Williamwhite Essay Writing

With the prevalence of obesity, diabetes, and other metabolic diseases caused by so-called "American high-fat and high-sugar diets", the nonalcoholic fatty liver disease (NAFLD) has increasingly become one of the major concerns worldwide. NAFLD may develop from simple steatosis into nonalcoholic steatohepatitis (NASH) and further progress to severe liver fibrosis, cirrhosis, and other end-stage liver diseases. Though lipotoxicity-elicited, innate, and adaptive immunity-mediated inflammation and subsequent autoimmune reactions are believed to be key pathological factors in the development and progression of steatohepatitis, the relationship between the immune system and NASH has not been completely characterized yet.

Researchers have developed animal models of NASH by feeding mice that have a type 2 diabetes-like syndrome a high-fat and high-sugar diet for three months. Then these models grow obese and NASH-like fat starts to accumulate around their livers, which enables researchers to examine their liver immune cells and find out how is the immune system involved in the NASH pathogenesis.

Innate immunity in NASH

Kupffer cells (KCs) situated on the liver sinusoids and lymph nodes are primary tissue-specific macrophages in the liver, the major function of which is to remove pathogens or bacteria-derived toxins and debris and generate innate immune responses. Researchers were able to demonstrate the role of KCs in NASH by depleting hepatic KCs using clodronate liposomes or gadolinium chloride, which alleviates liver steatosis and inflammation in NASh animal models. Moreover, the C-C motif chemokine receptor 2 (CCR2+) monocytes derived from bone marrow and recruited to the liver by CCR2, are crucial in contributing to hepatic fibrosis, since their inhibition features have been reported to the NASH target for CCL2-CCR2.

Adaptive immunity in NASH

Recent investigation displayed that in addition to innate immunity, adaptive immunity also plays a critical part in the pathogenesis of NASH. In a study published in Science Immunology, researchers looked into the changes in cell behavior of NASH animal models, focusing on whether adaptive immunity, to which T cells and B cells belong, was involved in NASH progress. In this study, researchers found a type of immune cell called dendritic cell is stressed to show T cells and B cells antigens or pathogens and train them to attack threats. This process is known as antigen presentation and grants T cells and B cells antigen-specific ability to target only certain antigens.

Under this condition, dendritic cells in the livers of NASH mouse models presented a protein called PDIA3 to other immune cells. However, T cells and B cells also mistakenly gain antigen specificity to this protein, leading to the production and accumulation of autoantibodies that could induce liver toxicity. That's to say, T cells and B cells could also be pathogenic in NASH and harm liver cells.

By analyzing serum from patients with autoimmune hepatitis, researchers further demonstrated that PDIA3 protein is a target not only during chronic inflammation but also in an autoimmune disease, indicating the possibility in the future to discover novel targets for NASH therapy and other autoimmune diseases.

Although significant advancement has been seen in demonstrating the mechanism of chronic inflammation and the role of immune cells in NASH, many critical questions remain unanswered. Hopefully, researchers can gain more insights into the underlying cellular and molecular mechanisms of NASH and identify new potential therapeutic targets through advanced techniques, such as single-cell or single-nucleus RNA sequencing combined with interactive analysis.