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.