Discussion
SARS-CoV-2 is associated with a spectrum of illness during the acute viral infection, persisting during convalescence and as part of the long COVID syndrome. Constitutional, respiratory, cardiac, neurological, musculoskeletal and psychiatric symptoms are being increasingly described but the mechanisms behind these are uncertain [15]. It is not known whether these phenomena arise as direct effect of the virus or from off-target immune effects, including autoimmunity. Our study finds that there is a high prevalence of autoantibodies found in the acute and convalescent phase of COVID-19 suggesting that SARS-CoV-2 infection is associated with significant perturbations of immunological tolerance and raising the possibility that autoimmunity may play a role in the pathogenesis of acute and chronic symptoms.
Two fifths of the acute non COVID-19 ITU patients had autoantibodies suggesting that acute severe illness per se is associated with autoantibody production and the wide range of target autoantigens may reflect the diversity of this cohorts’ underlying disease. Three fifths of the acute COVID-19, ITU patients had autoantibodies and these were of a narrower diversity with antibodies against epidermal intercellular cement and skeletal muscle predominant. These antibodies were persistent over time and also detected in convalescence post ITU COVID-19, over 5 months from symptoms onset. In addition, cardiac and smooth muscle antibodies were also identified. Cardiac and skeletal muscle autoantibodies were not found in convalescent individuals with non-hospitalised COVID-19, although smooth muscle antibodies were detected and a quarter had antibodies directed at epidermal intercellular cement. The narrow array of tissue specific autoantibodies associated with COVID-19 infection suggests loss of tolerance to these antigens may be disease specific, rather than a phenomenon associated with critical illness.
The link between infection and autoimmunity is well described with multiple genetic and environmental factors implicated [1]. Pathogenic mechanisms elucidated include molecular mimicry, epitope spreading, revelation of cryptic antigen and bystander activation, although which specific mechanism in which situation is usually uncertain. Similarly, just because an autoantibody is generated doesn’t necessarily mean that the autoantibody is pathogenic. In some conditions such as myasthenia gravis there is a clear link between acetyl choline receptor antibodies and dysfunction of the motor end plate whereas in some conditions such as systemic lupus erythematosus the presence of high titre ANA is a non-specific biomarker of disease and the autoantibodies are not thought to be pathogenic. One of the limitations in understanding the role of autoantibodies in infectious disease has been the relative paucity of cases that are available to study within a reasonable time-frame. The sheer extent of the COVID-19 pandemic obviously overcomes this and work such as that presented here are first steps in interrogating these links.
The pattern of skin and muscle autoantibodies is intriguing and further studies are needed to elucidate the antigenic target and the clinical significance of these autoantibodies. One interesting possibility is the desmoglein family and DSG1 and 3 are found in the autoimmune blistering pemphigus disorders. Whilst oral ulceration and blistering has been described in COVID-19 [16, 17]) it is by no means a commonly reported feature in large clinical studies such as ISARIC4C (Coronavirus Clinical Characterisation Consortium) [18].
This is an observational hypothesis generating clinical laboratory study that has raised the possibility of COVID infection generating a specific spectrum of autoantibodies. Determining the clinical relevance of these findings is still required but highlights specific history and examination that should be undertaken in COVID follow up clinics. Further studies examining the link between autoantibodies and COVID-19 are required to help understand how one virus can drive a myriad of presentations in different patients.