Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2

Bittencourt, Paulo Lisboa; Goldberg, Anna Carla; Cançado, Eduardo Luiz Rachid; Porta, Gilda; Carrilho, Flair José; Farias, Alberto Queiróz; Palácios, Selma A.; Chiarella, Josely Marchi; Abrantes-Lemos, Clarice Pires; Baggio, Vera Lúcia; Laudanna, Antônio Atílio; Kalil, Jorge

doi:10.1016/s0002-9270(99)00285-3

Cited by 51 publications

(16 citation statements)

References 38 publications

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“…The RR of HLA-DR4 for type 1 AIH is 2.14, much higher than that for the Italian/North American-type 1 AIH. Other HLA-DR antigens, including HLA-DR13 and HLA-DR3 (DR17 or DR18) [ 28 – 31 ], were not associated with AIH in our study population.…”

Section: Discussionmentioning

confidence: 75%

Evaluation of the role of HLA-DR antigens in Japanese type 1 autoimmune hepatitis

et al. 2015

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BackgroundThe role of HLA-DR antigens in the clinicopathological features of autoimmune hepatitis (AIH) is not clearly understood. We examined the implications of HLA-DR antigens in Japanese AIH, including the effect of HLA-DR4 on the age and pattern of AIH onset, clinicopathological features, and treatment efficacy.MethodsA total of 132 AIH patients consecutively diagnosed and treated in 2000–2014 at 2 major hepatology centers of eastern Tokyo district were the subjects of this study. The frequency of HLA-DR phenotypes was compared with that in the healthy Japanese population. AIH patients were divided into HLA-DR4–positive or HLA-DR4–negative groups and further sub-classified into elderly and young-to-middle-aged groups, and differences in clinical and histological features were examined. Clinical features associated with the response to immunosuppressive therapy were also determined.ResultsThe frequency of the HLA-DR4 phenotype was significantly higher in AIH than in control subjects (59.7 % vs. 41.8 %, P < 0.001), and the relative risk was 2.14 (95 % CI; 1.51–3.04). HLA-DR4–positive AIH patients were younger than HLA-DR4–negative patients (P = 0.034). Serum IgG and IgM levels were higher (P < 0.001 and P = 0.007, respectively) in HLA-DR4–positive patients. These differences were more prominent in elderly AIH patients. However, there was no difference in IgG and IgM levels between HLA-DR4–positive and HLA-DR4–negative patients of the young-to-middle-aged group. There were no differences in the histological features. In patients with refractory to immunosuppressive therapy, higher total bilirubin, longer prothrombin time, lower serum albumin, and lower platelet count were found. Imaging revealed splenomegaly to be more frequent in refractory patients than in non-refractory patients (60.0 % vs. 30.8 %, P = 0.038). HLA-DR phenotype distribution was similar regardless of response to immunosuppressive therapy.ConclusionsHLA-DR4 was the only DR antigen significantly associated with Japanese AIH. The clinical features of HLA-DR4–positive AIH differed between elderly patients and young-to-middle-aged patients. Treatment response depended on the severity of liver dysfunction but not on HLA-DR antigens.

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Section: Discussionmentioning

confidence: 75%

Evaluation of the role of HLA-DR antigens in Japanese type 1 autoimmune hepatitis

et al. 2015

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“… 30 The primary genetic associations with autoimmune hepatitis pertain to the HLA region of the major histocompatibility complex (MHC) locus on chromosome six. 31 The clinical manifestations of disease are variable and an individual's symptomatology can follow an undulating course. Diagnosis is based on clinical, histological, biochemical, and serological findings.…”

Section: Discussionmentioning

confidence: 99%

Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury

et al. 2015

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Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophen-mediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.

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“…In Latin Americans, DRB1*1301 is correlated with susceptibility to type 1 AIH 18. DRB1*1301 is also correlated with child type 1 AIH in Germany 19.…”

Section: Immunogenetic Background Of Aihmentioning

confidence: 97%

Autoimmune hepatitis: current challenges and future prospects

Aizawa¹,

Hokari²

2017

CEG

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Autoimmune hepatitis (AIH) is a chronic progressive liver disease characterized by high levels of aminotransferases and autoantibodies, hypergammaglobulinemia, and interface hepatitis. AIH affects all races and all ages worldwide, regardless of sex, although a preponderance of females is a constant finding. The etiology of AIH has not been completely elucidated, but immunogenetic background and environmental parameters may contribute to its development. The most important genetic factor is human leukocyte antigens (HLAs), especially HLA-DR, whereas the role of environmental factors is not completely understood. Immunologically, disruption of the immune tolerance to autologous liver antigens may be a trigger of AIH. The diagnosis of classical AIH is fairly easy, though not without pitfalls. In contrast, the diagnosis of atypical AIH poses great challenges. There is confusion as to the definition of the disease entity and its boundaries in the diagnosis of overlap syndrome, drug-induced autoimmune hepatitis, and AIH with concomitant nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C. Centrilobular zonal necrosis is now included in the histological spectrum of AIH. However, the definition and the significance of AIH presenting with centrilobular zonal necrosis have not been examined extensively. In ~20% of AIH patients who are treated for the first time with standard therapy, remission is not achieved. The development of more effective and better tolerated novel therapies is an urgent need. In this review, we discuss the current challenges and the future prospects in relation to the diagnosis and treatment of AIH, which have been attracting considerable recent attention.

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Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2

Cited by 51 publications

References 38 publications

Evaluation of the role of HLA-DR antigens in Japanese type 1 autoimmune hepatitis

Evaluation of the role of HLA-DR antigens in Japanese type 1 autoimmune hepatitis

Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury

Autoimmune hepatitis: current challenges and future prospects

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