Activated CD8 T-cell Hepatitis in Children With Indeterminate Acute Liver Failure: Results From a Multicenter Cohort
| Autor: | Lorena A. Ostilla, Portia A. Kreiger, Mike A. Leonis, Sarah A. Taylor, Katie Neighbors, Catherine A Chapin, Robert H. Squires, Simon Horslen, Hector Melin-Aldana, Estella M. Alonso, Joshua B. Wechsler, Thomas Burn, Edward M. Behrens, Kathleen M. Loomes |
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| Rok vydání: | 2020 |
| Předmět: |
Pathology
medicine.medical_specialty Adolescent Pilot Projects CD8-Positive T-Lymphocytes Hepatitis Cohort Studies 03 medical and health sciences 0302 clinical medicine Antigen 030225 pediatrics medicine Humans Cytotoxic T cell Child CD20 biology business.industry Gastroenterology Infant Liver Failure Acute medicine.disease Staining Perforin Child Preschool Pediatrics Perinatology and Child Health biology.protein 030211 gastroenterology & hepatology business CD163 CD8 |
| Zdroj: | Journal of Pediatric Gastroenterology & Nutrition. 71:713-719 |
| ISSN: | 1536-4801 0277-2116 |
| DOI: | 10.1097/mpg.0000000000002893 |
| Popis: | Objectives In many pediatric acute liver failure (PALF) cases, a diagnosis is not identified, and the etiology is indeterminate (IND-PALF). Our pilot study found dense CD8 T-cell infiltrates and increased T-cell clonality in liver specimens from IND-PALF patients. We aimed to validate these findings in a multicenter cohort with investigators blinded to diagnosis. Methods PALF Study Group registry subjects with IND-PALF (n = 37) and known diagnoses (DX-PALF) (n = 18), ages 1 to 17 years, with archived liver tissue were included. Liver tissue slides were stained for T cells (CD8 and CD4), B cells (CD20), macrophages (CD163), perforin, and tissue resident-memory T cells (Trm, CD103), and scored as minimal, moderate, or dense. Lymphocytes were isolated from frozen liver tissue for T-cell receptor beta (TCRβ) sequencing. Results Dense hepatic CD8 staining was found in significantly more IND-PALF (n = 29, 78%) compared with DX-PALF subjects (n = 5, 28%) (P = 0.001). IND-PALF subjects were more likely to have dense or moderate perforin (88% vs 50%, P = 0.03) and CD103 (82% vs 40%, P = 0.02) staining compared with DX-PALF subjects. TCRβ sequencing of 15 IND-PALF cases demonstrated increased clonal overlap compared with 6 DX-PALF cases (P = 0.002). Conclusions Dense infiltration of effector Trm CD8 T cells characterizes liver tissue from IND-PALF subjects. Increased clonality suggests the T-cell expansion is antigen(s)-driven as opposed to a nonspecific inflammatory response. These findings support CD8 staining as a new biomarker of the activated CD8 T-cell PALF phenotype. Future studies are needed to characterize potential antigens, host risk factors, and inflammatory pathways with the goal of developing targeted therapies. |
| Databáze: | OpenAIRE |
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