Shared 6mer Peptides of Human and Omicron (21K and 21L) at SARS-CoV-2 Mutation Sites

Abstract

We investigated the short sequences involving Omicron 21K and Omicron 21L variants to reveal any possible molecular mimicry-associated autoimmunity risks and changes in those. We first identified common 6mers of the viral and human protein sequences present for both the mutant (Omicron) and nonmutant (SARS-CoV-2) versions of the same viral sequence and then predicted the binding affinities of those sequences to the HLA supertype representatives. We evaluated change in the potential autoimmunity risk, through comparative assessment of the nonmutant and mutant viral sequences and their similar human peptides with common 6mers and affinities to the same HLA allele. This change is the lost and the new, or de novo, autoimmunity risk, associated with the mutations in the Omicron 21K and Omicron 21L variants. Accordingly, e.g., the affinity of virus-similar sequences of the Ig heavy chain junction regions shifted from the HLA-B*15:01 to the HLA-A*01:01 allele at the mutant sequences. Additionally, peptides of different human proteins sharing 6mers with SARS-CoV-2 proteins at the mutation sites of interest and with affinities to the HLA-B*07:02 allele, such as the respective SARS-CoV-2 sequences, were lost. Among all, any possible molecular mimicry-associated novel risk appeared to be prominent in HLA-A*24:02 and HLA-B*27:05 serotypes upon infection with Omicron 21L. Associated disease, pathway, and tissue expression data supported possible new risks for the HLA-B*27:05 and HLA-A*01:01 serotypes, while the risks for the HLA-B*07:02 serotypes could have been lost or diminished, and those for the HLA-A*03:01 serotypes could have been retained, for the individuals infected with Omicron variants under study. These are likely to affect the complications related to cross-reactions influencing the relevant HLA serotypes upon infection with Omicron 21K and Omicron 21L.

1. Introduction

COVID-19 pandemic had a distinct impact on our lives and will possibly affect us more due to its potentially prolonged health outcomes. The disease severity of COVID-19 is immune-related, but the relationship is not straightforward [1,2,3,4,5,6]. The immune responses of people with the disease can lead to autoimmune reactions through the involvement of HLA alleles [7,8,9,10]. Autoimmunity related features are observed in patients with COVID-19 [11,12,13,14,15,16]. Such a probable connection [17,18,19,20,21,22] also led to therapeutic suggestions [23,24,25]. Molecular mimicry is a possible mechanism of autoimmunity induction after infection and even vaccination, where Kanduc and Shoenfeld [26,27,28], and several authors have studied that possibility, along with disease severity upon infection [29,30,31,32,33,34,35,36,37]. A molecular mimicry map of SARS-CoV-2 was also generated [38], and earlier [39], autoimmune-linked MHC alleles (class I and class II) were published [38,40,41,42,43,44]. Emerging variants of concern, specifically the widespread Omicron variant, drew attention [45,46,47] without an Omicron-sourced autoimmunity focus, despite some literature with a broader or a different focus [48,49,50]. Changes in infectivity, prevention by vaccination, and other concerns [51,52,53,54], were of more interest. On a similar basis, there is a need to investigate the possible changes in molecular mimicry-based autoimmunity risk. In accordance, cross-reactivities of Ig antibodies and virus neutralization in mRNA vaccinated people were reported [55], implying the need for more studies. Consequently, the possible molecular mimicry-based autoimmunity risk of the Omicron Nextstrain clades 21K and 21L was investigated here.

We looked for SARS-CoV-2 and Omicron (21K and 21L) peptides at the respective mutation sites and identified those not only similar human proteins but also with affinities to the same HLA alleles as those binding strongly to their similar human peptides. The results were evaluated comparatively. Therefore, the purpose of this work was primarily to identify peptides of human proteins sharing the 6mer with the Omicron 21K and Omicron 21L variants, and with a cross-reaction risk, compared to the respective nonmutant SARS-CoV-2 peptides. This was suggested to pose a risk of molecular mimicry-based autoimmunity, in susceptible individuals, once infected.

2. Materials and Methods

This study is conducted with the dataset (Supplementary Data mentioned at the data availability statement, Figure S1 and Document S1–S10) generated to investigate the possible health effects of concern, aroused by human protein-similarities of Omicron (21K and 21L) sequences with mutations. Here, potentially susceptible HLA serotypes were identified through similar human proteins with high affinity peptides. We started this work by generating 6mer sequences of the viral peptides at mutation sites, including both nonmutant (SARS-CoV-2) and mutant (Omicron 21K and Omicron 21L) versions. Then we performed NCBI [56] Blastp [57] searches of these peptides by limiting the search to human. Afterwards, we identified the 6mer-sharing human proteins present for both mutant and nonmutant versions of the viral sequences at the same mutation sites. Human protein-sequences with the aligned 6mers were retrieved from UniProt [58] and NCBI [56] in fasta format. The 8mers of these identified similar virus and human peptide pairs were predicted for their HLA affinities [59,60,61,62,63,64,65]. Strong-binder (SB < 0.5% rank) and weak-binder (0.5% < WB < 2% rank) results of NetMHCcons, and epitope (E) results of NetCTLpan were high affinity peptides, also referred to as peptides with affinity. Peptide pairs with high affinities to the same HLA allele were deemed as autoimmunity risk-bearing peptides in the susceptible individuals with those serotypes, upon infection with the virus of concern. Viral/human peptide pairs with high affinities were evaluated to infer changes in the autoimmunity risks for the susceptible serotypes upon infection, through lost or gained affinities of the viral/human peptide pairs. We also evaluated changes in the alleles with high affinities to the viral/human peptide pairs.

Features of the proteins were outlined through the information retrieved from NCBI Entrez [66], UniProtKB/Swiss Prot [58], MalaCards [67,68], SuperPathways [69], and ProteinDB [70,71], collected from the dedicated websites of the GeneCards [72]. Network images were prepared with that information and the data, using Cytoscape [73] version 3.8.2, running with Java 11.0.6. Phylogeny images were generated at covariants.org, on 26 May 2022. Further details of the methodology are provided in the Appendix A, within Appendix A.1.

3. Results and Discussion

The methodology of this study is summarized in Figure 1. Targeting only the human/Omicron peptide pairs with affinities to the same HLA allele, namely, identifying the human peptides that can cross-react with peptides of the Omicron 21K and Omicron 21L, would have been a classical approach. Differently, evaluation of its results compared to the results of human peptides that can cross-react with SARS-CoV-2 peptides at the mutation sites is a novel approach. This approach enabled us to obtain the essence of Omicron 21K- and Omicron 21L-sourced changes. With this, one may recognize how molecular mimicry-based autoimmunity risk could shift from one susceptible group to the other.

3.1. Identified Human Proteins and Peptides

Information on the general features of the identified human proteins is provided in alphabetical order in the Appendix A, within Appendix A.2. The results of our current Blastp search extended the list of sequences obtained through our preliminary work [37] (

Table 1. Omicron 21K and Omicron 21L spike protein sequences with similar sequences in the human proteome and with affinities to the same HLA alleles as those of the human sequences. Omicron/human common residues are written in bold, and residues with mutations are additionally underlined. Only the highlighted results at the fifth results-line are specific to Omicron 21L [37]. Adapted with permission from Kenes.

Omicron Peptide	Human Peptide	Human Protein Name	Human Protein ID	Allele	Tool for Prediction
NLAPFFTF	LLSPFFTF	Ig kappa chain variable region	ABA71433.1	HLA-A*24:02	NetCTLpan
NLAPFFTF	LLSPFFTF	Ig kappa chain variable region	ABA71433.2	HLA-B*15:01	NetCTLpan
NLAPFFTF	YLSPFFTY	hCG2003071	EAW54993.1	HLA-B*15:01	NetCTLpan
YNLAPFFTF	YYLSPFFTY	hCG2003071	EAW54993.1	HLA-A*24:02	NetCTLpan/NetMHCcons
NFAPF-FAF	FAPFLFAF	hCG2023603	EAW76558.1	HLA-A*24:02	NetCTLpan
FPLRSYSF	FPLRSFSY	Ig heavy chain junction region	MOM40044.1	HLA-B*07:02	NetCTLpan

). That preliminary work used more restricted parameters, and did not focus on 6mers, as in this work.

Table 2. Virus and human peptides sharing 6mers at the mutation sites of interest and having affinity to the same HLA. The first 11 data rows are the respective SARS-CoV-2 and human peptides. The corresponding SARS-CoV-2 peptides are those at the Omicron 21K-specific mutation sites, and at the mutation sites common to Omicron 21K and Omicron 21L (i.e., 21K + 21K/21L). The rows from 12 to the end display human peptides sharing 6mers with the respective Omicron (21K + 21K/21L) sequences. Empty cells indicate that the data is the same as the data in the last filled cell above that row. Shared residues in the human peptides are written in bold.

