COVID-19 News: Mysterious Pediatric Hepatitis Infections Were Actually Autoimmune-Hepatitis Triggered by COVID-19 Due To T Cell Cross-Reactivity

COVID-19 News: Over 1,300 cases of pediatric hepatitis, shrouded in mystery, have been reported worldwide since the first case emerged in the United Kingdom in 2022. Researchers have struggled to pinpoint the exact etiology of this condition.


TCR cross-reactivity in COVID-19 patients
(A) The proposed immunological mechanisms underlying COVID-19-related autoimmune-like hepatitis. (B) Venn diagram showing the overlap of antigen-specific CDR3β sequence (SARS-CoV-2, human proteome and EBV) obtained from VDJdb database with TCR repertoire of COVID-19 patients obtained from ImmuneCODE. (C) The incidence of five representative CDR3β sequences in the healthy control individuals and COVID-19 cohorts. (D) Annotation of LC13-TCR and CoV-TCR.

Initially, adenovirus was suspected to be the culprit due to its presence in the blood samples of a majority of cases. Additionally, some cases have tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), further muddying the waters. Some COVID-19 News reports even speculated that new variants of the SARS-CoV-2 virus was behind this pediatric hepatitis surge but this was later proven to be not the case. However, the connection between these viruses and pediatric hepatitis remained unclear.
 
A Turning Point: T-Cell Infiltration in COVID-19 Patients
A breakthrough occurred when a pediatric patient with a confirmed SARS-CoV-2 infection underwent a liver biopsy. The biopsy revealed acute submassive hepatocyte necrosis, accompanied by a significant increase in T-cell infiltration.
 
This revelation prompted researchers from the Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou-China to delve deeper into the role of T-cells in COVID-19-related hepatitis. Furthermore, cases of CD8 T-cell dominant hepatitis induced by COVID-19 vaccination had also recently emerged, raising questions about the involvement of the immune system in this enigmatic condition.
 
T-Cell Cross-Reactivity: A New Perspective
The world of immunology has long acknowledged that T-cell receptors (TCRs) are capable of distinguishing between self and non-self antigens. However, recent research has illuminated the phenomenon of TCR cross-reactivity, where T-cells can recognize similar or even distinct antigen peptides. Armed with this knowledge, researchers hypothesized that SARS-CoV-2 infection or vaccination might trigger the clonal expansion of T-cells carrying TCRs capable of recognizing self-antigens. This, in turn, could lead to the development of autoimmune-like hepatitis.
 
Investigating the Hypothesis
To put their hypothesis to the test, the study team embarked on a journey to identify clonally expanded TCRs that might recognize self-antigens following SARS-CoV-2 infection. They cross-referenced two publicly available TCR binding datasets, VDJdb and ImmuneCODE, with a focus on TCRs exhibiting similar complementarity determining region 3 of the β chain (CDR3β) sequen ces. The rationale was that TCRs with analogous CDR3β sequences might recognize the same antigens.
 
A Network of Cross-Reactivity
Recent studies had hinted at cross-reactivity between SARS-CoV-2 and a spectrum of other viruses, such as cytomegalovirus (CMV) and seasonal coronaviruses. The researchers' analysis indeed revealed 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. Ten CDR3β sequences emerged, demonstrating cross-reactivity with both SARS-CoV-2 and human proteome-derived T-cell epitopes. Astonishingly, five of these sequences were also present in an independent dataset of TCR repertoires from COVID-19 patients.
 
Clonal Expansion in COVID-19 Patients
The analysis didn't stop there. Comparing the incidence of different CDR3 sequences between healthy control individuals and COVID-19 cohorts revealed a significant increase in the frequency of multiple CDR3β sequences in COVID-19 patients. Notably, one CDR3β sequence, CASSLGQAYEQYF, stood out with statistical significance. This finding suggested the clonal expansion of T-cells bearing these specific CDR3β sequences in individuals with COVID-19.
 
The Discovery of CoV-TCR
Taking their investigation a step further, the study team turned their attention to a paired TCRαβ dataset identified through single-cell TCR sequencing in individuals with SARS-CoV-2 antigen exposures. Within this dataset, they identified a TCR containing the COVID-19-enriched CDR3β sequence CASSLGQAYEQYF, subsequently dubbed CoV-TCR. Surprisingly, CoV-TCR shared an identical TCRβ sequence with LC13-TCR, a previously reported TCR known to recognize an immunodominant EBV epitope (FLRGRAFGL) presented by the human leukocyte antigen (HLA)-B*08:01. LC13-TCR also displayed cross-reactivity with various other peptides, including a self-peptide (EEYLQAFTY) from the ATP Binding Cassette Subfamily D Member 3 (ABCD3) protein.
 
ABCD3: A Key Player
ABCD3, a peroxisomal membrane protein responsible for transporting various fatty acids, emerged as a key player in this puzzle. Intriguingly, the expression of ABCD3 was found to be significantly higher in liver tissues compared to other normal tissues, as indicated by the Human Protein Atlas. Moreover, hepatocytes, liver's primary cell type, exhibited the highest level of ABCD3 gene expression.
 
CoV-TCR's Specificity
Through binding and cytotoxicity assays, the study team confirmed that CoV-TCR indeed recognized a self-peptide derived from ABCD3 (EEYLQAFTY) presented by HLA-B*44:05. This discovery shed light on a crucial aspect of the autoimmune-like hepatitis puzzle, albeit with a twist: CoV-TCR didn't recognize the previously reported SARS-CoV-2 antigenic peptide (TTDPSFLGRY) derived from Nonstructural protein 3 (NSP3). This divergence suggested that CoV-TCR's role might extend beyond known SARS-CoV-2 peptides.
 
The EBV Connection
As the pieces of this complex puzzle fell into place, the study team also considered the possibility of EBV reactivation in COVID-19 patients as an alternative explanation for the clonal expansion of T-cell clones with the CDR3β sequence CASSLGQAYEQYF. This potential link between EBV and COVID-19-related autoimmune-like hepatitis added another layer of complexity to the investigation.
 
Conclusion
In summary, the enigma of pediatric hepatitis of unknown etiology, along with autoimmune-like hepatitis in COVID-19 patients, appears to have found a possible explanation. The discovery of cross-reactivity in clonally expanded T-cells, particularly the CoV-TCR recognizing a self-peptide derived from ABCD3, brings us closer to understanding the complex interplay between viral infections, the immune system, and autoimmune responses. While this discovery sheds light on a potential mechanism behind COVID-19-related autoimmune hepatitis, including the mysterious pediatric cases, it also underscores the need for further comprehensive research and investigation. As the world grapples with the ongoing COVID-19 pandemic, unraveling the intricacies of its impact on the human immune system remains a critical endeavor, with far-reaching implications for both treatment and prevention.
 
The study findings were published as a letter in the peer reviewed journal: hLife
https://www.sciencedirect.com/science/article/pii/S2949928323000093
 
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