Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis†

Doherty, Derek G.; Donaldson, Peter; Underhill, James A.; Farrant, J. Mark; Duthie, Ann; Mieli‐Vergani, Giorgina; McFarlane, Ian G.; Johnson, Philip J.; Eddleston, A. L. W. F.; Mowat, Alex P.; Williams, Roger

doi:10.1002/hep.1840190311

Cited by 204 publications

(173 citation statements)

References 47 publications

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“…Multiple antigens may have structural or conformational similarities that favor their presentation in these class II MHC molecules, and numerous homologous peptides may trigger the same disease. 34 HLA DR4 is associated with 38 alleles, of which 10 are common in the normal white North American and northern European populations. 35 In contrast, HLA DR3 is associated with 18 alleles, of which only one is common in these same normal ethnic populations.…”

Section: Discussionmentioning

confidence: 99%

Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly

2006

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Autoimmune hepatitis is classically a disease of young women. Our aims were to determine its occurrence, clinical phenotype, and outcome in elderly patients and contrast findings to young adults. Two-hundred-and-five white North American adults with definite type 1 autoimmune hepatitis were grouped according to age at presentation and the groups compared. Forty-seven patients (23%) were aged >60 years (median age, 68 years), and 31 patients (15%) were aged <30 years (median age, 25 years). The patients >60 years had a higher frequency of cirrhosis at presentation than the patients <30 years (33% versus 10%, P ‫؍‬ .03). They also had thyroid or rheumatic diseases more commonly (42% vs. 13%, P ‫؍‬ .006). HLA DR3 occurred more frequently in the patients <30 years than in those >60 years (58% vs. 23%, P ‫؍‬ .004), and HLA DR4 occurred more often in the patients >60 years (47% vs. 13%, P ‫؍‬ .003). Patients aged >60 years failed corticosteroid treatment less commonly than those aged <30 years (5% vs. 24%, P ‫؍‬ .03). Autoimmune hepatitis occurred in patients aged 18-30 years (15%), 31-39 years (15%), 40-49 years (21%), 50-59 years (25%), and >60 years (23%). Differences in age distribution, HLA frequencies, and treatment outcome occurred after age >40 years. In conclusion, elderly patients have a greater frequency of cirrhosis at presentation and HLA DR4 than patients <30 years, and they have a lower occurrence of treatment failure. Transitions in clinical and genetic phenotypes occur after age >40 years. Genetic susceptibilities may favor etiologic factors that are age-related. (HEPATOLOGY 2006;43:532-538.)

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Section: Discussionmentioning

confidence: 99%

Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly

2006

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“…In nontransplanted patients with AIH, HLA A1, B8, and DR3 haplotypes are associated with a more aggressive clinical course and poor response to treatment. [41][42][43] An increased relative risk for type 1 AIH in patients with HLA DR3 and DR4 has been described. HLA DR3 patients experience higher rates of treatment failure, relapse, referral to LTX, and recurrent AIH after LTX, 44 whereas HLA DR4 is associated with a better disease behavior.…”

Section: Discussionmentioning

confidence: 99%

Response to steroids in de novo autoimmune hepatitis after liver transplantation

et al. 2002

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Graft dysfunction associated with autoimmune phenomena has been recently described in liver transplant recipients without previous autoimmune disease. However, the natural history, diagnostic criteria, and definitive therapeutic approach of de novo autoimmune hepatitis (de novo AIH) are poorly understood. We report 12 cases of de novo AIH 27.9 ؎ 24.5 months after liver transplantation: the outcome of 7 patients treated with steroids is compared with a group of 5 nontreated patients. Nontreated patients lost the graft after 5.8 ؎ 2.6 months from de novo AIH onset. All treated patients were alive after 48.4 ؎ 14 (29-65) months from de novo AIH onset, and none of them lost the graft. However, 5 patients relapsed in relation to steroid tapering. All patients presented an atypical antiliver/ kidney cytosolic autoantibody, associated to classical autoantibodies in 10 cases. Histological study showed several degrees of lobular necrosis and inflammatory infiltrate. HLA antigen frequencies and matching were compared with 2 control groups (16 orthotopic liver transplantation [LTX] patients without de novo AIH and 929 healthy blood donors); de novo AIH patients showed a higher prevalence of HLA-DR3 (54.5% vs. 25.9%, P ‫؍‬ .04) than healthy controls, which was not observed in LTX patients without de novo AIH. In conclusion, this new disease should be included in the differential diagnosis of unexplained graft dysfunction. In addition, treatment with steroids results in a dramatically improved outcome. However, maintenance therapy is usually required. (HEPATOLOGY 2002;35:349-356.)

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“…AIH spontaneously develops in genetically predisposed individuals, showing strong association with particular HLA (2,3) and allelic variants of other immune-related genes, such as CTLA-4 (4). Liver biopsies from AIH patients characteristically contain large numbers of CD4 ϩ Th1 cells (5), which produce high levels of the hepatotoxic cytokines IFN-␥ and TNF-␣ when stimulated ex vivo (6), suggesting that CD4 ϩ T cells contribute to the development and/or progression of hepatocellular damage.…”

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confidence: 99%

Necroinflammatory Liver Disease in BALB/c Background, TGF-β1-Deficient Mice Requires CD4+ T Cells

Rudner¹,

Lin

Park

et al. 2003

The Journal of Immunology

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The etiology of autoimmune liver disease is poorly understood. BALB/c mice deficient in the immunoregulatory cytokine TGF-β1 spontaneously develop necroinflammatory liver disease, but the immune basis for the development of this pathology has not been demonstrated. Here, we show that BALB/c-TGF-β1−/− mice exhibit abnormal expansion in hepatic mononuclear cells (MNCs) compared with wild-type littermate control mice, particularly in the T cell and macrophage lineages. To test whether lymphocytes of the adaptive immune system are required for the spontaneous development of necroinflammatory liver disease, BALB/c-TGF-β1−/− mice were rendered deficient in B and T cells by crossing them with BALB/c-recombinase-activating gene 1−/− mice. BALB/c-TGF-β1−/−/recombinase-activating gene 1−/− double-knockout mice showed extended survival and did not develop necroinflammatory liver disease. The cytolytic activity of BALB/c-TGF-β1−/− hepatic lymphocytes was assessed using an in vitro CTL assay. CTL activity was much higher in BALB/c-TGF-β1−/− hepatic MNCs compared with littermate control hepatic MNCs and was particularly pronounced in the CD4+ T cell subset. Experimental depletion of CD4+ T cells in young BALB/c-TGF-β1−/− mice prevented the subsequent development of necroinflammatory liver disease, indicating that CD4+ T cells are essential for disease pathogenesis in vivo. These data definitively establish an immune-mediated etiology for necroinflammatory liver disease in BALB/c-TGF-β1−/− mice and demonstrate the importance of CD4+ T cells in disease pathogenesis in vivo. Furthermore, TGF-β1 has a critical role in homeostatic regulation of the hepatic immune system, inhibiting the development or expansion of hepatic cytolytic CD4+ T cells.

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Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis†

Cited by 204 publications

References 47 publications

Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly

Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly

Response to steroids in de novo autoimmune hepatitis after liver transplantation

Necroinflammatory Liver Disease in BALB/c Background, TGF-β1-Deficient Mice Requires CD4+ T Cells

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