	HLA 1	SARS-CoV-2 Peptide	Prediction 2	Human Peptide	Prediction 2	Human Protein Name	Human Protein ID 3
1	A2	TLACFVLA	WB	TLACFVAI	WB	Presenilin 2 (Alzheimer disease 4), isoform CRA_b	EAW69797.1
2				FLACFVLV	SB	Adenosine receptor A2b	NP_000667.1
3	B7	SPRRARSV	SB/E	SPRRARII	SB	Zinc finger protein 462 isoform X1	XP_006717272.1
4				SPRRARGH	WB	Pleckstrin homology domain-containing family A member 7 isoform X1	XP_047282382.1
5				GPRRARSA	WB	Unnamed protein product 4	BAG54301.1
6				PPRRARSV	WB	RhoGEF	AAF79955.1
7				SPRRARSS	WB	Hermansky-Pudlak syndrome 1, isoform CRA_c	EAW49879.1
8	B7	PPTSFGPL	WB	VPTSFGPL	SB	hCG1989297, isoform CRA_a	EAW55845.1
9	B8	SPRRARSV	WB/E	SPRRARII	WB	Zinc finger protein 462 isoform X1	XP_006717272.1
10	B44	SEETGTLI	WB/E	PETGTLIV	WB	hCG1656811	EAW75628.1
11	B44	EETGTLIV	WB
	HLA 1	Omicron Peptide	Prediction 2	Human Peptide	Prediction 2	Protein Name	Human Protein ID 3
12	A1	SGNYNYLY	WB/E	GLSGNYNY	WB	Immunoglobulin heavy chain junction region	MOL95178.1
13				YGSGNYNY	WB	Immunoglobulin heavy chain junction region	MOL73314.1
14				GSGNYNYY	SB	Immunoglobulin heavy chain junction region	MBB1884951.1
15				SGNYNYFY	WB	Immunoglobulin heavy chain junction region	MOL21912.1
16	A1	LTSFGPLV	WB	ILTSFGPY	WB	Dual specificity mitogen-activated protein kinase kinase 3 isoform X1	XP_016880346.2
17	B39	MHSALRLV	WB	DRHSALRL	WB	Human KCC1 structure determined in KCl and detergent GDN	6KKR_A
18	B44	SEEIGTLI	WB/E	AEEEIGTL	SB	130K protein 5	CAA53661.1
19	B44	EEIGTLIV	WB/E
20	B62	FLARGVVF	SB/E	AGARGVVF	WB	Immunoglobulin light chain junction region	MCC96497.1
21				SGARGVVF	WB	Immunoglobulin light chain junction region	MCB29717.1

¹ A1: HLA-A*01:01, A2: HLA-A*02:01, A3: HLA-A*03:01, A24: HLA-A*24:02, A26: HLA-A*26:01, B7: HLA-B*07:02, B8: HLA-B*08:01, B62: HLA-B*15:01, B27: HLA-B*27:05, B39: HLA-B*39:01, B44: HLA-B*40:01, B58: HLA-B*58:01. ² Weak-binder (WB) and strong-binder (SB) predictions by NetMHCcons, and epitope (E) predictions by NetCTLpan. ³ Only one protein ID, commonly the first one that appeared in the alignments, is provided. ⁴ Ring Finger Protein 10 was identified as an unnamed protein product in the Blastp alignment document. ⁵ RB Transcriptional Corepressor Like 2 was identified as 130K protein in the Blastp alignment document.

(row 1 to 11) displays the first part of the current results, belonging to SARS-CoV-2 peptides containing the Omicron 21K-specific, and Omicron 21K- and Omicron 21L-common, mutation sites. Human peptides sharing 6mers with them and having affinity to the same HLA allele are presented along. Table 2 (row 12 to 21) also displays the results for the corresponding mutant sequences, along with their similar human peptide sequences. The two parts of the table, i.e., results until row 12 and the results afterwards, exclude each other. Accordingly, potential cross-reactive peptides until row 10 represent the diminished risks due to mutations and those after row 11, except those at rows 18 and 19, represent the novel risks in the susceptible individuals, upon getting infected. Viral peptides displayed at rows 10 and 11, and at rows 18 and 19 are nonmutant and mutant versions of the same mutation site, respectively. Accordingly, human peptides mimicking those represent a retaining risk in case of the HLA-B*15:01 serotypes.

Table 3. Viral (SARS-CoV-2 and Omicron 21L) and human peptides that share 6mers at the Omicron 21L-specific mutation sites and have affinity to the same HLA. The first 16 data rows are the respective SARS-CoV-2 and human peptides. The rest are the Omicron 21L and human peptides. (Table format features are the same as the relevant explanation at the caption of Table 2).

	HLA 1	SARS-CoV-2 Peptide	Prediction 2	Human Peptide	Prediction 2	Human Protein Name	Human Protein ID 3
1	A1	RTQLPPAY	WB/E	SIQLPPAY	E	Immunoglobulin light chain junction region	MCD11024.1
2	A3	FLGVYYHK	WB/E	GTFLGVYY	WB	Immunoglobulin heavy chain junction region	MBN4196023.1
3	A3	VLLPLTQY	WB	RLLPLTQY	WB	Protein HGH1 homolog	NP_057542.2
4				RLLPLTQR	WB	Mitochondrial uncoupling protein 4 isoform 1	NP_004268.3
5				VLLPLTYY	WB	Immunoglobulin heavy chain junction region	MBN4485217.1
6				KVLLPLTY	WB	Signaling lymphocytic activation molecule isoform a precursor	NP_001317683.1
7	A26	NSASFSTF	E	SVASFSTF	SB	Immunoglobulin heavy chain variable region, partial	UNJ97266.1
8	B58	RTQLPPAY	E	IQLPPAYW	SB	Immunoglobulin heavy chain junction region	MOQ03906.1
9	B58	NSASFSTF	WB/E	ASFSTFTI	WB	Immunoglobulin heavy chain variable region, partial	UNJ97266.1
10	B62	RTQLPPAY	WB	YQLPPAYY	WB	Immunoglobulin heavy chain junction region	MCG70934.1
11				CQLPPAYY	WB	Ankyrin and armadillo repeat-containing protein isoform X1	XP_011508975.1
12	B62	VLYNSASF	SB/E	YNSASFTF	WB	Immunoglobulin light chain junction region	MBB1719028.1
13	B62	NSASFSTF	WB/E	SVASFSTF	SB	Immunoglobulin heavy chain variable region, partial	UNJ97266.1
14	B62	KGAGGHSY	WB	QGAGGHSY	WB	Immunoglobulin heavy chain junction region	MBN4552893.1
15	B62	VLLPLTQY	WB	VLLPLTYY	WB	Immunoglobulin heavy chain junction region	MBN4485217.1
16				RLLPLTQY	WB	Protein HGH1 homolog	NP_057542.2
	HLA 1	Omicron 21L Peptide	Prediction 2	Human Peptide	Prediction 2	Human Protein Name	Human Protein ID 3
17	A1	FLDVYYHK	WB	FLDVYYGM	WB	Immunoglobulin heavy chain junction region	MBN4448374.1
18				FLDVYYYY	SB	Immunoglobulin heavy chain junction region	MCG72449.1
19				FLDVYYNL	WB	Beta-1,3-galactosyltransferase 5 isoform b	NP_149362.2
20	A3	VLLPFTQY	WB/E	KVLLPFTR	WB	Nuclear pore membrane glycoprotein 210 precursor	NP_079199.2
21	A24	DYSVLYNF	WB/E	SQSVLYNF	WB	Immunoglobulin light chain variable region, partial	AHZ09416.1
22	A24	LYNFAPFF	SB/E	YNFAPFTF	WB	Immunoglobulin light chain junction region	MCE34472.1
23	A24	NFAPFFAF	SB/E	VSAPFFAF	WB	Solute carrier family 22 member 6 isoform a	NP_004781.2
24				SAPFFAFF	WB	Solute carrier family 22 member 6 isoform a	NP_004781.2
25	B7	FPLRSYGF	WB/E	SPLRSYGM	WB	Immunoglobulin heavy chain junction region	MBB2034746.1
26	B27	HRYGADLK	SB/E	HRYGADYY	WB	Immunoglobulin heavy chain junction region	MBB1980753.1
27	B27	ARLCAKHY	WB/E	LRARLCAK	SB	Mucin, partial	AAC15950.1
28				ARLCAKGV	WB	Mucin, partial	AAC15950.1
29	B62	VLYNFAPF	SB/E	YNFAPFTF	WB	Immunoglobulin light chain junction region	MCE34472.1

¹ A1: HLA-A*01:01, A2: HLA-A*02:01, A3: HLA-A*03:01, A24: HLA-A*24:02, A26: HLA-A*26:01, B7: HLA-B*07:02, B8: HLA-B*08:01, B62: HLA-B*15:01, B27: HLA-B*27:05, B39: HLA-B*39:01, B44: HLA-B*40:01, B58: HLA-B*58:01. ² Weak-binder (WB) and strong-binder (SB) predictions by NetMHCcons, and epitope (E) predictions by NetCTLpan. ³ Only one protein ID, commonly the first one that appeared in the alignments, is provided. e.g., FLDVYYGM was also a part of immunoglobulin heavy chain alpha VDJ region, partial (ID: AAD15877.1).

(row 1 to 16) displays the results for SARS-CoV-2 peptides at the sites mutated specifically in Omicron 21L, and the human peptides both shared 6mers with them and had affinity to the same HLA allele. Table 3 (row 17 to 29) also displays results for the viral peptides with Omicron 21L-specific mutations, and human peptides both sharing 6mers with them and having an affinity to the same HLA allele. Potential cross-reactive peptides with the sequences displayed until row 17, except the results in rows 3–6, represent the diminished risks with mutations and the remaining peptides, except that displayed at row 20, represent novel risks. However, some data in Table 3 can be interpreted as de novo risks. For example, human peptides in rows 12 and 29, which are at two separate parts of the table, both shared 6 aa with the corresponding viral peptides at positions 367–374 of the spike protein, had affinity to the same allele, and belonged to the same type of protein. In another case, human peptides in rows 6 and 20, also shared 6 aa with the corresponding viral peptides and had affinity to the same allele but did not belong to the same type of protein. Additionally, viral peptides at row 3, and at row 20 are nonmutant and mutant versions of the same mutation site, respectively. Accordingly, human peptides mimicking those represent a retaining risk in case of the HLA-A*03:01 serotypes.

