Early-onset autoimmune hepatitis is associated with a C4A gene deletion

Scully, L. J.; Toze, Cynthia L.; Sengar, D. P. S.; Goldstein, Rose

doi:10.1016/0016-5085(93)90359-k

Cited by 72 publications

(31 citation statements)

References 30 publications

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“…Rather, the deposition of C3 in the same liver tissues suggests that complement-mediated cell cytotoxicity might in fact be the responsible mechanism in this in vivo model. As has been previously reported, 23,24 many Caucasian AIH patients have deletions in C4A and C5B loci, resulting in a reduced C4 level in relatively younger AIH patients. A C4A loci deletion is known to be in strong linkage disequilibrium with HLA-A1, B8, DR3, DR52a, and DQ2, of all of which are associated with susceptibility to AIH in Caucasian AIH patients.…”

Section: Discussionsupporting

confidence: 55%

A Murine Model of Acute Liver Injury Induced by Human Monoclonal Autoantibody *

et al. 2005

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We have previously reported an immunoglobulin (Ig) M autoantibody to hepatocyte-related 190-kd molecules in patients with type 1 autoimmune hepatitis (AIH). This molecule was first isolated by hepatocyte-specific human monoclonal antibody (MoAb). To elucidate the role of this IgM autoantibody in hepatocyte injury, we examined the reactivity of this MoAb to murine hepatocytes and then questioned whether acute hepatic injury could be induced in mice via injection of this MoAb. The reactivity of MoAb was examined via both FACS analysis using murine hepatocytes and immunostaining of liver tissues. We then identified the murine hepatocyte membrane molecule recognized by this MoAb A utoimmune hepatitis (AIH) is a chronic disorder of hepatocytes that is accompanied by immunological abnormality as determined by serological examination. 1,2 Based on the observation of alterations in several T cell functions, AIH is generally thought to be a disorder mediated by T cells. [3][4][5][6] However, various types of hepatocyte-specific autoantibodies frequently found in AIH patients are also suspected of being involved in immune-mediated liver injury in this disease. This was supported by the following results: (1) Serum autoantibodies obtained from AIH patients were able to kill human hepatocytes, 7-12 (2) the titer of hepatocyte-specific autoantibody was tightly correlated with liver damage in AIH patients. 13,14 However, despite these important observations, because of the lack of an adequate in vivo system, the precise role of such autoantibodies in immunomediated liver injury has remained obscure.We have previously reported the hepatocyte-specific human monoclonal autoantibody (MoAb) produced by human clone established by peripheral blood mononuclear cells of patients with AIH. 15 This MoAb recognized a 190-kd molecule on the hepatocyte membrane and was able to kill human hepatocyte cell lines in a complementdependent manner. In addition, a similar 190-kd molecule-recognizing immunoglobulin M (IgM) autoantibody was also found in AIH patients, and its titer was Abbreviations: Ig, immunoglobulin; AIH, autoimmune hepatitis; MoAb, monoclonal autoantibody; MP, myeloma protein; TBS, C3, complement component 3; AST, asparate aminotransferase; ALT, alanine aminotransferase. From the

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Section: Discussionsupporting

confidence: 55%

A Murine Model of Acute Liver Injury Induced by Human Monoclonal Autoantibody *

et al. 2005

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“…3,4 In addition, tumor necrosis factor ␣ (TNF-␣) and complement C4 alleles have been associated with AIH, despite the observation that both genes exhibit a strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype. [5][6][7] Polymorphisms of the cytotoxic T-lymphocyte antigen 4 (CTLA4*2) have been identified as non-major histocompatibility complex (MHC) susceptibility determinants in AIH type 1. 8 In a recent analysis we have shown a lack of genetic association between idiopathic autoimmune liver diseases and hepatitis as part of the autoimmune polyendocrine syndrome type 1, which is caused by mutations in the autoimmune regulator (AIRE) gene.…”

