Interferons and other cytokines, genetics and beyond in COVID-19 and autoimmunity

Highlights

• Autoantibodies against interferons and other cytokines are detected in COVID-19 patients, but it is unclear whether these are cause or consequence of infection or may be caused by genetic defects.

• Acute virus infection and inflammation yield local and systemic proteolysis as a posttranslational modification. Together with glycosylation and citrullination, it enhances the formation of neo-antigens as remnant epitopes generating autoimmunity.

• B cell repertoires in systemic lupus erythematosus resemble those of patients with COVID-19 and it is questioned whether considerable cytolysis by SARS-CoV-2 releases abundant intracellular proteins into the extracellular space, followed by proteolysis and remnant epitope formation.

• Neutrophils as cells and cytokines, chemokines and proteases as molecules deserve more critical studies to understand pathogenetic roles, now, after successful vaccination campaigns and in the post−COVID-19 era.

Abstract

Interferons are the best antiviral agents in vitro against SARS-CoV-2 so far and genetic defects in their signaling cascade or neutralization of alfa-interferons by autoantibodies come with more severe COVID-19. However, there is more, as the SARS-CoV-2 dysregulates not only innate immune mechanisms but also T and B cell repertoires. Most genetic, hematological and immunological studies in COVID-19 are at present phenomenological. However, these and antecedent studies contain the seed grains to resolve many unanswered questions and a whole range of testable hypotheses. What are the links, if existing, between genetics and the occurrence of interferon-neutralizing antibodies? Are NAGGED (neutralizing and generated by gene defect) antibodies involved or not? Is the autoimmune process cause or consequence of virus infection? What are the roles played by cytokine posttranslational modifications, such as proteolysis, glycosylation, citrullination and others? How is systemic autoimmunity linked with type 1 interferons? These questions place cytokines and growth factors at pole positions as keys to unlock basic mechanisms of infection and (auto)immunity. Related to cytokine research, (1) COVID-19 patients develop neutralizing autoantibodies, mainly against alpha interferons and it is not yet established whether this is the consequence or cause of virus replication. (2) The glycosylation of recombinant interferon-beta protects against breaking tolerance and the development of neutralizing antibodies. (3) SARS-CoV-2 induces severe inflammation and release of extracellular proteases leading to remnant epitopes, e.g. of cytokines. (4) In the rare event of homozygous cytokine gene segment deletions, observed neutralizing antibodies may be named NAGGED antibodies. (5) Severe cytolysis releases intracellular content into the extracellular milieu and leads to regulated degradation of intracellular proteins and selection of antibody repertoires, similar to those observed in patients with systemic lupus erythematosus. (6) Systematic studies of novel autoimmune diseases on single cytokines will complement the present picture about interferons. (7) Interferon neutralization in COVID-19 constitutes a preamble of more studies about cytokine-regulated proteolysis in the control of autoimmunity. Here we reformulate these seven conjectures into testable questions for future research.