The numerical results of the data in Table 2 and Table 3 are presented in

Table 4. The number of WB/SB/E predictions of human proteins (i.e., similar) sharing 6mer with SARS-CoV-2 or Omicron (21K and 21L) at mutation sites and having affinity to the same HLA allele. The first 4 data-columns exclude the relevant data of the Omicron 21L-specific mutation sites. The last 4 columns are the relevant data of the Omicron 21L-specific mutation sites.

	SARS-CoV-2 Similar Sequences at Omicron (21K + 21K/21L) Sites		Similar of Omicron (21K + 21K/21L) Sequences with Mutations		SARS-CoV-2 Similar Sequences at Omicron 21L Sites		Similar of Sequences with Omicron 21L-Specific Mutations
	WB	SB	WB	SB	WB	SB	WB	SB
Orf1ab	0	1	3	0	7 1	0	3	1
Spike	5	1	3	1	6	3	8	1
Orf9b	0	0	1	0	0	0	0	0
Envelope	1	0	0	1	0	0	0	0
Matrix	1	1	0	0	0	0	0	0
Total	7	3	7	2	13	3	11	2

One different sequence was predicted as E by NetCTLpan. It was included in the WB column. The other respective predictions of NetCTLpan were common to NetMHCcons.

. WB/SB/E peptides of human proteins sharing 6mers with SARS-CoV-2 sequences at Omicron 21L-specific mutation sites in the Orf1ab protein region decreased the most (from 7 to 3). Deletions were more common than insertions among the mutations of interest in Omicron. Accordingly, a decrease in the number of sequences that can cross-react with human proteins was expected. However, this was not the case (Table 4).

Figure 2 presents the numbers of SARS-CoV-2 and Omicron (21K and 21L) similar human peptides (SARS-CoV-2sim and Omicronsim) with predicted-affinities to the given HLA alleles of interest. Figure 2 indicates a possible shift of the alleles, which could put the individuals at risk. One can roughly view the SARS-CoV-2sim data in Figure 2 as the lost risks due to the mutations and the Omicronsim data as the new or de novo risks, with exceptions of those termed as retaining risks, mentioned above. Six of the Omicron-similar peptides with HLA-A*01:01 affinities were immunoglobulin (Ig) heavy chain junction regions (Table 2, rows 12−15, and Table 3, rows 17−18). Ig light chain or heavy chain parts made-up 5 of the 7 SARS-CoV-2 similar peptides with affinities to the HLA-B*15:01 allele (Table 3, rows 10–16). Such peptides can lead to the generation of anti-idiotypic autoantibodies. These results were interpreted as a shift of the Ig heavy chain junction-sourced peptide affinities from the HLA-B*15:01 allele to the HLA-A*01:01 allele. This interpretation was based additionally on the overall comparison of the data in Table 2 and Table 3. This shift is also illustrated in Figure 2. Along with this shift, there was also a decrease in the potential risk of anti-idiotypic antibodies generated against the Ig heavy chain variable regions.

Differences in the peptides with HLA-A*24:02 affinities were due to Omicron 21L-specific mutations, as they are observed exclusively in the second part of Table 3, which belongs to the respective results of the 21L-specific mutations. These mutations led to new, similar human peptides with WB/SB affinity. Differences in the peptides with HLA-B*07:02 affinities were due to mutations other than the Omicron 21L-specific ones, which led to the loss of similar human peptides with affinities to that allele (rows 3−7, Table 2). Additionally, in that case, peptides sourced by different types of proteins shared the same 6mer of the SARS-CoV-2 peptide. This is well illustrated in Figure 2 as well. Finally, any possible molecular mimicry-associated novel risk seemed to be the most prominent in Omicron 21L-infected HLA-A*24:02 and HLA-B*27:05 serotypes (Figure 2), based on the present data.

3.2. Disorders, Pathways, and Expression Sites

Figure 3 displays the number of disorders per protein identified here, excluding those without data at Genecards. Mucin, viral-peptide mimicking part of which was identified to be involving in a novel risk for the HLA-B*27:05 serotypes, was associated with the highest number of disorders, and the next protein was presenilin 2, which was suggested to be rather in a lost risk due to containing a SARS-CoV-2 mimicking peptide with affinity to the HLA-A*02:01 allele. The identified proteins did not share the associated disorders.

Table A1. Disorders associated with the identified proteins, in the order of ascending number of associated diseases. (Information retrieved from the resources detailed in the Materials and Methods).

Protein       Disorder(s)