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confidence: 99%

Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis

2002

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Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are immune-mediated chronic inflammatory diseases of the liver of unknown etiology. Genetic factors appear to be involved in the pathogenesis of both diseases. 1,25-Dihydroxyvitamin D 3 has been implicated as an immunomodulator, which acts through its own receptor (VDR). Polymorphisms of the VDR have been linked to a variety of autoimmune diseases. In this study VDR polymorphisms were analyzed in 123 patients with AIH, 74 patients with PBC, and 214 controls. VDR polymorphisms were assessed by BsmI, TaqI, ApaI, and Fok endonuclease digestion after specific polymerase chain reaction (PCR) amplification. We found a significant association between the BsmI polymorphisms in PBC patients in comparison with controls ( 2 ‫؍‬ 9.49, P ‫؍‬ .009). Furthermore we detected a significant association of the Fok polymorphims in AIH patients in comparison to controls ( 2 ‫؍‬ 9.71, P ‫؍‬ .008) indicating a genetic link of VDR polymorphisms to autoimmune liver diseases such as PBC and AIH in German patients. These findings contribute to the knowledge of the complex events determining immunologic tolerance in the liver. Further studies are needed to elucidate the mechanisms by which the vitamin D receptor contributes to the development of autoimmune diseases. (HEPATOLOGY 2002;35:126-131.) A utoimmune hepatitis (AIH) is an immune-mediated chronic inflammation of the liver of unknown etiology, which is characterized by elevated serum transaminase levels, hypergammaglobulinemia, serum autoantibodies, histologic signs of interface hepatitis, and a response to immunosuppressive treatment. 1,2 Genetic factors appear to be involved in the pathogenesis of AIH. However, a conclusive role of a single genetic locus capable of explaining the etiology of AIH has not been identified thus far, and the genetic background of AIH is therefore considered to be polygenic. In previous studies human leukocyte antigens (HLA) DRB1*0301and DRB*0401 have been identified as independent determinants of susceptibility to AIH. 3,4 In addition, tumor necrosis factor ␣ (TNF-␣) and complement C4 alleles have been associated with AIH, despite the observation that both genes exhibit a strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype. [5][6][7] Polymorphisms of the cytotoxic T-lymphocyte antigen 4 (CTLA4*2) have been identified as non-major histocompatibility complex (MHC) susceptibility determinants in AIH type 1. 8 In a recent analysis we have shown a lack of genetic association between idiopathic autoimmune liver diseases and hepatitis as part of the autoimmune polyendocrine syndrome type 1, which is caused by mutations in the autoimmune regulator (AIRE) gene. 9 In primary biliary cirrhosis (PBC) similar genetic factors have been analyzed to elucidate genetic susceptibility. The genetic typing of HLA class II and III alleles revealed a highly significant increase of HLA DRw8 and C4A-Q0 alleles in patients with PBC compared with controls. 10

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“…Oligonucleotides of human C4 and RCCX constituents were designed based on published DNA sequences (51)(52)(53) 1,3,4,5,6,8,9,10,11,12,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,31,32,33,34,35,37,38,39,40, and 41. The primers were designed based on the genomic DNA sequence of C4A3a (51).…”

Section: Synthetic Dna Primersmentioning

confidence: 99%

“…For examples, deficiency of C4A or C4B is associated with type 1 diabetes (25)(26)(27). Complete or partial deficiency of C4A is linked to systemic lupus erythematosus (SLE) (28 -31), autoimmune hepatitis (32,33), and disease manifestation and rapid progression of AIDS in HIV-infected patients (34,35). Deficiency of C4B increases the vulnerability to bacterial (36,37) and viral (38,39) infections.…”

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confidence: 99%

The Molecular Basis of Complete Complement C4A and C4B Deficiencies in a Systemic Lupus Erythematosus Patient with HomozygousC4AandC4BMutant Genes

Rupert

Moulds

Yang

et al. 2002

The Journal of Immunology

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The disease course of a complete C4-deficient patient in the U.S. was followed for 18 years. The patient experienced multiple episodes of infection, and he was diagnosed with systemic lupus erythematosus at age 9 years. The disease progressed to WHO class III mild lupus nephritis and to fatal CNS vasculitis at age 23 years. Immunochemical experiments showed that the patient and his sibling had complete absence of C4A and C4B proteins and were negative for the Rodgers and Chido blood group Ags. Segregation and definitive RFLP analyses demonstrated that the patient and his sibling inherited two identical haplotypes, HLA A2 B12 DR6, each of which carries a defective long C4A gene and a defective short C4B gene. PCR and DNA sequencing revealed that the mutant C4A contained a 2-bp insertion in exon 29 at the sequence for codon 1213. The identical mutation was absent in the mutant C4B. The C4B mutant gene was selectively amplified by long range PCR, and its 41 exons were completely sequenced. The C4B mutant had a novel single C nucleotide deletion at the sequence for codon 522 in exon 13, leading to frame-shift mutation and premature termination. Thus, a multiplex PCR is designed by which known mutations in C4A and C4B can be elucidated conveniently. Among the 28 individuals reported with complete C4 deficiency, 75–96% of the subjects (dependent on the inclusion criteria) were afflicted with autoimmune or immune complex disorders. Hence, complete C4 deficiency is one of the most penetrant genetic risk factors for human systemic lupus erythematosus.

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Early-onset autoimmune hepatitis is associated with a C4A gene deletion

Cited by 72 publications

References 30 publications

A Murine Model of Acute Liver Injury Induced by Human Monoclonal Autoantibody *

A Murine Model of Acute Liver Injury Induced by Human Monoclonal Autoantibody *

Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis

The Molecular Basis of Complete Complement C4A and C4B Deficiencies in a Systemic Lupus Erythematosus Patient with HomozygousC4AandC4BMutant Genes

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