A murine model of type 2 autoimmune hepatitis: Xenoimmunization with human antigens

Lapierre, Pascal; Djilali-Saiah, Idriss; Vitozzi, Susana; Álvarez, Fernando

doi:10.1002/hep.20109

Cited by 142 publications

(145 citation statements)

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“…Studies on AIH susceptibility factors, including its sex bias, have been severely limited by the lack of experimental models. Recently, a murine experimental model of AIH has been produced 9 in which mice develop a disease very similar to that observed in humans. 10 This murine model of type 2 AIH is initiated by xenoimmunization of 6-week-old to 8-weekold female C57BL/6 mice with human type 2 AIH antigens that, by molecular mimicry, triggers an autoreactive immune response against homologous murine liver proteins.…”

Section: Foxp3mentioning

confidence: 93%

“…Experimental AIH was induced in mice by xenoimmunization as previously described. 9,11 Briefly, C57BL/6 or B6.129S2-Aire tm1.1Doi /J mice (male or female at 4, 7, or 14 weeks of age) were injected in the tibialis cranialis muscle with 100 lg (50 lL) of plasmids coding for type 2 AIH human autoantigens and murine interleukin (IL)-12 (pRc/CMV-CTLA-4-CYP2D6-FTCD and pVR-IL12) 9,11 dissolved in saline buffer. Mice were injected three times, at 2-week intervals.…”

Section: Methodsmentioning

confidence: 99%

“…Enzymelinked immunosorbent assay was performed as described. 9,11,14 Briefly, the fusion protein produced by the pMAL-cR1-CYP2D6-FTCD plasmid (human FTCD and CYP2D6) or pEt-30C-mFTCD (murine FTCD) or pEt-30c-CYP2D9 (murine member of the P450 2D subfamily homologous to human CYP2D6) were purified and used as antigen in the enzyme-linked immunosorbent assay (0.2 lg/well). An antiserum was considered positive if its specific OD was at least 2 times higher than the mean optical density of the preimmune mice sera.…”

Section: Methodsmentioning

confidence: 99%

“…The western blot technique was carried out as previously described. 9,11 Flow Cytometry Analysis. Regulatory T cells' frequency in blood, spleen, or amongst liver-infiltrating lymphocytes was assessed by simultaneous surface and intracellular immunofluorescence staining using the mouse regulatory T cell staining kit (eBioscience, CA).…”

Section: Methodsmentioning

confidence: 99%

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Forkhead box p3+ regulatory T cell underlies male resistance to experimental type 2 autoimmune hepatitis

et al. 2010

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Autoimmune hepatitis (AIH), like many autoimmune diseases, is most prevalent in young women. The immunological basis of this age and sex susceptibility bias was investigated in a murine model of AIH. Xenoimmunization of 7-week-old female C57BL/6 mice resulted in more severe AIH with higher levels of liver inflammation, serum alanine aminotransferase, specific T-cell cytotoxicity, and autoantibody than younger and older females. Vaccinated males developed minimal liver inflammation and higher percentages of CD4 FoxP31 regulatory T cell in peripheral blood mononuclear cells, spleen, and liver than females. Regulatory T cells (Tregs) were virtually absent in liver-lymphocytes infiltrates of females. Castration of C57BL/6 mice, with or without 17b-estradiol supplementation, did not modify susceptibility in males, nor Treg numbers, suggesting minimal contribution of testosterone and estradiol to autoimmune hepatitis (AIH) susceptibility. Xenoimmunized Aire(1/0) mouse displayed similar AIH susceptibility, sex bias, and Tregs numbers as C57BL/6 mice, suggesting that susceptibility in females is not the result of less stringent thymic central tolerance. Autoreactive B cell response against formiminotransferase-cyclodeaminase correlated with disease activity, possibly linking B-cell autoreactivity and AIH pathogenesis. Conclusion: Peripheral tolerance and development of regulatory T cells after self-mimicking antigen exposure, and not sexual hormone nor central tolerance, are the main factors for susceptibility to AIH in females. (HEPATOLOGY 2010;51:1789-1798 P revalence of most autoimmune diseases shows a striking sex difference, with women being affected more often than men.1,2 The ratio of female patients to male ranges from 20:1 in Sjögren's syndrome, to 3:2 in multiple sclerosis.2 Less frequently, the ratio approaches 1:1, as in ulcerative colitis and diabetes.2 In autoimmune hepatitis (AIH), the female to male ratio ranges from 3:1 in type 1 AIH to 9:1 in type 2 AIH. 3Differences in the immune response have also been observed between women and men. Higher level of antibodies and stronger T cell activation are observed in women after vaccination. 4 Women also have higher absolute numbers of CD4 þ T cells and produce higher levels of Th1 cytokines than men.5 Age also affects immune responses, including incidence of several autoimmune diseases. In AIH, 40% of cases of type 1 are diagnosed before the age of 18 years, with a mean age at onset of 10 years, 6,7 and 80% of cases of type 2 are diagnosed before the age of 18 years, with a mean age at onset of 6.5 years.6,7 A second peak of incidence of AIH has also been reported in women after menopause.8 These prepubertal and postmenopausal peaks of incidence suggest that the hormonal status could influence susceptibility to AIH.Research on autoimmune diseases sex bias is scarce. Studies on AIH susceptibility factors, including its sex bias, have been severely limited by the lack of experimental models. Recently, a murine experimental model of AIH has been produced 9 in whi...