HGH1 Homolog

Maturity-Onset Diabetes Of The Young, Type 3

Solute Carrier Family 25 Member 27

Ecthyma

Hepatocellular Carcinoma

Rho Guanine Nucleotide Exchange Factor 4

Epidermolysis Bullosa Simplex 1a, Generalized Severe

Locked-In Syndrome

Beta-1,3-Galactosyltransferase 5

Mood Disorder

Pancreatic Cancer

Ring Finger Protein 10

Spastic Paraplegia 80, Autosomal Dominant

superficial keratitis

Ankyrin And Armadillo Repeat Containing

Cowden Syndrome

Cowden Syndrome 1

Hemochromatosis, Type 4

Loeys-Dietz Syndrome

Solute Carrier Family 22 Member 6

Acute Kidney Failure

Fanconi Syndrome

Fanconi-Like Syndrome

Methotrexate Toxicity

N-Acetylglutamate Synthase Deficiency

Tubulointerstitial Kidney Disease, Autosomal Dominant, 1

Mitogen-Activated Protein Kinase Kinase 3

Breast Cancer

Cardiomyopathy, Familial Hypertrophic, 25

Colorectal Cancer

Cutaneous Anthra

Inhalation Anthrax

Parkinson Disease, Late-Onset

Von Hippel-Lindau Syndrome

Solute Carrier Family 12 Member 4

Agenesis Of The Corpus Callosum with Peripheral Neuropathy

Bartter Disease

Chronic Cervicitis

Fish-Eye Disease

Hemoglobin C Disease

Hypomagnesemia 4, Renal

Sickle Cell Disease

Pleckstrin Homology Domain Containing A7

Blepharocheilodontic Syndrome 1

Cleft Lip With Or Without Cleft Palate

Glaucoma, Primary Open Angle

Marshall Syndrome

Nanophthalmos

Primary Angle-Closure Glaucoma

Renal Adenoma

Stickler Syndrome

Zinc Finger Protein 462

Acrofacial Dysostosis 1, Nager Type

Craniosynostosis

Hypermobility Syndrome

Metopic Ridging-Ptosis-Facial Dysmorphism Syndrome

Premature Menopause

Ptosis

Syndromic Intellectual Disability

Weiss-Kruszka Syndrome

Nucleoporin 210

Achalasia-Addisonianism-Alacrima Syndrome

Amelogenesis Imperfecta, Type Ie 64

Autoimmune Cholangitis

Autoimmune Disease Of Gastrointestinal Tract

Cholangitis

Cholangitis, Primary Sclerosing

Crest Syndrome

Peliosis Hepatis

Primary Biliary Cholangitis

HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1

Albinism

Chediak-Higashi Syndrome

Hermansky-Pudlak Syndrome

Hermansky-Pudlak Syndrome 1

Hermansky-Pudlak Syndrome Due To Bloc-3 Deficiency

Melanoma In Congenital Melanocytic Nevus

Nonspecific Interstitial Pneumonia

Oculocutaneous Albinism

Pulmonary Fibrosis

RB Transcriptional Corepressor Like 2

Bilateral Retinoblastoma

Brunet-Wagner Neurodevelopmental Syndrome 6 109

Burkitt Lymphoma

Extraocular Retinoblastoma

Eye Disease

Hypoglycemia, Leucine-Induced

Ocular Cancer

Osteogenic Sarcoma

Papilloma

Retinal Cancer

Retinoblastoma

Spastic Paraplegia 27, Autosomal Recessive

Spastic Paraplegia 36, Autosomal Dominant

Unilateral Retinoblastoma

Signaling Lymphocytic Activation Molecule Family Member 1

Dysgammaglobulinemia

Herpangina

Immune Deficiency Disease

Leukemia, Acute Myeloid

Lymphoma, Hodgkin, Classic

Lymphoproliferative Syndrome 2

Lymphoproliferative Syndrome

Lymphoproliferative Syndrome, X-Linked, 1

Lymphoproliferative Syndrome, X-Linked, 2

Measles

Pfeiffer Syndrome

Postinfectious Encephalitis

Selective Immunoglobulin Deficiency Disease

Subacute Sclerosing Panencephalitis

Systemic Lupus Erythematosus

Trochlear Nerve Disease

Viral Infectious Disease

Presenilin 2

Acute Conjunctivitis

Acute Hemorrhagic Conjunctivitis

Agraphia

Alzheimer Disease 2

Alzheimer Disease 3

Alzheimer Disease 4

Alzheimer Disease, Familial, 1

Alzheimer’S Disease 1

Amyloidosis

Amyotrophic Lateral Sclerosis 1

Apperceptive Agnosia

Basal Ganglia Calcification

Breast Cancer

Cardiomyopathy, Dilated, 1v

Cerebral Amyloid Angiopathy, App-Related

Cerebral Amyloid Angiopathy, Cst3-Related

Cerebral Amyloid Angiopathy, Itm2b-Related

Chromosomal Disease

Chromosomal Duplication Syndrome

Conjunctival Folliculosis

Dementia

Dementia, Lewy Body

Dilated Cardiomyopathy

Disease Of Mental Health

Dyscalculia

Early-Onset Autosomal Dominant Alzheimer Disease

Familial Isolated Dilated Cardiomyopathy

Frontotemporal Dementia

Gerstmann Syndrome

Gerstmann-Straussler Disease

Huntington Disease-Like Syndrome

Hyperlucent Lung

Ideomotor Apraxia

Leber Congenital Amaurosis 7

Mild Cognitive Impairment

Mitochondrial Dna Depletion Syndrome 12b

Movement Disease

Nervous System Disease

Pharyngoconjunctival Fever

Pick Disease Of Brain

Polycystic Lipomembranous Osteodysplasia With Sclerosing Leukoencephalopathy 1

Posterior Cortical Atrophy

Prosopagnosia

Shipyard Eye

Simultanagnosia

Speech And Communication Disorders

Supranuclear Palsy, Progressive, 1

Tactile Agnosia

Visual Agnosia

Mucin 5AC, Oligomeric Mucus/Gel-Forming

Acute Cholangitis

Acute Dacryocystitis

Acute Inflammation Of Lacrimal Passage

Adenocarcinoma

Adenoma

Ampulla Of Vater Adenocarcinoma

Ampulla Of Vater Cancer

Anal Canal Adenocarcinoma

Anal Gland Adenocarcinoma

Androgen Insensitivity Syndrome

Anus Adenocarcinoma

Appendix Cancer

Appendix Disease

Asthma

Atopic Keratoconjunctivitis

Barrett Esophagus

Bile Duct Adenocarcinoma

Bile Duct Cancer

Bile Duct Cystadenocarcinoma

Bile Duct Mucinous Adenocarcinoma

Bile Duct Mucoepidermoid Carcinoma

Bile Reflux

Biliary Papillomatosis

Biliary Tract Benign Neoplasm

Biliary Tract Disease

Bladder Benign Neoplasm

Blepharitis

Breast Mucoepidermoid Carcinoma

Bronchial Disease

Bronchiolo-Alveolar Adenocarcinoma

Cap Polyposis

Cholangiocarcinoma

Cholecystitis

Chronic Asthma

Chronic Conjunctivitis

Chronic Ethmoiditis

Colloid Carcinoma Of The Pancreas

Colorectal Cancer

Colorectal Cancer, Hereditary Nonpolyposis, Type 8

Common Cold

Complete Androgen Insensitivity Syndrome

Conjunctival Disease

Corneal Ulcer

Cystadenocarcinoma

Cystadenoma

Cystic Fibrosis

Cystic Teratoma

Dacryocystitis

Diverticulitis

Dry Eye Syndrome

Duodenum Adenocarcinoma

Duodenum Cancer

Duodenum Disease

Endobronchial Lipoma

Endocervical Adenocarcinoma

Endometrial Mucinous Adenocarcinoma

Exercise-Induced Bronchoconstriction

Eye Disease

Eyelid Disease

Filamentary Keratitis

Gastric Cancer

Gastric Tubular Adenocarcinoma

Inflammatory Bowel Disease

Interstitial Lung Disease 2

Intrahepatic Biliary Papillomatosis

Intrahepatic Cholangiocarcinoma

Keratoconjunctivitis Sicca

Keratoconjunctivitis

Lacrimal Apparatus Disease

Limbal Stem Cell Deficiency

Lung Cancer Susceptibility 3

Lung Disease

Lung Mucoepidermoid Carcinoma

Meconium Ileus

Microinvasive Gastric Cancer

Middle Ear Disease

Mucinous Adenocarcinoma

Mucinous Cystadenocarcinoma Of Pancreas

Mucinous Intrahepatic Cholangiocarcinoma

Mucoepidermoid Carcinoma

Neurotrophic Keratoconjunctivitis

Otitis Media

Ovarian Cancer

Ovarian Cystadenocarcinoma

Ovarian Mucinous Adenocarcinoma

Ovarian Mucinous Neoplasm

Pancreatic Cancer

Pancreatic Ductal Carcinoma

Pancreatic Mucinous Cystadenoma

Pancreatic Signet Ring Cell Adenocarcinoma

Poikiloderma With Neutropenia

Polyposis, Skin Pigmentation, Alopecia, And Fingernail Changes

Primary Ciliary Dyskinesia

Pseudomyxoma Peritonei

Pulmonary Disease, Chronic Obstructive

Punctate Epithelial Keratoconjunctivitis

Respiratory Allergy

Respiratory Failure

Senile Ectropion

Severe Cutaneous Adverse Reaction

Signet Ring Cell Adenocarcinoma

Silo Filler’S Disease

Small Intestine Adenocarcinoma

Small Intestine Cancer

Solid Adenocarcinoma With Mucin Production

Status Asthmaticus

T2-Low Asthma

Tubular Adenocarcinoma

Urinary Bladder Villous Adenoma

Vernal Conjunctivitis

Villous Adenoma

at Appendix A presents the list of disorders associated with the identified proteins.

Figure 4 presents the number of the associated superpathways with the identified proteins. The majority of involved superpathways were associated with only one identified protein. Each identified protein associated with several numbers of different superpathways, as revealed by the excess of associated superpathways compared to the present number of identified proteins. In four cases, more than 2 proteins associated with a superpathway, as follows:

Mucin 5AC (MUC5AC), mitogen activated protein kinase kinase 3 (MAP2K3), and nucleoporin 210 (NUP210) share the innate immune system.

Presenilin 2 (PSEN2), MAP2K3, and Rho Guanine Exchange Factor 4 (ARHGEF4) share ERK signaling.

NUP210, beta-1,3-galactosyltransferase 5, and solute carrier family 25 member, 27 share metabolism.

MUC5AC, NUP210, MAP2K3, and PSEN2 share the superpathway disease.

The number of superpathways shared by 2 proteins was 22. MAP2K3 was the most frequently (i.e., 13) observed protein in those superpathways shared by 2 proteins. Among those superpathways, MAPK-Erk was shared by the proteins MAP2K3 and RB transcriptional corepressor like 2 (130K protein). Although viral-peptide mimicking part of the 130K protein was identified here to be involving in a retained risk for the HLA-B*40:01 serotypes, that of the MAP2K3 protein was found to carry a potential of leading to a new autoimmune reaction risk in the HLA-A*01:01 serotypes. The risk would have been more if the respective peptide of 130K protein and the Omicron peptide it mimicked both had affinities to the HLA-A*01:01 allele.

PSEN2 and NUP210 were the two succeeding proteins associated with the highest number of superpathways (Figure 4), ARHGEF4 had the second-highest rate of presence (i.e., 7) in the superpathways shared by 2 proteins. ARHGEF4 and MAP2K3 comprised the two proteins in 5 superpathways shared by 2 proteins, but ARHGEF4 viral-peptide mimicking part of it was identified to be involving in a lost risk for the HLA-B*07:02 serotypes.

Table A2. Associated superpathways of the identified proteins, in the order of ascending number of associated superpathways. (Information retrieved from the resources detailed in the Materials and Methods).

Superpathway       Protein(s)

Jak-Stat Signaling Pathway

Mitogen-Activated Protein Kinase Kinase 3

16p11.2 Proximal Deletion Syndrome

Mitogen-Activated Protein Kinase Kinase 3

JNK (c-Jun kinases) Phosphorylation and Activation Mediated by Activated Human TAK1

Mitogen-Activated Protein Kinase Kinase 3

4-Hydroxytamoxifen, Dexamethasone, and Retinoic Acids Regulation of p27 Expression

Mitogen-Activated Protein Kinase Kinase 3

LKB1 Signaling Events

Presenilin 2

ABH and Lewis Epitopes Biosynthesis from Type 1 Precursor Disaccharide

Beta-1,3-Galactosyltransferase 5

Macrophage Differentiation and Growth Inhibition by METS

RB Transcriptional Corepressor Like 2

Acyclovir/Ganciclovir Pathway, Pharmacokinetics/Pharmacodynamics

Solute Carrier Family 22 Member 6

Malignant Pleural Mesothelioma

Mitogen-Activated Protein Kinase Kinase 3

Akt Signaling

Mitogen-Activated Protein Kinase Kinase 3

MAP Kinase Signaling

Mitogen-Activated Protein Kinase Kinase 3

Alzheimers Disease Pathway

Presenilin 2

MAPK Signaling Pathway

Mitogen-Activated Protein Kinase Kinase 3

Angiopoietin-Like Protein 8 Regulatory Pathway

Mitogen-Activated Protein Kinase Kinase 3

MAPK Signaling: Oxidative Stress

Mitogen-Activated Protein Kinase Kinase 3

Apoptosis and Survival_Anti-Apoptotic Action of Nuclear ESR1 and ESR2

Mitogen-Activated Protein Kinase Kinase 3

Mesodermal Commitment Pathway

Zinc Finger Protein 462

Zidovudine Pathway, Pharmacokinetics/Pharmacodynamics

Solute Carrier Family 22 Member 6

Methotrexate Pathway, Pharmacokinetics

Solute Carrier Family 22 Member 6

Bacterial Infections in CF Airways

Mitogen-Activated Protein Kinase Kinase 3

MicroRNAs in Cardiomyocyte Hypertrophy

Mitogen-Activated Protein Kinase Kinase 3

Beta-2 Adrenergic-Dependent CFTR Expression

Mitogen-Activated Protein Kinase Kinase 3

MIF Mediated Glucocorticoid Regulation

Mitogen-Activated Protein Kinase Kinase 3

Blood Group Systems Biosynthesis

Beta-1,3-Galactosyltransferase 5

Mitotic G1 Phase and G1/S Transition

RB Transcriptional Corepressor Like 2

Canonical and Non-Canonical Notch Signaling

Presenilin 2

Monoamine Transport

RB Transcriptional Corepressor Like 2

Cell adhesion_Plasmin Signaling

Mitogen-Activated Protein Kinase Kinase 3

Nanog in Mammalian ESC Pluripotency

Mitogen-Activated Protein Kinase Kinase 3

Cell Cycle Regulation of G1/S Transition (Part 1)

