COVID-19 and autoantibodies
Autoantibodies are antibodies produced by autoreactive B cells that can
penetrate a wide variety of threats [104]. Autoantibodies can be
produced against DNA, RNA, lipids, proteins, centromeres, chromatin and
ribosomal properties [104, 105]. Loss of B cell tolerance, defective
apoptosis, loss of regulatory cells and cells may cause offspring of
autoantibodies [104]. Autoantibodies can be seen in IgM and IgG
isotypes [104,105]. The place of autoantibodies is indispensable to
recognizing and treating autoimmune clearance [106]. In
organ-specific autoimmune diseases, autoantibodies are present against
those with organ antigens, whereas, in systemic autoimmune diseases, no
autoantibodies are present against antigens found in most tissues
[104]. In autoimmune thyroiditis and Graves’ disease, which are
organ-specific autoimmune diseases, autoantibodies can develop against
the thyroid antigens thyroglobulin, thyroperoxidase, and thyroid
stimulating hormone stores [104,107]. In myesthenia gravis, another
neuro-autoimmune disease, autoantibodies against the acetylcholine
receptor can be formed by B cells [107]. 107 In
systemic autoimmune diseases, it consists of autoantibodies against
common antigens found in most tissues [108]. For example, in
systemic lupus erythematosus, anti-nuclear antibodies against nuclear
material consist of anti-dsDNA against DNA and anti-histone
autoantibodies against histone proteins [109]. However,
auto-antibodies detected in some departments controls may not spread
with autoimmune diseases [110]. Viral infections can also cause
autoimmune diseases in various ways [111]. Viral infections can
cause autoimmune disease by mimicry, bystander activation, by adjuvant
rearrangements, and by epitope spreading [112].
Autoantibodies were detected in the COVID-19 and post-COVID-19 patients
[103]. It has been shown that patients with positive autoantibodies
have a more severe course of COVID-19 than other cases [113]. As a
result of the study of Pascolini et al. on 33 COVID-19 patients,
antinuclear antibodies, anti-cytoplasmic neutrophil antibodies (ANCA),
and anti-antiphospholipid antibodies (APL) showed that these
autoantibodies develop due to COVID-19 [114]. Severe and critical
COVID-19 patients have a higher frequency of APL autoantibody and the
presence of APL antibody positivity is associated with extremely
high-level ferritin, CRP, IL-6, and pulmonary thromboembolism [115].
This explains the hypercoagulable state in severe and critical COVID-19
cases and indicates that SARS-CoV-2 can induce autoimmune responses
[114,116]. COVID-19 patients have a higher risk of lupus
anticoagulant positivity [117]. Lupus anticoagulant-positive
patients have a higher risk of thrombosis [118]. Several case
reports demonstrated autoantibodies against RBC antigens which they can
contribute to hemolytic anemia and are related to the severity of anemia
in COVID-19 [119,120]. Some COVID-19 patients have neurologic
symptoms. These patient’s case reports have been shown to develop
autoantibodies against contactin-associated protein 2 (anti-Caspr2),
ganglioside GD1b (anti-GD1b), and myelin oligodendrocyte glycoprotein
(anti-MOG) [121,122]. COVID-19 patients can develop the hematologic
system autoimmunity [123].
Material-Method
Data Collection
Structural proteins of SARS-CoV-2 (Spike, Nucleocapsid, Membrane,
Envelope) were obtained from the NCBI database. The structural proteins
aminoacid sequences of SARS-CoV-2 were fragmented into 8 amino acid-long
peptide fragments.
Peptide Matching
The peptide-match server is an online tool to reveal the amino acid
sequence similarity between amino acid sequences and desired organism
[124]. Fragmented eight amino acid length peptides uploaded
peptide-match server. This server predicts similarity between 8mers and
human sequences [124].
Antigenicity prediction
In order to generate immune responses based on molecular mimicry, the
8mers that we constructed from SARS-CoV-2 structural proteins must be
antigenic [125]. Predicted similar epitopes assessed for
antigenicity in Vaxijen v2.0 antigenicity prediction server [125].
Prediction of binding affinity of peptides to
TAP
The compatibility of 8mers with the TAP protein must be met for them to
be presented as epitopes. Similar epitopes were analyzed for TAP
affinity. For the analysis, we use the TAPreg tool [126].
Allergenicity prediction
To elicit an autoimmune response through molecular mimicry, 8mers must
not possess allergenicity as this would result in the activation of an
IgE-mediated response.The predicted similar epitopes were analyzed for
allergenicity. For analyses of allergenicity, we use the AllerTOP v2.0
tool [127].
Toxicity prediction
Similar epitopes were
analyzed for toxicity, the toxicity prediction we use the ToxinPred tool
[128].
IL-10, and IFN-gamma inducing
prediction
Similar epitopes were analyzed for IL-10, and IFN-gamma induction. The
prediction of IL-10 [129] inducing predicted in IL-10pred, and
prediction of IFN-gamma inducing predicted in IFNepitope[130]
server.
HLA docking calculation
Matched best peptide (identical, antigenic, non-allergenic, non-toxic,
IL-4 inducer, and IFN-gamma inducer, non-IL-10 inducer, and high
affinity to TAP) docked to Class-I and Class-II MHC molecules. Class-I
HLA docking simulated in CABS-dock server [131]. Structures of HLA-I
molecules were retrieved from the RCSB-PDB server (4NQV, 4UQ3, 3RL2,
1X7Q, 5HGA, 5EO1, 3SPV, 1OGT, 3LKN, 1E27, 5INC). The docked models were
analyzed for ΔG (kcal mol-1) and Kd (M) at 37.0 °C values. For this
analysis, the PRODIGY server was used [132,133]. The Epidock server
was used for DEDDSEPV peptide docking to the MHC-II receptor.
Results
Peptide Matching
Fragmented peptides imported to the peptide match server. We found six
identical amino acid sequences (VNSVLLFL, VFLLVTLA, KKDKKKKA, SRSSSRSR,
RRARSVAS, DEDDSEPV) to the human proteome. Table-1 shows the UniProt
codes and protein names of similar proteins with identical amino acid
sequences.
Table-1
List of the identified 8mers of SARS-CoV-2 that have mimicry with human
proteome.