Over 1,000 cases of this perplexing condition have been reported worldwide since its first appearance in the UK. Despite extensive research efforts, the exact cause of pediatric hepatitis remains elusive and subject to controversy.
The Role of Adenovirus and SARS-CoV-2
Early investigations into the etiology of pediatric hepatitis initially pointed to adenovirus as a potential culprit, as it was detected in the blood samples of a majority of affected cases. However, the puzzle deepened as partial cases were found to be positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19. The question that arose was how these viral infections contributed to the onset of pediatric hepatitis.
Pathological Insights
To shed light on this mystery, liver biopsies from pediatric patients with SARS-CoV-2 infection were examined.
The findings were striking, revealing acute submassive hepatocyte necrosis accompanied by a significant increase in T cell infiltration. This observation prompted further investigation into the role of T cells in the development of pediatric hepatitis.
Emergence of T Cell-Dominant Hepatitis
Remarkably, cases of T cell-dominant hepatitis induced by COVID-19 vaccination were also reported. This phenomenon led researchers to delve deeper into the role of T cell receptors (TCRs) in the context of viral infections. TCRs are known for their ability to discriminate between self and non-self-antigens, but recent studies have revealed their potential for cross-reactivity towards a wide range of antigens.
Hypothesis and Research Approach
Building upon these observations, researchers formulated a hypothesis that after SARS-CoV-2 infection or vaccination, T cells carrying TCRs recognizing self-antigens might undergo clonal expansion. This expansion could potentially lead to the development of autoimmune-like hepatitis, as illustrated in Figure 1A. To test this hypothesis, the research aimed to identify clonally expanded TCRs recognizing self-antigens following SARS-CoV-2 infection.
Data Cross-Referencing
The research cross-referenced two publicly available TCR binding datasets, namely VDJdb and ImmuneCODE. This cross-referencing was based on the concept that TCRs with similar complementarity-determining region 3 of β chain (CDR3β) sequences might recognize the same antigen. Recent studies had suggested the possibility of cross-reactivity between SARS-CoV-2 and various other viruses.
Cross-Reactivity with Multiple Antigens
As anticipated, the analysis revealed a significant number of TCRs exhibiting cross-reactivity with T cell epitopes derived from not only SARS-CoV-2 but also other viruses such as Epstein-Barr virus (EBV) and even components of the human proteome (Figure 1B). Ten CDR3β sequences were identified, demonstrating cross-reactivity with T cell epitopes derived from both SARS-CoV-2 and the human proteome, with five of these sequences also present in an independent dataset of TCR repertoires from COVID-19 patients (Figure 1C).
Clonal Expansion in COVID-19 Patients
Notably, the analysis of healthy control individuals and COVID-19 cohorts indicated a significant increase in the frequency of multiple CDR3β sequences, including CASSLGQAYEQYF (p<2.2e-16, Wilcox. test), suggesting clonal expansion of T cells with these CDR3β sequences in COVID-19 patients (Figure 1C).
Identification of CoV-TCR
Further investigation led to the identification of a TCR containing the same COVID-19-enriched CDR3β sequence, namely CoV-TCR (Figure 1D). Intriguingly, CoV-TCR shared an identical TCRβ sequence with LC13-TCR, which had previously been reported to recognize an immunodominant epitope (FLRGRAFGL) of EBV presented by human leukocyte antigen (HLA)-B*08:01 and also exhibited cross-reactivity with multiple other peptides, including a self-peptide (EEYLQAFTY) from the ATP Binding Cassette Subfamily D Member 3 (ABCD3) protein.
ABCD3 and Its Significance
ABCD3, a peroxisomal membrane protein responsible for transporting various fatty acids, was found to be highly expressed in liver tissues, particularly in hepatocytes (Figure 1E). Furthermore, hepatocytes exhibited the highest level of ABCD3 gene expression compared to other cell types. Binding and cytotoxicity assays confirmed that CoV-TCR specifically recognized the HLA-B44:05-restricted self-peptide derived from ABCD3 (EEYLQAFTY) (Figure 1F-K). Interestingly, no interaction was observed between the CoV-TCR and the HLA-A01:01-restricted SARS-CoV-2 peptide (TTDPSFLGRY), previously identified in a large-scale detection of SARS-CoV-2-specific T cells.
Implications of the Findings
In conclusion, this study has identified a CoV-TCR that recognizes a self-peptide derived from ABCD3, an abundant peroxisomal membrane protein in hepatocytes, in COVID-19 patients. Although this TCR does not recognize the previously reported SARS-CoV-2 antigenic peptide, it raises the possibility that it could recognize other yet unidentified antigenic peptides derived from SARS-CoV-2. Additionally, the expansion of T cell clones with the same CDR3β sequence (CASSLGQAYEQYF) may also be attributed to the reactivation of EBV in COVID-19 patients.
Future Research Directions
These findings support the notion that cross-reactivity of clonally expanded T cells may be one of the causes of COVID-19-related autoimmune-like hepatitis, including the enigmatic pediatric hepatitis of unknown etiology. Further comprehensive research and investigation are warranted to explore this possibility in greater detail. Understanding the mechanisms underlying this phenomenon could provide valuable insights into the pathogenesis of pediatric hepatitis and autoimmune responses triggered by viral infections.
reference link : https://www.sciencedirect.com/science/article/pii/S2949928323000093
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