RB Transcriptional Corepressor Like 2

Nervous System Development

Presenilin 2

Cellular Roles of Anthrax Toxin

Mitogen-Activated Protein Kinase Kinase 3

Neuropathic Pain-Signaling in Dorsal Horn Neurons

Mitogen-Activated Protein Kinase Kinase 3

Ceramide Pathway

Mitogen-Activated Protein Kinase Kinase 3

Neuroscience

Presenilin 2

CLEC7A (Dectin-1) Signaling

Mucin 5AC, Oligomeric Mucus/Gel-Forming

NFAT and Cardiac Hypertrophy

Mitogen-Activated Protein Kinase Kinase 3

Colorectal Cancer Metastasis

Mitogen-Activated Protein Kinase Kinase 3

NgR-p75(NTR)-Mediated Signaling

Rho Guanine Nucleotide Exchange Factor 4

CXCR3-Mediated Signaling Events

Mitogen-Activated Protein Kinase Kinase 3

Non-Canonical Wnt Pathway

Mitogen-Activated Protein Kinase Kinase 3

Death Receptor Signaling

Mitogen-Activated Protein Kinase Kinase 3

Notch Pathway

Presenilin 2

Dendritic Cells Developmental Lineage Pathway

Signaling Lymphocytic Activation Molecule Family Member 1

Notch Signaling (Qiagen)

Presenilin 2

Development A3 Receptor Signaling

Mitogen-Activated Protein Kinase Kinase 3

Notch Signaling (WikiPathways)

Presenilin 2

Development FGFR Signaling Pathway

Mitogen-Activated Protein Kinase Kinase 3

Notch Signaling Pathways

Presenilin 2

Development Notch Signaling Pathway

Presenilin 2

NOTCH2 Activation and Transmission of Signal to the Nucleus

Presenilin 2

Development_TGF-beta Receptor Signaling

Mitogen-Activated Protein Kinase Kinase 3

O-linked Glycosylation of Mucins

Mucin 5AC, Oligomeric Mucus/Gel-Forming

Diseases of Glycosylation

Mucin 5AC, Oligomeric Mucus/Gel-Forming

p38 MAPK signaling pathway (Pathway Interaction Database)

Mitogen-Activated Protein Kinase Kinase 3

DNA Damage

RB Transcriptional Corepressor Like 2

P38 MAPK Signaling Pathway (sino)

Mitogen-Activated Protein Kinase Kinase 3

Endoderm Differentiation

Mitogen-Activated Protein Kinase Kinase 3

p70S6K Signaling

Mitogen-Activated Protein Kinase Kinase 3

Epithelial to Mesenchymal Transition in Colorectal Cancer

Mitogen-Activated Protein Kinase Kinase 3

Phospholipase-C Pathway

Rho Guanine Nucleotide Exchange Factor 4

FoxO Family Signaling

RB Transcriptional Corepressor Like 2

Physiological and Pathological Hypertrophy of the Heart

Mitogen-Activated Protein Kinase Kinase 3

G0 and Early G1

RB Transcriptional Corepressor Like 2

PI3K-Akt Signaling Pathway

RB Transcriptional Corepressor Like 2

G-AlphaQ Signaling

Rho Guanine Nucleotide Exchange Factor 4

Pre-NOTCH Expression and Processing

Presenilin 2

Gene Silencing by RNA

Nucleoporin 210

Presenilin-Mediated Signaling

Presenilin 2

Glycolysis (REACTOME)

Nucleoporin 210

Processing of Capped Intron-Containing Pre-mRNA

Nucleoporin 210

GPER1 Signaling

Mitogen-Activated Protein Kinase Kinase 3

Rab Regulation of Trafficking

HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1

G-Protein Signaling Regulation of p38 and JNK Signaling Mediated by G-proteins

Mitogen-Activated Protein Kinase Kinase 3

RAC1 GTPase Cycle

Rho Guanine Nucleotide Exchange Factor 4

Guidance Cues and Growth Cone Motility

Rho Guanine Nucleotide Exchange Factor 4

RAF/MAP Kinase Cascade

Presenilin 2

Hematopoietic Stem Cells and Lineage-Specific Markers

Signaling Lymphocytic Activation Molecule Family Member 1

Regulation of Actin Cytoskeleton

Rho Guanine Nucleotide Exchange Factor 4

HIV Life Cycle

Nucleoporin 210

Regulation of p38-alpha and p38-beta

Mitogen-Activated Protein Kinase Kinase 3

IL-9 Signaling Pathways

Mitogen-Activated Protein Kinase Kinase 3

Regulation of TP53 Activity

RB Transcriptional Corepressor Like 2

Immune Response_Role of Integrins in NK Cells Cytotoxicity

Mitogen-Activated Protein Kinase Kinase 3

Respiratory Electron Transport, ATP Synthesis by Chemiosmotic Coupling, and Heat Production by Uncoupling Proteins

Solute Carrier Family 25 Member 27

Influenza Infection

Nucleoporin 210

RhoA Signaling Pathway

Mitogen-Activated Protein Kinase Kinase 3

Integrin-Mediated Cell Adhesion

Mitogen-Activated Protein Kinase Kinase 3

RHOC GTPase Cycle

Rho Guanine Nucleotide Exchange Factor 4

4-1BB Pathway

Mitogen-Activated Protein Kinase Kinase 3

RhoGDI Pathway

Rho Guanine Nucleotide Exchange Factor 4

Actin Nucleation by ARP-WASP Complex

Rho Guanine Nucleotide Exchange Factor 4

SARS-CoV-2 Infection

Nucleoporin 210

Alzheimer’s Disease and miRNA Effects

Presenilin 2

Senescence and Autophagy in Cancer

Mitogen-Activated Protein Kinase Kinase 3

Antiviral Mechanism by IFN-Stimulated Genes

Nucleoporin 210

Serotonin HTR1 Group and FOS Pathway

Mitogen-Activated Protein Kinase Kinase 3

B Cell Receptor Signaling Pathway

Mitogen-Activated Protein Kinase Kinase 3

Sertoli-Sertoli Cell Junction Dynamics

Mitogen-Activated Protein Kinase Kinase 3

Beta-Adrenergic Signaling

Mitogen-Activated Protein Kinase Kinase 3

Signaling by ERBB4

Presenilin 2

CCR3 Pathway in Eosinophils

Mitogen-Activated Protein Kinase Kinase 3

Signaling by NOTCH3

Presenilin 2

Cellular Response to Heat Stress

Nucleoporin 210

Signaling by Receptor Tyrosine Kinases

Presenilin 2

Chromatin Regulation/Acetylation

RB Transcriptional Corepressor Like 2

Signaling by Rho GTPases

Rho Guanine Nucleotide Exchange Factor 4

Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants

Presenilin 2

Signaling by Slit

Rho Guanine Nucleotide Exchange Factor 4

Defective Binding of RB1 Mutants to E2F1,(E2F2, E2F3)

RB Transcriptional Corepressor Like 2

Signaling Events Mediated by HDAC Class I

Nucleoporin 210

Development Beta-Adrenergic Receptors Regulation of ERK

Mitogen-Activated Protein Kinase Kinase 3

Signaling Events Mediated by Hepatocyte Growth Factor Receptor (c-Met)

Rho Guanine Nucleotide Exchange Factor 4

Development VEGF signaling via VEGFR2—Generic Cascades

Mitogen-Activated Protein Kinase Kinase 3

Signaling Events Mediated by VEGFR1 and VEGFR2

Mitogen-Activated Protein Kinase Kinase 3

Disorders of Transmembrane Transporters

Nucleoporin 210

Signaling Mediated by p38-gamma and p38-delta

Mitogen-Activated Protein Kinase Kinase 3

EPH-Ephrin Signaling

Presenilin 2

Stabilization and Expansion of the E-cadherin Adherens Junction

Pleckstrin Homology Domain Containing A7

FOXO-mediated Transcription

RB Transcriptional Corepressor Like 2

Statin Pathway—Generalized, Pharmacokinetics

Solute Carrier Family 22 Member 6

GDNF-Family Ligands and Receptor Interactions

Mitogen-Activated Protein Kinase Kinase 3

Sumoylation by RanBP2 Regulates Transcriptional Repression

Nucleoporin 210

GPCR Downstream Signalling

Rho Guanine Nucleotide Exchange Factor 4

superpathway of glycosphingolipids biosynthesis

Beta-1,3-Galactosyltransferase 5

G-protein Signaling—Regulation of RAC1 Activity

Rho Guanine Nucleotide Exchange Factor 4

Sweet Taste Signaling

Mitogen-Activated Protein Kinase Kinase 3

HIF1Alpha Pathway

Mitogen-Activated Protein Kinase Kinase 3

Tacrolimus/Cyclosporine Pathway, Pharmacodynamics

Mitogen-Activated Protein Kinase Kinase 3

Immune Response Fc Epsilon RI Pathway

Mitogen-Activated Protein Kinase Kinase 3

TCR Signaling (Qiagen)

