytochrome P450 db 1 in autoimmune hepatitis type II. Proc.
Natl. Acad. Sci. USA, 27, 8256-8260
rhosis (PBC) [1] and a microsomal antigen (LKM-1) in autoimmune hepatitis [2],
Antimitochondrial antibodies (AMA) in PBC react with subunits of the pyruvate
dehydrogenase complex while LKM 1 antibodies react with human cytochrome
P450 dbl. LKM-1 autoantibodies characterize a subgroup of autoimmune type
chronic active hepatitis which can be distinguished serologically from classical
autoimmune type “lupoid” hepatitis associated with antinuclear antibodies
(ANA) and a third subgroup associated with antibodies to a soluble liver antigen
(SLA) [3]. LKM-1 autoantibodies affinity purified from LKM-l-cDNA derived
fusion protein recognize a 50 kD protein of liver as well as kidney microsomes.
LKM-1 antibodies against P450 db 1 are almost exclusively of subclass IgGl. A
sensitive and specific diagnostic test based on LKM-l-cDNA derived fusion pro-
tein was developed for differential diagnosis of chronic hepatitis, namely to dis-
tinguish LKM-1 associated autoimmune hepatitis from virus induced liver dis-
eases. In contrast to virus induced liver diseases autoimmune hepatitis profits
from immunosuppression. LKM-1 specifically inhibit the function of P450 dbl
in vitro [4]. P450 db 1 is known to metabolize several drugs, such as debrisoquin,
bufuralol and sparteine. Due to a genetic polymorphism, 10% of the normal
Caucasian population are deficient for this protein and are phenotypically slow
metabolizers. Patients with LKM 1 antibody positive liver disease express db 1
protein in their liver, their sera inhibit the enzyme function in vitro but not P450
db 1 catalysed drug metabolism in vivo. Thus autoantibodies reacting with the ac-
tive site of an enzyme inhibit its function in vitro without affecting its drug
metabolism in vivo. Possibly these findings serve as a model for other autoim-
mune disorders. The availability of specific cDNA’s allows now a precise iden-
tification of the autoepitopes and facilitates new possibilities to study T-cell
response.
References
1. Gershwin, N.E., Mackay, I.R., Sturgess, A. et al. (1987): Identification and
specificity of a cDNA encoding the 70 kD mitochondrial antigen recognized in prima-
ry biliary cirrhosis. J. Immunol. 138, 3525
2. Manns, M., Johnson, E. F., Griffin, I.C. J., Tan, E.M., Sullivan, K. F. (1989): The
major target of liver kidney microsomal autoantibodies in idiopathic autoimmune
hepatitis is cytochrome P450 dbl. J. Clin. Invest. 83, 1066-1972
3. Manns, M., Gerken, G., Kyriatsoulis, A., Staritz, M., Meyer Zum
Buschenfelde, K.-H. (1987): Characterisation of a new subgroup of autoimmune
chronic active hepatitis by autoantibodies against a soluble liver antigen. Lancet 1,
292-294
4. Zanger, U.M., Hauri, H.P., Loeper, J., Homberg, J.-C., Meyer, U.A. (1988): An-
tibodies against human cytochrome P450 db 1 in autoimmune hepatitis type II. Proc.
Natl. Acad. Sci. USA, 27, 8256-8260