COVID-19 Shots Can Induce CD8 T-Cell Dominant Hepatitis

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A new study led by researchers from the University of Freiburg-Germany has found that current COVID-19 shots can induce CD8 T-cell dominant hepatitis.

The study findings were published in the peer reviewed Journal of Hepatology. (Science Direct-Elsevier) 

https://www.sciencedirect.com/science/article/pii/S0168827822002343

Vaccination is the key strategy to fight the global COVID19 pandemic.

There was no hepatitis safety signal in COVID19 vaccination trials[1], however several reports have recently associated autoimmune hepatitis (AIH)-like conditions with COVID19 vaccines[[2], [3], [4], [5], [6], [7], [8], [9], [10], [11]].

To our knowledge, no severe case with liver failure requiring liver transplantation was reported. Liver injury was observed after both, mRNA and vector-based vaccines, while time from vaccine administration to symptom onset ranged between 4 days after the first dose to 6 weeks after the second dose.

One patient was re-exposed to the vaccine which led to a worsening of liver injury[11]. It remains unclear whether the reported association of autoimmune hepatitis with vaccination is coincidental, might reflect transient drug-induced liver injury, or could involve unique SARS-CoV-2-induced antigen-specific immune activation[12].

However, the fact that AIH-like conditions also occurred after SARS-CoV-2 infection[13] suggests that the latter could be a driving factor for the sporadic cases.

Here, we describe the case of a 52-year-old male presenting with acute mixed hepatocellular/cholestatic hepatitis after the first dose of BNT162b2 mRNA vaccine and severe hepatitis after the second dose. Diagnostic evaluation was compatible with criteria for autoimmune hepatitis (AIH).

After initiation of oral budesonide therapy, liver function tests improved for a month before a relapse occurred that was successfully treated with systemic prednisolone and ursodeoxycholic acid. Comprehensive immunologic assessment of the inflammatory infiltrates in the liver revealed the presence of a highly activated cytotoxic CD8 T cell infiltrate including a SARS-CoV-2-specific CD8 T cell population that correlated with the peripheral activation of SARS-CoV-2-specific CD8 T cells, indicating that post-COVID19 vaccination hepatitis involves vaccination-elicited antigen-specific immune responses with distinct histological features compared to bona fide autoimmune hepatitis.

Discussion

Autoimmune-hepatitis-like disease after vaccination against SARS-CoV-2 is now recognized as a rare adverse event not identified in early trials. The widespread use of the vaccine with administration of hundreds of million doses worldwide raises also questions of causality vs. coincidence.

In particular, AIH-like disease after vaccination was reported in patients with age and gender characteristics typical for spontaneous AIH[6, 7, 10]. While some of these cases thus may represent coincidence, a causal relationship to the vaccine is also possible, such as bystander hepatitis driven by elevation of systemic cytokines or chemokines after vaccination, similar to cases occurring in association with natural SARS-CoV-2 infection[13].

The varying patterns of clinical manifestation and the wide range of time elapsed between vaccine administration and symptom onset clearly suggest that different mechanisms may contribute to these reported cases. Here, our analysis highlights that activated cytotoxic CD8 T cells including vaccine-induced spike-specific CD8 T cells could contribute to disease pathogenesis.

Importantly, autoimmune hepatitis is a condition that requires lifelong immunosuppressive therapy in many affected patients[16]. It is therefore important to differentiate AIH from possibly transient immune-mediated hepatitis post vaccination.

Diagnosis of autoimmune hepatitis is typically established using AIH scoring tools informed by liver function tests, auto-antibody serology and typical histological features such as interface hepatitis and enrichment of plasma cells[14]. In our case, prior to therapy, AIH diagnosis was deemed “probable” based on the modified original AIH score.

It is important to note in this context that the first episode of acute hepatitis after the first vaccine dose was self-limiting without therapy, which also guided our choice to initiate therapy with budesonide in an attempt to minimize systemic side effects and to maintain systemic anti-SARS-Cov2 immunity if possible.

