Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model

Hintermann, Edith; Holdener, Martin; Bayer, Monika; Loges, Stephanie; Pfeilschifter, Josef; Granier, Claude; Manns, Michael P.; Christen, Urs

doi:10.1016/j.jaut.2011.06.005

Cited by 52 publications

(53 citation statements)

References 44 publications

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“…Plasma from 4-week MCT rats produced banding in a range of sizes in all tissue lysates. This finding is consistent with reports of interepitope and intraepitope autoimmune spreading (20,21).…”

Section: Plasma From Ph Rats Contains Antifibroblast Antibodies Produsupporting

confidence: 94%

Bronchus-associated Lymphoid Tissue in Pulmonary Hypertension Produces Pathologic Autoantibodies

Colvin¹,

Cripe²,

Ivy³

et al. 2013

Am J Respir Crit Care Med

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Rationale: Autoimmunity has long been associated with pulmonary hypertension. Bronchus-associated lymphoid tissue plays important roles in antigen sampling and self-tolerance during infection and inflammation. Objectives: We reasoned that activated bronchus-associated lymphoid tissue would be evident in rats with pulmonary hypertension, and that loss of self-tolerance would result in production of pathologic autoantibodies that drive vascular remodeling. Methods: We used animal models, histology, and gene expression assays to evaluate the role of bronchus-associated lymphoid tissue in pulmonary hypertension. Measurements and Main Results: Bronchus-associated lymphoid tissue was more numerous, larger, and more active in pulmonary hypertension compared with control animals. We found dendritic cells in and around lymphoid tissue, which were composed of CD31 T cells over a core of CD45RA 1 B cells. Antirat IgG and plasma from rats with pulmonary hypertension decorated B cells in lymphoid tissue, resistance vessels, and adventitia of large vessels. Lymphoid tissue in diseased rats was vascularized by aquaporin-1 1 high endothelial venules and vascular cell adhesion molecule-positive vessels. Autoantibodies are produced in bronchus-associated lymphoid tissue and, when bound to pulmonary adventitial fibroblasts, change their phenotype to one that may promote inflammation. Passive transfer of autoantibodies into rats caused pulmonary vascular remodeling and pulmonary hypertension. Diminution of lymphoid tissue reversed pulmonary hypertension, whereas immunologic blockade of CCR7 worsened pulmonary hypertension and hastened its onset. Conclusions: Bronchus-associated lymphoid tissue expands in pulmonary hypertension and is autoimmunologically active. Loss of self-tolerance contributes to pulmonary vascular remodeling and pulmonary hypertension. Lymphoid tissue-directed therapies may be beneficial in treating pulmonary hypertension.Keywords: hypertension; pulmonary; lymphoid tissue; inflammation; autoimmunity Pulmonary hypertension (PH) is characterized by progressive increases in pulmonary artery pressure and pulmonary vascular resistance resulting in right ventricular failure (1). The primary histopathologic finding in PH is vascular remodeling, in which the pulmonary vasculature becomes stiff, occluded, and fibrotic (2). Vascular remodeling seems to require lung infiltration of inflammatory cells, and continual influx likely sustains a cycle of perpetual inflammation and remodeling by poorly defined mechanisms (3).The bronchovascular space is a structure that marries sterile (vasculature) and nonsterile (airway) components. Bronchusassociated lymphoid tissues (BALTs) are tertiary lymphoid organs that provide an elegant immune surveillance apparatus ensuring airway and vessel homeostatic patency. They are histologically similar to lymph nodes containing afferent lymphatic connection, B cells, T cells, antigen-presenting cells, stroma, and a vascular supply (4). The chief antigen-presenting cells in BALT are dendritic ce...

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Section: Plasma From Ph Rats Contains Antifibroblast Antibodies Produsupporting

confidence: 94%

Bronchus-associated Lymphoid Tissue in Pulmonary Hypertension Produces Pathologic Autoantibodies

Colvin¹,

Cripe²,

Ivy³

et al. 2013

Am J Respir Crit Care Med

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“…The hypothesis proposes that protracted or repeated exposure to foreign peptide sequences that are homologous to self-antigens can result in the loss of selftolerance, and it has been supported mainly by animal models [82,119,122,[181][182][183]. The infection of wild-type mice with an adenovirus expressing human CYP2D6 is able to break self-tolerance to mouse homologues of CYP2D6 and induce experimental autoimmune hepatitis [119,183].…”

Section: Insights Into Molecular Mimicry As a Basis For Autoimmunitymentioning

confidence: 99%

“…In patients with autoimmune hepatitis and animals infected with an adenovirus vector expressing human CYP2D6, the early humoral immune response is against the immune-dominant epitope of the human antigen [182]. The immune response later in the course of the disease involves epitopes in neighboring and remote regions of the human antigen, and sequence homologies to human pathogens have been recognized for all the involved epitopes [182].…”

