Different immune mechanisms leading to autoimmunity in primary sclerosing cholangitis and autoimmune chronic active hepatitis of childhood

Authors

  • Glorgina Mieli-Vergani M.D.,

    Corresponding author
    1. Departments of Child Health, Liver Unit and Immunology, King's College School of Medicine and Dentistry, King's College Hospital, London SE5 9PJ, England
    • Department of Child Health, King's College Hospital, Bessemer Road, London SE5 9PJ, England
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  • Ava Lobo-Yeo,

    1. Departments of Child Health, Liver Unit and Immunology, King's College School of Medicine and Dentistry, King's College Hospital, London SE5 9PJ, England
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  • Barbara M. McFarlane,

    1. Departments of Child Health, Liver Unit and Immunology, King's College School of Medicine and Dentistry, King's College Hospital, London SE5 9PJ, England
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  • Ian G. McFarlane,

    1. Departments of Child Health, Liver Unit and Immunology, King's College School of Medicine and Dentistry, King's College Hospital, London SE5 9PJ, England
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  • Alex P. Mowat,

    1. Departments of Child Health, Liver Unit and Immunology, King's College School of Medicine and Dentistry, King's College Hospital, London SE5 9PJ, England
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  • Diego Vergani

    1. Departments of Child Health, Liver Unit and Immunology, King's College School of Medicine and Dentistry, King's College Hospital, London SE5 9PJ, England
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Abstract

Children with primary sclerosing cholangitis or autoimmune chronic active hepatitis have similar high levels of immunoglobulin G and non-organ-specific autoantibodies and may have similar histological features. To investigate a possible immunopathogenesis of primary sclerosing cholangitis, we have studied a series of regulatory and/or effector immune mechanisms in eight children with primary sclerosing cholangitis, comparing them to 14 children with autoimmune chronic active hepatitis and 24 healthy children as controls. Antibodies to a liver membrane protein preparation were found in all children with autoimmune chronic active hepatitis tested and in seven of eight with primary sclerosing cholangitis, whereas antibodies against the hepatic asialoglycoprotein receptor were present in three of six patients with autoimmune chronic active hepatitis and in two of the eight with primary sclerosing cholangitis. Lymphocyte cytotoxicity values to autologous hepatocytes were similarly elevated in primary sclerosing cholangitis (median: 50%; range: 38 to 83%) and in autoimmune chronic active hepatitis (median: 52%; range 37 to 87%) compared to controls (median: 8%; range: 0 to 27%) (p<0.01 for both). In contrast, T suppressor cell number and function were normal in patients with primary sclerosing cholangitis (median: 23%; range: 19 to 28%; and median: 54%; range: 44 to 61%), but significantly decreased in patients with autoimmune chronic active hepatitis (median: 15%; range: 9 to 21%; and median: 9%; range: −40 to +21%) when compared to controls (median: 24%; range: 16 to 29%; and median: 53%; range: 8 to 77%) (p<0.01 for both). While the percentage of T lymphocytes expressing the activation marker HLA-DR was similarly increased in primary sclerosing cholangitis (median: 5%; range: 2 to 6%) and in autoimmune chronic active hepatitis (median: 5%; range: 1 to 10%) compared to controls (median: 3%; range: 1 to 5%, p<0.01 for both), the percentage of T lymphocytes expressing interleukin 2 receptors was greatly increased in autoimmune chronic active hepatitis (median: 19%; range: 12 to 22%) but normal in primary sclerosing cholangitis (median: 0%; range: 0 to 1%). These data suggest that liver-damaging effector mechanisms are similar in primary sclerosing cholangitis and autoimmune chronic active hepatitis but that factors leading to autoimmunity differ. Whereas in autoimmune chronic active hepatitis. autoimmunity probably derives from defective T-dependent immune regulation, in primary sclerosing cholangitis it could result from B lymphocyte activation bypassing T cells.

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