However, our patient experienced a relapse 3-4 weeks after budesonide therapy and then required systemic steroid therapy, that was empirically combined with ursodeoxycholic acid, a combination used in the therapy of autoimmune hepatitis overlap syndrome that was chosen due to presence of AMA-M2 antibodies typically found in primary biliary cholangitis[17].

The patient subsequently recovered quickly, with only a gingivitis occurring during systemic steroid therapy as a possible immunosuppression-related event. Due to relapse hepatitis after steroid tapering, the patient was put under long-term maintenance immunosuppressive therapy under which he achieved complete biochemical remission.

Mechanistically, the disease manifestation in our patient was distinct from classical spontaneous AIH, that is typically associated with elevated peripheral immunoglobulins, a plasma cell dominated infiltrate and prominent interface hepatitis. Here, while there was a slight elevation of peripheral immunoglobulins and intrahepatic enrichment of intrahepatic B cells and plasma cells, a more striking correlate was observed at the level of cytotoxic CD8 T cells.

Activated cytotoxic CD8 T cells were strongly enriched in the patient liver to an extent that they represented the most abundant intrahepatic immune cell population and included vaccine elicited SARS-CoV2 specific responses. Notably, the peripheral activation state of these spike-specific CD8 T cells correlated with hepatitis severity and the clinical course after introduction of immunosuppressive therapy.

These results implicate T cells as a key pathogenic immune cell type of this vaccine-associated immune hepatitis as a novel subtype of autoimmune hepatitis. The early increase in ALT values after first and second dose of BNT162b2 and the observation that CD8 T cells including spike-specific CD8+ T cells dominate the immune infiltrate also fits to recent observations that demonstrate an early mobilization of spike-specific CD8 T cells already after the first dose of the vaccine [15].

Of note, our tetramer reagent likely stains only a fraction of vaccination-induced antigen-specific T cells, fitting to the broad expression of T cell activation and cytotoxicity markers observed in the analysis of the bulk CD8 T cell population. However, it is also possible that the broad activation pattern observed involves other, non-SARS-CoV2 specific “bystander” CD8 T cell populations.

Moreover, the precise mechanism that causes infiltration of the spike-specific CD8 T cells into the liver which adopt features of tissue resident memory T cells (TRM) remains unclear. Virus-specific CD8+ T cells can accumulate in the liver even if the primary site of infection is distant, such as during influenza infection and it is possible that the liver can act as a “graveyard” for activated T cells [18, 19].

However, activated cytotoxic CD8 T cells can mediate hepatitis even in the absence of antigen [20]. In addition, TCR-independent, innate-like cytotoxicity of bystander T cells has been described in acute infections [21, 22]. Of note, CXCR6+ CD8+ TRM cells, such as those found in this patient, may mediate auto-aggression in metabolic liver diseases, in response to local inflammatory cues [23, 24].

Whilst these reports raise the possibility of an antigen-independent T cell-mediated hepatitis, another possible explanation could be the presence of their cognate antigen, i.e. the spike protein. While we could not detect spike protein by IHC in the liver, it has to be noted that biopsy was performed 27 days after the second vaccine dose and transient expression after vaccination, which could have caused CXCR6-expressing spike-specific CD8 T cells to home to the liver and target antigen-presenting cells, cannot be excluded.

However, additional mechanisms, such as antigen cross-recognition may also contribute to the immunopathology. In sum, BNTb163b2 vaccine may trigger immune-mediated hepatitis by mechanisms linked to vaccine-induced cellular immunity.

This case illustrates the induction of an unusual CD8 T cell-dominant autoimmune hepatitis after BNT162b2 mRNA vaccination, with enrichment of vaccine-induced SARS-Cov2-specific CD8 T cells. In patients with hepatitis manifesting after the first vaccine dose, additional doses may trigger significant hepatic autoimmunity and require long-term immune suppression.

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