Section: Insights Into Molecular Mimicry As a Basis For Autoimmunitymentioning

confidence: 99%

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

Czaja

2015

Dig Dis Sci

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Autoimmune hepatitis lacks an identifiable cause, and its diagnosis requires the exclusion of etiologically defined diseases that resemble it. Insights into its pathogenesis are moving autoimmune hepatitis from an idiopathic to explainable disease, and the goal of this review is to describe the insights that are hastening this transition. Two types of autoimmune hepatitis are justified by serological markers, but they also have distinctive genetic associations (DRB1 and DQB1 genes) and autoantigens. DRB1 alleles are the principal susceptibility factors in white adults, and a six amino acid sequence encoded in the antigen-binding groove of class II molecules of the major histocompatibility complex can influence the selection of autoantigens. Polymorphisms, including variants of SH2B3 and CARD10 genes, may affect immune reactivity and disease severity. The cytochrome mono-oxygenase, CYP2D6, is the autoantigen associated with type 2 autoimmune hepatitis, and it shares homologies with multiple viruses that might promote self-intolerance by molecular mimicry. Chemokines, especially CXCL9 and CXCL10, orchestrate the migration of effector cells to sites of injury and are associated with disease severity. Cells of the innate and adaptive immune responses promote tissue damage, and possible deficiencies in the number and function of regulatory T cells may facilitate the injurious process. Receptor-mediated apoptosis is the principal mechanism of hepatocyte loss, and cell-mediated and antibody-dependent mechanisms of cytotoxicity also contribute. Insights that explain autoimmune hepatitis will allow triggering exogenous antigens to be characterized, risk management to be improved, prognostic indices to be refined, and site-specific therapeutic interventions to emerge.

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“…In addition, the presence of high-titer anti-CYP2D6 antibodies with similar epitope specificity and spreading 13 to LKM-1 antibodies found in AIH-2 patients indicates the presence of a common chronic autoimmune reactivity. CYP2D6 is the major antigen in AIH-2, but it is not recognized by patients diagnosed with the more frequent type 1 AIH.…”

Section: Discussionmentioning

confidence: 91%

“…Fibrosis predominantly develops in the subcapsular region with some collagen bundles protruding into the parenchyma ( figure 3B). A third feature is the generation of high titers of anti-CYP2D6 antibodies, which have a similar epitope specificity to human LKM-1 antibodies 6,13 . Last, hCYP2D6-specific CD4 and CD8 T cells are generated that predominantly home to the liver.…”

Section: Representative Resultsmentioning

confidence: 99%

The CYP2D6 Animal Model: How to Induce Autoimmune Hepatitis in Mice

Hintermann

Ehser

Christen

2012

JoVE

Self Cite

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Autoimmune hepatitis is a rare but life threatening autoimmune disease of the liver of unknown etiology 1,2 . In the past many attempts have been made to generate an animal model that reflects the characteristics of the human disease [3][4][5] . However, in various models the induction of disease was rather complex and often hepatitis was only transient [3][4][5] . Therefore, we have developed a straightforward mouse model that uses the major human autoantigen in type 2 autoimmune hepatitis (AIH-2), namely hCYP2D6, as a trigger 6 . Type 1 liver-kidney microsomal antibodies (LKM-1) antibodies recognizing hCYP2D6 are the hallmark of AIH-2 7,8 . Delivery of hCYP2D6 into wildtype FVB or C57BL/6 mice was by an Adenovirus construct (Ad-2D6) that ensures a direct delivery of the triggering antigen to the liver. Thus, the ensuing local inflammation generates a fertile field 9 for the subsequent development of autoimmunity. A combination of intravenous and intraperitoneal injection of Ad-2D6 is the most effective route to induce a long-lasting autoimmune damage to the liver (section 1). Here we provide a detailed protocol on how autoimmune liver disease is induced in the CYP2D6 model and how the different aspects of liver damage can be assessed. First, the serum levels of markers indicating hepatocyte destruction, such as aminotransferases, as well as the titers of hCYP2D6 antibodies are determined by sampling blood retroorbitaly (section 2). Second, the hCYP2D6-specific T cell response is characterized by collecting lymphocytes from the spleen and the liver. In order to obtain pure liver lymphocytes, the livers are perfused by PBS via the portal vein (section 3), digested in collagen and purified over a Percoll gradient (section 4). The frequency of hCYP2D6-specific T cells is analyzed by stimulation with hCYP2D6 peptides and identification of IFNγ-producing cells by flow cytometry (section 5). Third, cellular infiltration and fibrosis is determined by immunohistochemistry of liver sections (section 6). Such analysis regimen has to be conducted at several times after initiation of the disease in order to prove the chronic nature of the model. The magnitude of the immune response characterized by the frequency and activity of hCYP2D6-specific T and/or B cells and the degree of the liver damage and fibrosis have to be assessed for a subsequent evaluation of possible treatments to prevent, delay or abrogate the autodestructive process of the liver.

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Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model

Cited by 52 publications

References 44 publications

Bronchus-associated Lymphoid Tissue in Pulmonary Hypertension Produces Pathologic Autoantibodies

Bronchus-associated Lymphoid Tissue in Pulmonary Hypertension Produces Pathologic Autoantibodies

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

The CYP2D6 Animal Model: How to Induce Autoimmune Hepatitis in Mice

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