Mitogen-Activated Protein Kinase Kinase 3

Integrin Pathway

Mitogen-Activated Protein Kinase Kinase 3

Tenofovir/Adefovir Pathway, Pharmacokinetics

Solute Carrier Family 22 Member 6

A-beta Plaque Formation and APP Metabolism

Presenilin 2

Termination of O-glycan Biosynthesis

Mucin 5AC, Oligomeric Mucus/Gel-Forming

AMPK Enzyme Complex Pathway

Mitogen-Activated Protein Kinase Kinase 3

TGF-beta Signaling Pathways

Mitogen-Activated Protein Kinase Kinase 3

BAFF in B-Cell Signaling

Mitogen-Activated Protein Kinase Kinase 3

The Fatty Acid Cycling Model

Solute Carrier Family 25 Member 27

Cell cycle

RB Transcriptional Corepressor Like 2

Thermogenesis

Mitogen-Activated Protein Kinase Kinase 3

CNTF Signaling

Mitogen-Activated Protein Kinase Kinase 3

TNF Signaling

Mitogen-Activated Protein Kinase Kinase 3

Development A2A Receptor Signaling

Mitogen-Activated Protein Kinase Kinase 3

TNF Superfamily—Human Ligand-Receptor Interactions and their Associated Functions

Mitogen-Activated Protein Kinase Kinase 3

Diseases Associated with O-glycosylation of Proteins

Mucin 5AC, Oligomeric Mucus/Gel-Forming

Toll Comparative Pathway

Mitogen-Activated Protein Kinase Kinase 3

fMLP Pathway

Rho Guanine Nucleotide Exchange Factor 4

Toll-Like receptor Signaling Pathways

Mitogen-Activated Protein Kinase Kinase 3

Globo Sphingolipid Metabolism

Beta-1,3-Galactosyltransferase 5

TP53 Regulates Transcription of Cell Cycle Genes

RB Transcriptional Corepressor Like 2

HCMV Infection

Nucleoporin 210

TRAF6 Mediated Induction of NFkB and MAP Kinases upon TLR7/8 or 9 Activation

Mitogen-Activated Protein Kinase Kinase 3

Inclusion Body Myositis

Presenilin 2

Translation Insulin Regulation of Translation

Mitogen-Activated Protein Kinase Kinase 3

Adipogenesis

RB Transcriptional Corepressor Like 2

Transport of Mature Transcript to Cytoplasm

Nucleoporin 210

Breast Cancer Pathway

Mitogen-Activated Protein Kinase Kinase 3

Transport of the SLBP Independent Mature mRNA

Nucleoporin 210

Cytoskeleton Remodeling Regulation of Actin Cytoskeleton by Rho GTPases

Presenilin 2

Trk Receptor Signaling Mediated by the MAPK Pathway

Mitogen-Activated Protein Kinase Kinase 3

DNA Damage Response (Only ATM Dependent)

RB Transcriptional Corepressor Like 2

tRNA processing

Nucleoporin 210

G-protein Signaling RAC1 in Cellular Process

Mitogen-Activated Protein Kinase Kinase 3

Uptake and Actions of Bacterial Toxins

Mitogen-Activated Protein Kinase Kinase 3

Interferon Gamma Signaling

Nucleoporin 210

Uricosurics Pathway, Pharmacodynamics

Solute Carrier Family 22 Member 6

Cellular Senescence

Mitogen-Activated Protein Kinase Kinase 3

VEGF Pathway (Qiagen)

Mitogen-Activated Protein Kinase Kinase 3

G12-G13 in Cellular Signaling

Mitogen-Activated Protein Kinase Kinase 3

VEGF Signaling Pathway

Mitogen-Activated Protein Kinase Kinase 3

Atenolol Pathway, Pharmacokinetics

Solute Carrier Family 22 Member 6

Vesicle-mediated Transport

HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1

IL12-mediated Signaling Events

Mitogen-Activated Protein Kinase Kinase 3

Vitamin D in Inflammatory Diseases

Mitogen-Activated Protein Kinase Kinase 3

Development Ligand-independent Activation of ESR1 and ESR2

Mitogen-Activated Protein Kinase Kinase 3

Wnt/Hedgehog/Notch

Presenilin 2

MAPK-Erk Pathway

Mitogen-Activated Protein Kinase Kinase 3

RB Transcriptional Corepressor Like 2

Transport of Inorganic Cations/Anions and Amino Acids/Oligopeptides

Solute Carrier Family 12 Member 4

Solute Carrier Family 22 Member 6

IL-17 Family Signaling Pathways

Mitogen-Activated Protein Kinase Kinase 3

Mucin 5AC, Oligomeric Mucus/Gel-Forming

Cytokine Signaling in Immune System

Mitogen-Activated Protein Kinase Kinase 3

Nucleoporin 210

TGF-Beta Pathway

Mitogen-Activated Protein Kinase Kinase 3

Rho Guanine Nucleotide Exchange Factor 4

Signal Transduction

Presenilin 2

Rho Guanine Nucleotide Exchange Factor 4

Gene expression (Transcription)

Nucleoporin 210

RB Transcriptional Corepressor Like 2

Regulation of Activated PAK-2p34 by Proteasome Mediated Degradation

Presenilin 2

RB Transcriptional Corepressor Like 2

Toll-like Receptor Signaling Pathway

Mitogen-Activated Protein Kinase Kinase 3

Signaling Lymphocytic Activation Molecule Family Member 1

Metabolism of Proteins

Mucin 5AC, Oligomeric Mucus/Gel-Forming

Nucleoporin 210

Proximal Tubule Transport

Solute Carrier Family 12 Member 4

Solute Carrier Family 22 Member 6

Glycosaminoglycan Metabolism

Beta-1,3-Galactosyltransferase 5

Nucleoporin 210

CREB Pathway

Mitogen-Activated Protein Kinase Kinase 3

Rho Guanine Nucleotide Exchange Factor 4

Cell Cycle, Mitotic

Nucleoporin 210

RB Transcriptional Corepressor Like 2

Cellular Responses to Stimuli

Mitogen-Activated Protein Kinase Kinase 3

Nucleoporin 210

GPCR Pathway

Mitogen-Activated Protein Kinase Kinase 3

Rho Guanine Nucleotide Exchange Factor 4

Apoptotic Pathways in Synovial Fibroblasts

Mitogen-Activated Protein Kinase Kinase 3

Rho Guanine Nucleotide Exchange Factor 4

Interferon Pathway

Mitogen-Activated Protein Kinase Kinase 3

Rho Guanine Nucleotide Exchange Factor 4

Prolactin Signaling

Mitogen-Activated Protein Kinase Kinase 3

Presenilin 2

IL-1 Family Signaling Pathways

Mitogen-Activated Protein Kinase Kinase 3

Mucin 5AC, Oligomeric Mucus/Gel-Forming

Thyroid Stimulating Hormone (tsh) Signaling Pathway

Mitogen-Activated Protein Kinase Kinase 3

RB Transcriptional Corepressor Like 2

p75 NTR Receptor-Mediated Signalling

Presenilin 2

Rho Guanine Nucleotide Exchange Factor 4

Innate Immune System

Mucin 5AC, Oligomeric Mucus/Gel-Forming

Mitogen-Activated Protein Kinase Kinase 3

Nucleoporin 210

ERK Signaling

Presenilin 2

Mitogen-Activated Protein Kinase Kinase 3

Rho Guanine Nucleotide Exchange Factor 4

Metabolism

Nucleoporin 210

Beta-1,3-Galactosyltransferase 5

Solute Carrier Family 25 Member 27

Disease

Mucin 5AC, Oligomeric Mucus/Gel-Forming

Nucleoporin 210

Mitogen-Activated Protein Kinase Kinase 3

Presenilin 2

at Appendix A presents the list of superpathways associated with the identified proteins.

Table A3. Tissues expressing the identified proteins, in ascending order according to the total average normalized intensities. (Information retrieved from the resources detailed in the Materials and Methods).

