sHLA levels are significantly increased in COVID-19 patients

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A new study by researchers from the University of Tübingen and the University Hospital Tübingen – Germany has found that inflammation-driven release of soluble HLA (sHLA) in COVID-19 influences immunopeptidome diversity and T cell immunity.

The study findings were published in the peer reviewed journal: iScience.
https://www.cell.com/iscience/fulltext/S2589-0042(22)01915-0

Several studies have reported elevated levels of sHLA molecules in different pathologies, including infectious, malignant, and autoimmune diseases, and their association with disease severity or outcome6–9. In this study, we quantified total sHLA class I and -DR serum levels in COVID-19 patients, convalescent individuals and a cohort of healthy control donors showing elevated sHLA levels in COVID-19 patients compared to the control cohort.

This is in line with recently reported elevated levels of the non-classical sHLA-G in COVID-19 patients20,22. In line with previous publications6–10,20,21 the amount of sHLA varied considerably among different individuals. Of note, sHLA class I levels even remained elevated in SARS-CoV-2 convalescents individuals up to six months after infection indicating long-term distorted sHLA release with elevated sHLA class I serum levels associated with persisting COVID-19 symptoms.

Patients with post- or long-COVID syndrome suffer from a huge variety of different symptoms including fatigue, shortness of breath or cognitive dysfunction. First evidence suggests that uncontrolled inflammation and autoimmunity plays a role in these patients24,25. In this context, sHLA serum levels might also be elevated in these patients, which would need to be further investigated in large cohort studies.

We further analyzed the soluble immunopeptidome of a COVID-19 and control cohort to characterize disease-associated alterations in the antigenic peptide repertoire carried by sHLA molecules17,18. Thereby, an increased diversity of sHLA-presented peptides, attributable to a COVID-19 signature of related source proteins, was observed compared to the healthy control cohort independently of COVID-19-specific therapies.

This indicates that the state of intracellular virus replication, inflammation, and immune activation in COVID-1926–29 is directly mirrored in the soluble immunopeptidome. No direct influence on antigen presentation of COVID-19-specific therapies remdesivir and dexamethasone was observed. Of note, our study demonstrates a direct correlation of sHLA class I serum levels with the diversity of the soluble immunopeptidome.

Furthermore, we were able to detect a naturally in vivo presented SARS-CoV-2-derived peptide from the nucleoprotein within the soluble plasma of a COVID-19 patient. Thus far, the identification of naturally presented SARS-CoV-2-derived HLA peptides was limited to immunopeptidomics approaches that use artificial systems with in vitro infected, protein- loaded or protein-overexpressed cells30–32.

A critical factor for the detection of in vivo presented SARS-CoV-2-derived HLA ligands might be the timepoint of sample collection after infection, which might explain the low frequent detection of SARS-CoV-2-derived peptides within our cohort, in which the samples were collected several days after infection.

A recent study detected SARS-CoV-2-derived HLA peptides in cell lines 3 to 24 hours post infection with a peak of viral peptides at 6 hours indicating rapid HLA presentation of virus-derived peptides that decreases over time32. In addition, the cells that are primarily targeted by SARS-CoV-233 are not well exposed to the plasma, which might impede the release of sHLA molecules carrying virus-derived peptides by these cells in the plasma.

However, especially sHLA class II molecules might not be derived from the SARS-CoV-2 target cells directly, but from antigen- presenting cells and are therefore more reliable to detect within the plasma of the patients. However, we have to emphasize that absence of evidence does not equal evidence of absence as the sensitivity of shotgun mass spectrometric discovery approaches, even in the context of immense technical improvements in the last decades, remains for sure limited as the immunopeptidome is a highly dynamic, rich, and complex assembly of peptides.

Nevertheless, the detection of the nucleoprotein-derived peptide within the soluble immunopeptidome proves the soluble immunopeptidome as an interesting and so far underinvestigated source  for the detection of in vivo presented virus-derived HLA-presented peptides. For tumor patients the soluble immunopeptidome was previously described as a source for the detection of tumor-associated antigens presented by sHLA molecules, which might serve as potential biomarkers17–19.

It is still a matter of intense debate to what extent sHLA complexes exert pro- or anti- immunomodulatory effects and whether shifts in sHLA levels contribute to disease outcome or are observed as a consequence of disease11.

We here demonstrated elevated sHLA class I and -DR serum levels in COVID-19 representing a highly diverse and disease-associated soluble immunopeptidome reflecting ongoing SARS-CoV-2-induced inflammation. Furthermore, we could demonstrate the association of long-term elevated sHLA class I serum levels with persisting COVID-19 symptoms.

On the other hand, we provided evidence for a positive correlation of anti-SARS-CoV-2-specific T cell responses with sHLA class I levels suggesting a positive role of sHLA molecules for anti-viral cellular immunity and T cell activation15,16. The induction of a potent SARS-CoV-2-directed T cell responses is essential to prevent severe courses of COVID-1934–41.

In line, patients with critical illness, in terms of required invasive ventilation, exhibited conspicuous low sHLA class I levels. Future large cohort studies are needed to further delineate and characterize the functional role of sHLA for T cell immunity and COVID-19 outcome.

Together, the findings of this study indicate an inflammation-driven higher release of sHLA molecules in COVID-19, which directly influence the diversity of the soluble immunopeptidome and positively modulate anti-SARS-CoV-2 cellular immunity.

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