Catherine A Chapin1, Thomas Burn2, Tomas Meijome2, Kathleen M Loomes2, Hector Melin-Aldana3, Portia A Kreiger4, Peter F Whitington1, Edward M Behrens2, Estella M Alonso1. 1. Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL. 2. Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA. 3. Department of Pathology and Laboratory Medicine, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL. 4. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA.
Abstract
The cause of pediatric acute liver failure (PALF) is unknown in up to 40% of cases. Evidence suggests that aberrant immune system activation may play a role. We hypothesized that indeterminate PALF cases would exhibit a unique pattern of hepatic inflammation. This was a retrospective and prospective study of PALF cases due to indeterminate (iPALF), autoimmune hepatitis, or known diagnosis (dPALF) etiology. Liver tissue sections were stained with immunohistochemical markers for cytotoxic T-cells (cluster of differentiation 8 [CD8]), perforin, and tissue resident memory T-cells (CD103) and scored as minimal, moderate, or dense. Lymphocytes were isolated from liver tissue for T-cell receptor beta sequencing and flow-cytometric studies. Thirty-three iPALF, 9 autoimmune hepatitis, and 14 dPALF cases were included. Dense hepatic infiltrates of CD8+ T-cells were found in 27 (82%) iPALF cases compared to 1 (7%) dPALF case (P < 0.0001). Perforin staining was dense or moderate in 19 (73%) of 26 iPALF cases compared to minimal in all 7 dPALF cases (P = 0.004); 16 (62%) of 26 iPALF cases had dense CD103 staining compared to none of the 6 dPALF cases (P = 0.001). T-cell receptor beta sequencing of iPALF cases demonstrated increased clonality compared to dPALF and control cases. Flow cytometry and immunohistochemistry revealed that iPALF intrahepatic leukocytes were predominantly tissue resident memory CD8+ T-cells. CONCLUSION: Indeterminate PALF is characterized by a dense CD8+ T-cell hepatic infiltrate consistent with expansion of a tissue resident memory T-cell phenotype; CD8+ T-cells are a biomarker of immune dysregulation in iPALF and may be used to better identify and define this group. (Hepatology 2018).
The cause of pediatric acute liver failure (PALF) is unknown in up to 40% of cases. Evidence suggests that aberrant immune system activation may play a role. We hypothesized that indeterminate PALF cases would exhibit a unique pattern of hepatic inflammation. This was a retrospective and prospective study of PALF cases due to indeterminate (iPALF), autoimmune hepatitis, or known diagnosis (dPALF) etiology. Liver tissue sections were stained with immunohistochemical markers for cytotoxic T-cells (cluster of differentiation 8 [CD8]), perforin, and tissue resident memory T-cells (CD103) and scored as minimal, moderate, or dense. Lymphocytes were isolated from liver tissue for T-cell receptor beta sequencing and flow-cytometric studies. Thirty-three iPALF, 9 autoimmune hepatitis, and 14 dPALF cases were included. Dense hepatic infiltrates of CD8+ T-cells were found in 27 (82%) iPALF cases compared to 1 (7%) dPALF case (P < 0.0001). Perforin staining was dense or moderate in 19 (73%) of 26 iPALF cases compared to minimal in all 7 dPALF cases (P = 0.004); 16 (62%) of 26 iPALF cases had dense CD103 staining compared to none of the 6 dPALF cases (P = 0.001). T-cell receptor beta sequencing of iPALF cases demonstrated increased clonality compared to dPALF and control cases. Flow cytometry and immunohistochemistry revealed that iPALF intrahepatic leukocytes were predominantly tissue resident memory CD8+ T-cells. CONCLUSION: Indeterminate PALF is characterized by a dense CD8+ T-cell hepatic infiltrate consistent with expansion of a tissue resident memory T-cell phenotype; CD8+ T-cells are a biomarker of immune dysregulation in iPALF and may be used to better identify and define this group. (Hepatology 2018).
Authors: Catherine A Chapin; Sarah A Taylor; Padmini Malladi; Katie Neighbors; Hector Melin-Aldana; Portia A Kreiger; Nina Bowsher; Matthew J Schipma; Kathleen M Loomes; Edward M Behrens; Estella M Alonso Journal: Hepatol Commun Date: 2021-05-06
Authors: Sonia Ghilas; Ana-Maria Valencia-Hernandez; Matthias H Enders; William R Heath; Daniel Fernandez-Ruiz Journal: Int J Mol Sci Date: 2020-11-13 Impact factor: 5.923