Expressing Tissue       Protein(s)	Total Average Normalized Intensity Average Normalized Intensity
Cervical Mucosa	3.02
Mucin 5AC, Oligomeric Mucus/Gel-Forming	3.02
Osteosarcoma Cell	3.73
Solute Carrier Family 12 Member 4	3.73
Bone	3.85
Zinc Finger Protein 462	3.85
Oral Epithelium	4.09
Mitogen-Activated Protein Kinase Kinase 3	4.09
Adipocyte	4.27
Mitogen-Activated Protein Kinase Kinase 3	4.27
Uterine Cervix	4.42
Mitogen-Activated Protein Kinase Kinase 3	4.42
Uterus	4.67
Mitogen-Activated Protein Kinase Kinase 3	4.67
Skin	5.31
Mitogen-Activated Protein Kinase Kinase 3	5.31
Prefrontal Cortex	8.39
Nucleoporin 210	3.47
Solute Carrier Family 25 Member 27	4.92
Breast	9.12
Mitogen-Activated Protein Kinase Kinase 3	4.77
Nucleoporin 210	4.35
Spermatozoon	9.98
Nucleoporin 210	5.64
RB Transcriptional Corepressor Like 2	4.34
Cardia	11.24
Mitogen-Activated Protein Kinase Kinase 3	5.31
Mucin 5AC, Oligomeric Mucus/Gel-Forming	5.93
Spinal Cord	13.50
Mitogen-Activated Protein Kinase Kinase 3	3.99
Nucleoporin 210	3.47
Pleckstrin Homology Domain Containing A7	3.02
Rho Guanine Nucleotide Exchange Factor 4	3.02
Natural Killer Cell	13.58
Mitogen-Activated Protein Kinase Kinase 3	5.29
Nucleoporin 210	5.41
RB Transcriptional Corepressor Like 2	2.88
Gut	17.30
Mitogen-Activated Protein Kinase Kinase 3	4.10
Mucin 5AC, Oligomeric Mucus/Gel-Forming	5.55
Nucleoporin 210	4.58
Pleckstrin Homology Domain Containing A7	3.07
Monocyte	17.99
Mitogen-Activated Protein Kinase Kinase 3	5.42
Nucleoporin 210	5.45
RB Transcriptional Corepressor Like 2	3.62
Solute Carrier Family 12 Member 4	3.50
Pancreatic Islet	18.45
Mitogen-Activated Protein Kinase Kinase 3	4.85
Nucleoporin 210	4.89
Pleckstrin Homology Domain Containing A7	4.35
Solute Carrier Family 12 Member 4	4.37
Blood Platelet	20.71
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	4.15
Mitogen-Activated Protein Kinase Kinase 3	5.04
Mucin 5AC, Oligomeric Mucus/Gel-Forming	1.82
Nucleoporin 210	2.14
Ring Finger Protein 10	2.66
Solute Carrier Family 12 Member 4	2.52
Zinc Finger Protein 462	2.38
Helper T-Lymphocyte	22.29
Mitogen-Activated Protein Kinase Kinase 3	5.33
Nucleoporin 210	5.71
RB Transcriptional Corepressor Like 2	3.67
Signaling Lymphocytic Activation Molecule Family Member 1	4.33
Zinc Finger Protein 462	3.25
Heart	22.30
Mitogen-Activated Protein Kinase Kinase 3	4.45
Nucleoporin 210	4.03
Pleckstrin Homology Domain Containing A7	4.64
RB Transcriptional Corepressor Like 2	2.84
Solute Carrier Family 12 Member 4	3.75
Solute Carrier Family 25 Member 27	2.60
Colonic Epithelial Cell	23.36
Beta-1,3-Galactosyltransferase 5	5.33
Mitogen-Activated Protein Kinase Kinase 3	4.61
Mucin 5AC, Oligomeric Mucus/Gel-Forming	3.57
Nucleoporin 210	5.36
Solute Carrier Family 25 Member 27	4.50
Ovary	23.41
Mitogen-Activated Protein Kinase Kinase 3	4.14
Nucleoporin 210	4.88
Pleckstrin Homology Domain Containing A7	5.25
RB Transcriptional Corepressor Like 2	3.16
Solute Carrier Family 12 Member 4	3.73
Zinc Finger Protein 462	2.25
Urinary Bladder	23.79
Mitogen-Activated Protein Kinase Kinase 3	4.68
Mucin 5AC, Oligomeric Mucus/Gel-Forming	3.03
Nucleoporin 210	3.93
Pleckstrin Homology Domain Containing A7	4.16
RB Transcriptional Corepressor Like 2	3.60
Solute Carrier Family 12 Member 4	4.39
B-lymphocyte	23.82
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	3.49
Mitogen-Activated Protein Kinase Kinase 3	5.74
Nucleoporin 210	5.55
RB Transcriptional Corepressor Like 2	4.47
Signaling Lymphocytic Activation Molecule Family Member 1	4.57
Cytotoxic T-lymphocyte	24.32
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	3.80
Mitogen-Activated Protein Kinase Kinase 3	5.66
Nucleoporin 210	5.72
RB Transcriptional Corepressor Like 2	4.47
Signaling Lymphocytic Activation Molecule Family Member 1	4.66
Kidney	24.46
Mitogen-Activated Protein Kinase Kinase 3	4.00
Nucleoporin 210	3.89
Pleckstrin Homology Domain Containing A7	3.83
RB Transcriptional Corepressor Like 2	3.64
Solute Carrier Family 12 Member 4	4.06
Solute Carrier Family 22 Member 6	5.03
Myometrium	25.05
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	4.53
Mitogen-Activated Protein Kinase Kinase 3	4.07
RB Transcriptional Corepressor Like 2	3.11
Ring Finger Protein 10	3.69
Solute Carrier Family 12 Member 4	3.79
Solute Carrier Family 25 Member 27	5.85
Retina	25.10
Mitogen-Activated Protein Kinase Kinase 3	4.79
Nucleoporin 210	4.99
Pleckstrin Homology Domain Containing A7	4.27
Solute Carrier Family 12 Member 4	3.17
Solute Carrier Family 25 Member 27	4.17
Zinc Finger Protein 462	3.70
Lymph node	25.12
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	2.76
Mitogen-Activated Protein Kinase Kinase 3	5.21
Nucleoporin 210	5.09
RB Transcriptional Corepressor Like 2	4.04
Signaling Lymphocytic Activation Molecule Family Member 1	4.53
Solute Carrier Family 12 Member 4	3.49
Esophagus	27.07
Mitogen-Activated Protein Kinase Kinase 3	4.47
Mucin 5AC, Oligomeric Mucus/Gel-Forming	2.89
Nucleoporin 210	3.93
Pleckstrin Homology Domain Containing A7	2.84
RB Transcriptional Corepressor Like 2	4.78
Signaling Lymphocytic Activation Molecule Family Member 1	3.38
Solute Carrier Family 12 Member 4	4.79
Liver	27.72
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	3.66
Mitogen-Activated Protein Kinase Kinase 3	4.67
Nucleoporin 210	4.52
Pleckstrin Homology Domain Containing A7	4.28
RB Transcriptional Corepressor Like 2	3.66
Ring Finger Protein 10	3.12
Solute Carrier Family 12 Member 4	3.81
Salivary Gland	30.07
Mitogen-Activated Protein Kinase Kinase 3	5.17
Mucin 5AC, Oligomeric Mucus/Gel-Forming	2.56
Nucleoporin 210	4.00
Pleckstrin Homology Domain Containing A7	4.48
Presenilin 2	3.15
RB Transcriptional Corepressor Like 2	3.38
Solute Carrier Family 12 Member 4	4.17
Zinc Finger Protein 462	3.17
Spleen	31.04
Mitogen-Activated Protein Kinase Kinase 3	4.91
Mucin 5AC, Oligomeric Mucus/Gel-Forming	2.14
Nucleoporin 210	4.15
Pleckstrin Homology Domain Containing A7	2.72
Presenilin 2	3.78
RB Transcriptional Corepressor Like 2	4.72
Signaling Lymphocytic Activation Molecule Family Member 1	4.41
Solute Carrier Family 12 Member 4	4.19
Adrenal Gland	32.13
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	3.69
Mitogen-Activated Protein Kinase Kinase 3	4.85
Nucleoporin 210	4.26
Pleckstrin Homology Domain Containing A7	3.41
Presenilin 2	3.96
RB Transcriptional Corepressor Like 2	3.86
Solute Carrier Family 12 Member 4	4.82
Zinc Finger Protein 462	3.28
Thyroid Gland	32.46
Beta-1,3-Galactosyltransferase 5	3.50
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	3.90
Mitogen-Activated Protein Kinase Kinase 3	4.65
Mucin 5AC, Oligomeric Mucus/Gel-Forming	2.53
Nucleoporin 210	4.68
Pleckstrin Homology Domain Containing A7	4.45
RB Transcriptional Corepressor Like 2	3.89
Solute Carrier Family 12 Member 4	4.85
Placenta	32.78
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	3.94
Mitogen-Activated Protein Kinase Kinase 3	5.03
Nucleoporin 210	4.48
Pleckstrin Homology Domain Containing A7	4.47
RB Transcriptional Corepressor Like 2	3.52
Ring Finger Protein 10	3.46
Solute Carrier Family 12 Member 4	5.26
Zinc Finger Protein 462	2.63
Prostate Gland	33.04
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	4.16
Mitogen-Activated Protein Kinase Kinase 3	4.49
Nucleoporin 210	4.40
Pleckstrin Homology Domain Containing A7	4.37
Presenilin 2	4.24
RB Transcriptional Corepressor Like 2	3.92
Solute Carrier Family 12 Member 4	4.48
Zinc Finger Protein 462	2.99
Testis	33.68
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	3.25
Mitogen-Activated Protein Kinase Kinase 3	4.51
Mucin 5AC, Oligomeric Mucus/Gel-Forming	2.54
Nucleoporin 210	4.79
Pleckstrin Homology Domain Containing A7	3.37
Presenilin 2	4.11
RB Transcriptional Corepressor Like 2	3.57
Solute Carrier Family 12 Member 4	4.19
Zinc Finger Protein 462	3.35
Stomach	33.79
Beta-1,3-Galactosyltransferase 5	3.44
Mitogen-Activated Protein Kinase Kinase 3	5.02
Mucin 5AC, Oligomeric Mucus/Gel-Forming	6.17
Nucleoporin 210	4.05
Pleckstrin Homology Domain Containing A7	4.06
RB Transcriptional Corepressor Like 2	3.11
Signaling Lymphocytic Activation Molecule Family Member 1	3.85
Solute Carrier Family 12 Member 4	4.09
Brain	37.57
Mitogen-Activated Protein Kinase Kinase 3	3.85
Nucleoporin 210	4.39
Pleckstrin Homology Domain Containing A7	4.38
Presenilin 2	3.24
RB Transcriptional Corepressor Like 2	4.59
Rho Guanine Nucleotide Exchange Factor 4	4.82
Solute Carrier Family 12 Member 4	4.88
Solute Carrier Family 25 Member 27	4.11
Zinc Finger Protein 462	3.31
Rectum	37.68
Beta-1,3-Galactosyltransferase 5	4.68
Mitogen-Activated Protein Kinase Kinase 3	4.83
Mucin 5AC, Oligomeric Mucus/Gel-Forming	3.33
Nucleoporin 210	4.83
Pleckstrin Homology Domain Containing A7	3.69
RB Transcriptional Corepressor Like 2	4.75
Solute Carrier Family 12 Member 4	3.74
Solute Carrier Family 25 Member 27	5.41
Zinc Finger Protein 462	2.42
Breast Cancer Cell	37.87
Mitogen-Activated Protein Kinase Kinase 3	4.93
Mucin 5AC, Oligomeric Mucus/Gel-Forming	5.99
Nucleoporin 210	5.44
Pleckstrin Homology Domain Containing A7	3.46
Presenilin 2	3.46
RB Transcriptional Corepressor Like 2	3.27
Solute Carrier Family 12 Member 4	4.12
Solute Carrier Family 22 Member 6	4.15
Zinc Finger Protein 462	3.04
Colon	39.21
Beta-1,3-Galactosyltransferase 5	4.41
Mitogen-Activated Protein Kinase Kinase 3	4.96
Mucin 5AC, Oligomeric Mucus/Gel-Forming	4.38
Nucleoporin 210	4.74
Pleckstrin Homology Domain Containing A7	4.87
RB Transcriptional Corepressor Like 2	4.10
Solute Carrier Family 12 Member 4	3.99
Solute Carrier Family 25 Member 27	4.90
Zinc Finger Protein 462	2.87
Tonsil	39.26
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	3.07
Mitogen-Activated Protein Kinase Kinase 3	5.31
Nucleoporin 210	4.11
Pleckstrin Homology Domain Containing A7	4.69
RB Transcriptional Corepressor Like 2	4.31
Rho Guanine Nucleotide Exchange Factor 4	2.74
Ring Finger Protein 10	2.58
Signaling Lymphocytic Activation Molecule Family Member 1	4.52
Solute Carrier Family 12 Member 4	3.92
Zinc Finger Protein 462	4.01
Pancreas	39.33
Beta-1,3-Galactosyltransferase 5	3.69
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	3.31
Mitogen-Activated Protein Kinase Kinase 3	4.64
Mucin 5AC, Oligomeric Mucus/Gel-Forming	3.80
Nucleoporin 210	3.84
Pleckstrin Homology Domain Containing A7	4.94
Presenilin 2	3.86
RB Transcriptional Corepressor Like 2	3.44
Rho Guanine Nucleotide Exchange Factor 4	3.39
Solute Carrier Family 12 Member 4	4.43
Gall Bladder	39.61
Beta-1,3-Galactosyltransferase 5	4.49
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	3.52
Mitogen-Activated Protein Kinase Kinase 3	5.08
Mucin 5AC, Oligomeric Mucus/Gel-Forming	5.15
Nucleoporin 210	4.40
Pleckstrin Homology Domain Containing A7	4.25
Presenilin 2	3.38
RB Transcriptional Corepressor Like 2	4.87
Solute Carrier Family 12 Member 4	4.46
Lung	39.90
HPS1 Biogenesis Of Lysosomal Organelles Complex 3 Subunit 1	4.18
Mitogen-Activated Protein Kinase Kinase 3	4.48
Mucin 5AC, Oligomeric Mucus/Gel-Forming	3.98
Nucleoporin 210	3.91
Pleckstrin Homology Domain Containing A7	3.53
Presenilin 2	3.85
RB Transcriptional Corepressor Like 2	4.39
Signaling Lymphocytic Activation Molecule Family Member 1	4.04
Solute Carrier Family 12 Member 4	3.71
Zinc Finger Protein 462	3.84
General Sum	1060.88

