Genetic aspects of adult and pediatric autoimmune hepatitis: A concise review

Engel, Bastian; Laschtowitz, Alena; Janik, Maciej K.; Junge, Norman; Baumann, Ulrich; Milkiewicz, Piotr; Taubert, Richard; Sebode, Marcial

doi:10.1016/j.ejmg.2021.104214

Cited by 12 publications

(8 citation statements)

References 222 publications

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“…Table 2 summarizes all non-HLA susceptibility variants from GWMA studies for AIH, PBC, and PSC. For a review of non-HLA susceptibility variants for AIH, PBC, and PSC from monocentric studies, including candidate studies, see Engel et al [ 56 ], Gerussi et al [ 41 ], and Chung/Hirschfeld [ 57 ], respectively. For PBC, Bayesian fine-mapping was recently performed for the 55 non-HLA PBC susceptibility loci [ 53 ].…”

Section: Non-hla-related Genetic Associations From Gwasmentioning

confidence: 99%

How genetic risk contributes to autoimmune liver disease

Ellinghaus

2022

Semin Immunopathol

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Genome-wide association studies (GWAS) for autoimmune hepatitis (AIH) and GWAS/genome-wide meta-analyses (GWMA) for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) have been successful over the past decade, identifying about 100 susceptibility loci in the human genome, with strong associations with the HLA locus and many susceptibility variants outside the HLA locus with relatively low risk. However, identifying causative variants and genes and determining their effects on liver cells and their immunological microenvironment is far from trivial. Polygenic risk scores (PRSs) based on current genome-wide data have limited potential to predict individual disease risk. Interestingly, results of mediated expression score regression analysis provide evidence that a substantial portion of gene expression at susceptibility loci is mediated by genetic risk variants, in contrast to many other complex diseases. Genome- and transcriptome-wide comparisons between AIH, PBC, and PSC could help to better delineate the shared inherited component of autoimmune liver diseases (AILDs), and statistical fine-mapping, chromosome X-wide association testing, and genome-wide in silico drug screening approaches recently applied to GWMA data from PBC could potentially be successfully applied to AIH and PSC. Initial successes through single-cell RNA sequencing (scRNA-seq) experiments in PBC and PSC now raise high hopes for understanding the impact of genetic risk variants in the context of liver-resident immune cells and liver cell subpopulations, and for bridging the gap between genetics and disease.

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Section: Non-hla-related Genetic Associations From Gwasmentioning

confidence: 99%

How genetic risk contributes to autoimmune liver disease

Ellinghaus

2022

Semin Immunopathol

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“…However, the acquired capacity of HCs to present antigen on MHC class II molecules is not sufficient to cause AIH ( 54 ). Further investigations are required to clarify the increased risk for AIH conferred by the expression of certain human leukocyte antigen (HLA)-DR and HLA-DQ loci ( 14 , 15 ).…”

Section: Initiation Of the Autoimmune Responsementioning

confidence: 99%

Impact of Antigen Presentation Mechanisms on Immune Response in Autoimmune Hepatitis

et al. 2022

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The liver is a very tolerogenic organ. It is continually exposed to a multitude of antigens and is able to promote an effective immune response against pathogens and simultaneously immune tolerance against self-antigens. In spite of strong peripheral and central tolerogenic mechanisms, loss of tolerance can occur in autoimmune liver diseases, such as autoimmune hepatitis (AIH) through a combination of genetic predisposition, environmental factors, and an imbalance in immunological regulatory mechanisms. The liver hosts several types of conventional resident antigen presenting cells (APCs) such as dendritic cells, B cells and macrophages (Kupffer cells), and unconventional APCs including liver sinusoidal endothelial cells, hepatic stellate cells and hepatocytes. By standard (direct presentation and cross-presentation) and alternative mechanisms (cross-dressing and MHC class II-dressing), liver APCs presents self-antigen to naive T cells in the presence of costimulation leading to an altered immune response that results in liver injury and inflammation. Additionally, the transport of antigens and antigen:MHC complexes by trogocytosis and extracellular vesicles between different cells in the liver contributes to enhance antigen presentation and amplify autoimmune response. Here, we focus on the impact of antigen presentation on the immune response in the liver and on the functional role of the immune cells in the induction of liver inflammation. A better understanding of these key pathogenic aspects could facilitate the establishment of novel therapeutic strategies in AIH.

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“…The majority of reports of HLA associations with AILD are from adults and include HLA class I ( A*01, B*08 ) and HLA class II alleles ( DRB1*03, -04, -07 and/or -13 ) ( 5 ). Children with AILD are unique compared to their adult counterparts based on higher incidences of type 2 AIH [anti-liver kidney microsomal type 1 (LKM1) and/or anti-liver cytosol type 1 (LC1) antibody positivity] and ASC ( 6 ).…”

Section: Hla Associations In Pediatric Aildmentioning

confidence: 99%

“…With regard to HLA DRB1*04 , the aforementioned pediatric Finnish report likewise showed no HLA DRB1*04 positivity in those with either AIH, ASC or PSC ( 16 ). In contrast, HLA DRB1*04 is considered a disease susceptibility HLA genotype in adults with AIH ( 5 ). The DRB1*04 risk allele in adult AIH is associated with a later age of onset of AIH ( 19 ) and likely represents a novel subtype of AIH not found in children.…”

Section: Hla Genotypes That Are Protective From Aildmentioning

confidence: 99%

HLA Associations in pediatric autoimmune liver diseases: Current state and future research initiatives

Mack

2022

Front. Immunol.

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The strongest genetic association with autoimmunity is within chromosome 6p21, where the human leukocyte antigen (HLA) complex resides. This review will focus on the HLA associations within pediatric autoimmune hepatitis, autoimmune sclerosing cholangitis and primary sclerosing cholangitis. In general, there is considerable overlap in HLA genotypes conferring susceptibility to pediatric autoimmune liver diseases, however unique HLA associations and protective HLA genotypes exist. There are numerous areas for future research initiatives in pediatric autoimmune liver diseases and HLA associations with clinical outcomes, autoantigen discovery and novel therapeutics targeting the HLA- autoantigen- T cell pathway will be highlighted.

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Genetic aspects of adult and pediatric autoimmune hepatitis: A concise review

Cited by 12 publications

References 222 publications

How genetic risk contributes to autoimmune liver disease

How genetic risk contributes to autoimmune liver disease

Impact of Antigen Presentation Mechanisms on Immune Response in Autoimmune Hepatitis

HLA Associations in pediatric autoimmune liver diseases: Current state and future research initiatives

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