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Section: Foxp3mentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Forkhead box p3+ regulatory T cell underlies male resistance to experimental type 2 autoimmune hepatitis

et al. 2010

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“…[25][26][27] In contrast, a plausible model of type 2 AIH has been generated in mice by DNA immunization against type 2 AIH self-antigens. 28 In this issue of HEPATOLOGY, Yamauchi et al describe yet another putative animal model of AIH. 29 The work is an extension of their recent studies on the generation of a human IgM ( -type) monoclonal antibody (MoAb) by Epstein-Barr virus (EBV) transformation of peripheral blood mononuclear cells from a Japanese patient with type 1 AIH.…”

mentioning

confidence: 99%

Of mice and women: Toward a mouse model of autoimmune hepatitis

Heneghan

McFarlane

2005

Hepatology

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Autoimmune Hepatitis

Lapierre

2018

Encyclopedia of Life Sciences

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Autoimmune hepatitis (AIH) is an organ‐specific autoimmune disease resulting from a loss of immunological tolerance against hepatocyte autoantigens. In the absence of treatment, this disease is fatal. Distinctive characteristics of AIH include hypergammaglobulinemia, presence of autoantibodies and interface hepatitis with lymphoplasmacytic infiltrates. AIH is a rare disease with an estimated point prevalence in Europe and North America of 50–200 cases per million. The pathogenesis of AIH remains unknown. AIH is believed to result from a combination of liver‐specific susceptibility factors, faulty immune tolerance mechanisms (central and peripheral) as well as host and environmental susceptibility factors. Patients respond well to immunosuppressive treatment, but 10–20% of patients are unable to achieve remission using standard treatment. Through a better understanding of AIH pathogenesis as well as cellular(s) and molecular(s) effectors involved, new and effective site‐specific immunotherapies are being developed to induce long‐term remission in patients with minimal deleterious side effects. Key Concepts Autoimmune hepatitis is characterised by a loss of tolerance against hepatocytes leading to the progressive destruction of the hepatic parenchyma. About 70–90% of AIH patients are women. Hallmark characteristics of AIH include hypergammaglobulinemia, presence of autoantibodies and an interface hepatitis with lymphoplasmacytic infiltrates. Type 1 AIH is characterised by the presence of ANA and/or SMA autoantibodies while Type 2 AIH is characterised by the presence of anti‐LKM1 and/or anti‐LC1 autoantibodies. There is a genetic association between AIH and HLA class II genes suggesting a role for CD4 + T cells autoimmune response in AIH pathogenesis. Conventional therapy for AIH patients consists of nonspecific immunosuppression, usually through the use of a combination of prednisone/prednisolone and azathioprine. New biologics‐based specific immunotherapies are currently in development and aim to induce long‐term remission with minimal unwanted side effects.

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A murine model of type 2 autoimmune hepatitis: Xenoimmunization with human antigens

Cited by 142 publications

References 41 publications

Forkhead box p3+ regulatory T cell underlies male resistance to experimental type 2 autoimmune hepatitis

Forkhead box p3+ regulatory T cell underlies male resistance to experimental type 2 autoimmune hepatitis

Of mice and women: Toward a mouse model of autoimmune hepatitis

Autoimmune Hepatitis

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