at Appendix A presents the list of tissues expressing the identified proteins, along with the expression levels. The total number of tissues expressing MAP2K3 was the highest (i.e., 42, Figure 5). It is expressed in almost all tissues displayed in Figure 6, except the prefrontal cortex, osteosarcoma cells, spermatozoon, cervical mucosa, and bone. Therefore, if infected, cross-reaction of the Omicron 21K-mimicking peptide of MAP2K3 in the HLA-A*01:01 serotypes could involve several tissues and organs. Among those, adipocyte, oral epithelium, skin, uterine cervix, and uterus are expressing only MAP2K3, while cervical mucosa is expressing only MUC5AC, and cardia is expressing MAP2K3 and MUC5AC, among the identified proteins (Appendix A, Table A3).

If we look at the total average normalized intensities of the expression levels of the identified human proteins, gall bladder has the highest expressions of the identified proteins with Omicron-similar sequences, followed by breast cancer cell, colon, rectum, stomach, thyroid glands, and pancreas (Figure 7). High expression of the given proteins in those tissues could categorize them as potentially the most vulnerable targets if an autoimmune reaction is developed against those proteins, in the susceptible individuals who are infected with the Omicron variant. The total average normalized intensity of the expressed proteins exclusively with Omicron similar sequences was approximately two times greater than that of proteins exclusively with SARS-CoV-2 similar sequences. It should be reminded that any suggested biological relevance is limited to the possible effects of the mutation sites of the Omicron 21K and Omicron 21L variants.

The efforts in this study were to specify the serotypes at risk and to explain a possible mechanism of the shift in disease severity among certain serotypes, due to mutations in Omicron 21K and Omicron 21L. However, other than individual susceptibilities, there is also the possibility of becoming infected with a different variant, which is immense even among the Omicron 21K and Omicron 21L, in addition to the other variants (Figure 8). Studies such as this one aim to provide a generalized understanding. In line with this aim, Section 3.2 of this study revealed that associated disorders and superpathways of the identified human proteins with Omicron mimicking peptides revealed possible new risk for the HLA-B*27:05 and HLA-A*01:01 serotypes, respectively (Figure 9). The latter is supported by the tissue-expression data (Figure 9). On the other hand, risk for the HLA-B*07:02 serotypes could have been diminished (Figure 9) and that for the HLA-A*03:01 serotypes could have been retained. Finally, high affinity peptides of the human proteins identified here are not yet observed in vivo or in vitro as autoantigens. However, that is likely because of lacking experimental studies aiming to detect those autoantibodies. In support of the possibility of demonstrating the presence of autoantibodies, cross-reaction of peptide PFERD at 463–467 positions of the spike protein receptor binding domain (S1-RBD) of SARS-CoV-2 with the human cell receptor angiotensin-converting enzyme 2 was delicately identified by Lai et al. [74], through several experimental steps, which are the demonstration of cross-reaction in patients’ sera (1), demonstration of cross-reaction in sera of mice immunized with recombinant S1-RBD (2), identification of monoclonal antibodies (mAbs) that could cross-react (3), and finding the cross-reactive antigenic peptide that could bind strongly to the autoreactive mAb (4).

This work focused on human molecular mimicry-based autoimmunity risk changes in different HLA serotypes, by considering only the sequences at mutation sites of the nonmutant SARS-CoV-2 and mutant Omicron (21K and 21L) sequences into account. Such changes can influence viral evolution, yet the involvement of the HLA interactions with the spike protein [75] could be the major driving factor, along with its effects on transmissibility [76], and with the contribution of vaccines to this phenomenon. Accordingly, amendments of our work can involve conducting a study with a broader perspective, by including considerations on different aspects of HLA interactions, in addition to evaluating the missed and eliminated data due to selected search parameters/criteria, including a possible future work on the shared 5mers. Studying mutations of the other variants, plus their recombination [77], and predicting affinities to the other alleles, including especially the class II alleles, are of importance.

4. Conclusions

A change in the potential autoimmunity risk is any loss in the potential autoimmunity risk due to mutations, with any new or de novo risks associated with those mutation sites. We identified the lost and gained similarities with the human peptides, as a risk of triggering autoimmunity due to cross-reactivity in susceptible individuals infected with Omicron 21K and Omicron 21L. Among all, any possible molecular mimicry-associated novel risk seemed to be the most prominent in HLA-B*27:05 and maybe also in HLA-A*24:02 serotypes who are infected with Omicron 21L. Results further supported possible new risk for the HLA-B*27:05 and HLA-A*01:01 serotypes, while the risk for the HLA-B*07:02 serotypes could have been lost or diminished, and that for the HLA-A*03:01 serotypes could have been retained, for the individuals infected with Omicron variants under study. While the results require clinical validation, they may provide an explanation for such a possible autoimmunity-related new or lost symptoms in Omicron 21K- or Omicron 21L-infected susceptible individuals.