Since the emergence of the first case in the UK in 2022, over 1,300 cases of pediatric hepatitis have been reported worldwide. The exact cause of this condition has been a mystery, with researchers struggling to identify its etiology. Initially, adenovirus was suspected, but the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in some cases added to the complexity. The possibility of new variants of the SARS-CoV-2 virus causing the surge in pediatric hepatitis was considered but later ruled out. Despite these efforts, the link between the viruses and pediatric hepatitis remained unclear.
A breakthrough occurred when a liver biopsy of a pediatric patient with a confirmed SARS-CoV-2 infection revealed acute submassive hepatocyte necrosis and a significant increase in T-cell infiltration. This finding prompted researchers to further investigate the role of T-cells in COVID-19-related hepatitis. Cases of CD8 T-cell dominant hepatitis induced by COVID-19 vaccination also raised questions about the involvement of the immune system in this condition.
Recent research has shed light on the phenomenon of T-cell cross-reactivity, where T-cells can recognize similar or even distinct antigen peptides. With this knowledge, researchers hypothesized that SARS-CoV-2 infection or vaccination could trigger the clonal expansion of T-cells capable of recognizing self-antigens, leading to autoimmune-like hepatitis. To test this hypothesis, the study team analyzed publicly available TCR binding datasets and found a substantial number of TCRs displaying cross-reactivity with T-cell epitopes derived from SARS-CoV-2, Epstein-Barr virus (EBV), and even the human proteome.
The analysis revealed a significant increase in the frequency of multiple CDR3β sequences in COVID-19 patients compared to healthy control individuals. One specific CDR3β sequence, CASSLGQAYEQYF, stood out with statistical significance, suggesting the clonal expansion of T-cells with this sequence in individuals with COVID-19. The study team also identified a TCR containing the COVID-19-enriched CDR3β sequence, which shared an identical TCRβ sequence with a previously reported TCR known to recognize an immunodominant EBV epitope. The TCR exhibited cross-reactivity with various peptides, including a self-peptide from the ABCD3 protein.
ABCD3, a peroxisomal membrane protein, emerged as a key player in this puzzle. Its higher expression in liver tissues and hepatocytes indicated its significance in autoimmune-like hepatitis. The study team confirmed that the TCR recognized a self-peptide derived from ABCD3, shedding light on the autoimmune-like hepatitis puzzle.
The investigation also considered the possibility of Epstein-Barr virus reactivation in COVID-19 patients as an alternative explanation for the clonal expansion of T-cell clones. This added another layer of complexity to the investigation.
In conclusion, the discovery of cross-reactivity in clonally expanded T-cells, particularly the TCR recognizing a self-peptide derived from ABCD3, provides a possible explanation for pediatric hepatitis of unknown etiology and autoimmune-like hepatitis in COVID-19 patients. However, further comprehensive research and investigation are needed to fully understand the complex interplay between viral infections, the immune system, and autoimmune responses in these conditions. Unraveling the intricacies of the impact of COVID-19 on the human immune system remains crucial for effective treatment and prevention strategies.