Distinct epitopes on formiminotransferase cyclodeaminase induce autoimmune liver cytosol antibody type 1

Abstract

Liver cytosol antibody type 1 (LC1) is regarded as a serologic marker of type 2 autoimmune hepatitis, in addition to liver kidney microsomal antibody type 1. Among 38 patients with type 2 autoimmune hepatitis, 23 were positive for LC1 antibodies. The antigen recognized by LC1 has been identified as a liver-specific 58-kd metabolic enzyme named formiminotransferase cyclodeaminase (FTCD). All 23 LC1-positive sera immunoprecipitated rat FTCD, and 22 gave an identity reaction with rat FTCD by immunodiffusion. No reaction was observed with sera from 10 patients with type 1 autoimmune hepatitis, 10 with primary biliary cirrhosis, 10 with chronic hepatitis C, and 10 healthy controls. By Western immunoblotting all 23 LC1-positive sera and all the controls tested negative, suggesting that all the antigenic epitopes were destroyed by denaturation. Liver cytosol antibody type 1 (LC1) has been first described, alone or in association with liver kidney microsomal antibody type 1 (LKM1), in patients with type 2 autoimmune hepatitis. 1,2 Only sporadically is it detected in patients with chronic hepatitis C virus infection, usually in association with LKM1. 3,4 Among the different autoantibodies deemed as serologic markers of autoimmune hepatitis, 5 LC1 is particularly intriguing because it targets a liver-specific antigen. 1,2 In addition, serum LC1 concentrations appear to fluctuate in parallel with aminotransferase levels, an observation that suggests a possible role of LC1 autoreactivity in the pathogenic mechanisms leading to hepatocyte injury. 6 In a recent report, Lapierre et al. after screening a complementary DNA (cDNA) library of HepG2 cells with an LC1-positive serum isolated a clone with high sequence homology to pig formiminotransferase cyclodeaminase (FTCD), and showed that a construct encoding the C-terminal portion of FTCD can be recognized by LC1 antibodies. 7 FTCD is a mammalian metabolic enzyme involved in the conversion of histidine to glutamic acid, 8 and is most highly expressed in the liver. FTCD is bifunctional and is composed of distinct FT and CD domains connected by a short linker. The FT activity transfers a formimino group from N-formimino-L-glutamic acid to tetrahydrofolate to generate glutamic acid and 5-formiminotetrahydrofolate, and the CD activity then converts the 5-formiminotetrahydrofolate to 5,10-methenyl tetrahydrofolate and ammonia. Native FTCD is an octamer with 8 identical subunits arranged in a planar ring. 8 FTCD is a soluble cytosolic protein, but in cells appears to be preferentially associated with the cytosolic side of Golgi membranes. [9][10][11] In addition, FTCD appears to be a dynamic component of the Golgi, and cycles between the Golgi and earlier compartments of secretory pathways. 9 In this report, we show that a human liver cytosol protein immunoprecipitated with a pool of LC1-positive autoimmune sera is FTCD, and that LC1 sera recognize distinct epitopes on FTCD. We used full-length recombinant rat FTCD as antigenic substratum for immunodiffusion, immunoblotting, and immu...

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

“…Alleles of the DRB1 gene affect susceptibility to type 1 autoimmune hepatitis [29,31], and the DQB1 gene has been implicated in the occurrence of type 2 autoimmune hepatitis [56]. Reactivities to the cytochrome P450 2D6 (CYP2D6) [54,55] and to formiminotransferase cyclodeaminase [57,58] distinguish type 2 autoimmune hepatitis, and CYP2D6 has been recognized as the principal antigenic target [59]. Type 1 and type 2 autoimmune hepatitides are being drawn apart by more than their serological markers.…”

Autoantibody-Negative Autoimmune Hepatitis

“…Antibodies to liver cytosol type 1 are directed against formiminotransferase cyclodeaminase [125,126], and they occur in 32% of patients with anti-LKM1 [31,127]. Titers fluctuate with disease activity, and like anti-ASGPR and ANCA, anti-LC1 may reflect variations in the severity of liver inflammation [98].…”

Autoantibodies in Autoimmune Hepatitis

“…Cytochrome P4502D6 (CY-P2D6), a cytochrome of the P450 family involved in the metabolism of drugs and xenobiotics is the molecular target of anti-LKM1 [33,34] ; formiminotransferase-cyclodeaminase, a cytosolic enzyme involved in the conversion of histidine to glutamic acid, is the target antigen of anti-LC1 [35,36] ; and Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase -SEPSECS for short -is the antigenic target of anti-SLA [37,38] .…”