Role of USP35 in the Detection of Ferroptosis in Juvenile Autoimmune Hepatitis: an Immunohistochemical Study

Autoimmune hepatitis (AIH) is a rare and chronic inflammatory disease of the liver of unknown etiology characterized by loss of immune tolerance against liver antigens leading to progressive destruction of hepatic parenchyma and if untreated leads to end-stage liver disease.

It affects all ages with a peak incidence in pediatric age, where it is referred to as Juvenile Autoimmune Hepatitis (JAIH).JAIH is a long-term condition that varies in intensity over time. It occurs more frequently in females and is marked by increased levels of serum gamma globulins, the presence of autoantibodies in the bloodstream, and interface hepatitis observed in liver histology. JAIH can occur at any age from infancy to adolescence with an incidence reported of 0.4 and a prevalence of 3.0 per 100,000 children, respectively. Diagnosing the condition can be difficult and relies on a mix of clinical, biochemical, immunological, and histological indicators, as well as ruling out any other known causes that could present similar characteristics to JAIH. Certain circulating autoantibodies are crucial indicators of the disease. AIH type 1 is characterized by anti-smooth Muscle Antibodies (SMA) and/or anti-nuclear Antibodies (ANA), AIH type 2 is defined by the detection of anti-Liver-Kidney Microsomal antibody type 1 (LKM1) and/or of anti-Liver-Cytosol antibody type 1 (LC1). Approximately 20% of children exhibiting clinical, biochemical, and histological characteristics of autoimmune hepatitis do not have either typical or atypical autoantibodies, including anti-soluble liver antigen (anti-SLA) or atypical perinuclear anti-neutrophil cytoplasmic antibody (pANCA). These individuals form a diverse category of inflammatory liver conditions referred to as "seronegative autoimmune hepatitis." A liver biopsy is frequently required to make a diagnosis in atypical situations. Histological examination helps assess the level of necro-inflammation and the extent of fibrosis. The majority of biopsies taken from children with JAIH display moderate to severe interface hepatitis and lobular inflammation. Interface hepatitis is characterized by a pronounced infiltration of mononuclear cells in the portal and periportal areas, including CD4 and CD8 T cells, macrophages, plasma cells, and, on occasion, eosinophils. Emperipolesis, which involves the infiltration of CD8 T-lymphocytes into hepatocytes, is regarded as a distinctive characteristic of autoimmune hepatitis. Its occurrence is linked to more severe necroinflammatory traits and increased levels of fibrosis.

An overview of ferroptosis:

In 2012, Dixon et al. formally named a new type of cell death as ferroptosis, according to its characteristics when studying the mechanism by which erastin killed cancer cells with RAS mutations. Ferroptosis is a new mode of cell death. Morphologically, ferroptosis presents mainly in cells as reduced mitochondrial volume, increased bilayer membrane density and reduction or disappearance of mitochondrial cristae but the cell membrane is still intact, the nucleus is normal in size, and there is no condensation of chromatin; biochemically, there is intracellular glutathione (GSH) depletion and decreased activity of glutathione peroxidase 4 (GPX4), lipid peroxides cannot be metabolized by the GPX4-catalyzed reduction reaction, and Fe2+ oxidizes lipids in a Fenton-like manner, resulting in a large amount of ROS, which induces ferroptosis and genetically, ferroptosis is a biological process regulated by multiple genes. Ferroptosis mainly includes genetic changes in iron homeostasis and lipid peroxidation metabolism, but the specific regulatory mechanism is still in a need to be further studied.As research continues, ferroptosis has been shown to be involved in the development and progression of autoimmune and inflammatory diseases.

Mechanism of ferroptosis: