Hepatic lymphocytes involved in the pathogenesis of pediatric and adult non-alcoholic fatty liver disease

Victoria Cairoli,Elena De Matteo,Paola Casciato,Carol Lezama,Gustavo Bertot,Cecilia Giadans,Marcela Galoppo,Pamela Valva,Daniela Rios,María Victoria Preciado,Eduardo Mullen

doi:10.1038/s41598-021-84674-z

Abstract

The immune response is critical in NAFLD pathogenesis, but the liver infiltrate’s composition and the role of each T cell population is still up for debate. To characterize liver pathogenesis in pediatric and adult cases, frequency and localization of immune cell populations [Cytotoxic T Lymphocytes (CD8+), T helper Lymphocytes (CD4+), Regulatory T lymphocytes (Foxp3+) and Th17 (IL-17A+)] were evaluated. In portal/periportal (P/P) tracts, both age groups displayed a similar proportion of CD8+ and CD4+ lymphocytes. However, comparable Foxp3+ and IL-17A+ cell frequencies were observed in pediatric cases, meanwhile, in adults Foxp3+ was higher than IL-17A+ cells. Interestingly, IL-17A+ lymphocytes seemed to be nearly exclusive of P/P area in both age groups. In intralobular areas, both pediatric and adult cases showed CD8+ lymphocytes predominance with lower frequencies of CD4+ lymphocytes followed by Foxp3+ . Severe inflammation was associated with higher intralobular Foxp3+ lymphocytes (p = 0.026) in children, and lower P/P Foxp3+ and higher IL-17A+ lymphocytes in adults. All cases with fibrosis ≥ 2 displayed P/P low Foxp3+ and high IL-17A+ lymphocyte counts. Pediatric cases with worse steatosis showed high P/P CD4+ (p = 0.023) and intralobular CD8+ (p = 0.027) and CD4+ cells (p = 0.012). In NAFLD cases, the lymphocyte liver infiltrate composition differs between histological areas. Treg and Th17 balance seems to condition damage progression, denoting their important role in pathogenesis.

Highlights

The immune response is critical in Non-alcoholic fatty liver disease (NAFLD) pathogenesis, but the liver infiltrate’s composition and the role of each T cell population is still up for debate
Non-alcoholic fatty liver disease (NAFLD) represents a serious nutritional worry which arises from the high prevalence of overweight and obesity because it is the most common form of chronic liver illness in children and adults[1]
NAFLD is characterized by an excessive hepatic fat accumulation and includes two conditions with different prognoses: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH)[6]

Summary

Introduction

The immune response is critical in NAFLD pathogenesis, but the liver infiltrate’s composition and the role of each T cell population is still up for debate. The fibrosis progression correlates with liverrelated outcomes and death; it is the most significant prognostic factor[10] It is still a matter of debate which are the complex pathophysiological pathways that participate in the progression from simple steatosis to NASH with the consequent liver damage, but it is taken for sure the existence of a crosstalk between various metabolically active t issues[11]. In this metabolic disease, insulin resistance, hepatic fatty acid accumulation, oxidative stress, mitochondrial dysfunction, and a systemic proinflammatory state are involved in liver damage and inflammation, in consequence, NASH could be assumed as a multifactorial condition. While sustained intrahepatic inflammation is considered critical in the progression from simple steatosis to NASH; it is still not clear the infiltrate composition and the role of each cell population in the pathogenesis

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