From influenza infection to anti-ADAMTS13 autoantibodies via cross-reactivity

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Abstract

Autoantibodies (AAbs) against von Willebrand factor (vWF)-cleaving protease ADAMTS13 causally relate to thrombotic thrombocytopenic purpura (TTP). How anti-ADAMTS13 AAbs are generated is unknown. Starting from reports according to which influenza infection can trigger TTP by the production of ADAMTS13 AAbs, this study explores influenza viruses and ADAMTS13 protein for common peptide sequences that might underlie anti-influenza immune responses able to cross-react with ADAMTS13. Results document that numerous peptides are shared between influenza A and B viruses and ADAMTS13, thus supporting the hypothesis of cross-reactivity as a mechanism driving the generation of anti-ADAMTS13 AAbs.

1 Introduction

Thrombotic thrombocytopenic purpura (TTP) is clinically characterized by the occurrence of thrombocytopenia and microangiopathic hemolytic anemia [1, 2, 3]. TTP was first described as a pathological entity in 1924 by Moschcowitz [1] and was clearly identified as an autoimmune disorder by Harrington et al. in 1951 [4]. Currently, after 70 years, we know that the majority of TTP patients suffer from acquired TTP caused by the presence of autoantibodies (AAbs) against ADAMTS13 [5, 6, 7], a protease that cleaves the von Willebrand factor (vWF) multimers into smaller forms thereby controlling vWF-mediated platelet thrombus formation [8]. However, the molecular basis and the mechanism(s) that lead to the loss of immunotolerance toward ADAMTS13 and permit the production of anti-ADAMTS13 AAbs are still unknown [9].

Therefore, it assumes a scientific relevance the clinical observation by Kosugi et al. [10], that influenza infection triggers TTP by producing anti-ADAMTS13 IgGs. The observation is crucial in light of the fact that the association between influenza infection and TTP is clinically well known [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29], so making feasible the hypothesis that the anti-influenza immune responses that follow influenza infection may cross-react with ADAMTS13 protein thus generating anti-ADAMTS13 AAbs. To prove or disprove the cross-reactivity hypothesis, the present study analyzed the peptide commonality between influenza virus and ADAMTS13 proteins since, actually, peptide sharing can lead to autoimmunity through cross-reactivity phenomena following pathogen infection. It was found a wide influenza virus vs ADAMTS13 peptide overlap that can represent a cross-reactive molecular platform underlying anti-ADAMTS13 AAb production.

2 Methods

Sequence analyses were conducted on ADAMTS13 (or A disintegrin and metalloproteinase with thrombospondin motifs 13 or vWF-cleaving protease) and cytoplasmic and perinuclear autoantigens of antineutrophil cytoplasmic antibodies, ie, c-ANCA myeloblastin and p-ANCA myeloperoxidase. The three human proteins are described in detail in the Uniprot database at https://www.uniprot.org [30, 31]. Protein primary sequences were decomposed into overlapping pentapeptides offset by one residue, ie, MGVPF, GVPFF, and VPFFS. Next, each pentapeptide was analyzed for occurrences in viral proteomes using Peptide Match program (https://research.bioinformatics.udel.edu/peptidematch) [32].

Proteomes from nine viruses were analyzed: influenza A virus, H1N1 (NCBI:txid211044), influenza A virus, H3N2 (NCBI:txid385580), influenza A virus, H5N1 (NCBI:txid93838), influenza A virus, H10N7 (NCBI:txid382838), influenza B virus (NCBI:txid518987), and influenza C virus (NCBI:txid11553). Tobacco mosaic virus (NCBI:txid12243), human parvovirus B19 (NCBI:txid648237), and dengue virus (NCBI:txid11059) were used as controls.

The immunologic potential of the shared peptides was explored using the Immune Epitope Database (IEDB, www.iedb.org) resource [33].

3 Results

ADAMTS13 protein sequence was analyzed for peptide sharing with influenza virus proteomes. In addition, c-ANCA myeloblastin and p-ANCA myeloperoxidase, two autoantigens that characterize a group of small vessel vasculitis [34, 35], were analyzed for comparison.

Analyses were extended to human parvovirus B19 because B19 infection, although predominantly affects erythrocytes, shows clinically nonsignificant lymphopenia, neutropenia, and thrombocytopenia [36] and to dengue virus because thrombocytopenia and clotting abnormalities are at the heart of dengue pathology [37]. Tobacco mosaic virus was utilized as a negative TTP-unrelated viral control.

Operationally, the pentapeptide was used as a probe in sequence analyses since, in immunobiology, a functional/structural unit is generally represented by five amino acid (aa) residues [38]. In fact, biological interactions can be described by peptide–protein interactions involving a pentapeptide [39, 40, 41, and pertinent references therein]. Alike, the capability of generating immune responses (immunogenicity) as well as the immune recognition process (antigenicity) appears to be circumscribed to the space of five residues [42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52].

4 Peptide sharing between influenza viruses and ADAMTS13

The pentapeptide sharing between the viral proteomes and c-ANCA myeloblastin, p-ANCA myeloperoxidase, and ADAMTS13 is described in Table 1. Main points are as follows:

Tab. 1

Description of the pentapeptide sharing between B19, dengue, and influenza proteomes and the ANCA and ADAMTS13 autoantigens

Virusc-ANCA myeloblastinp-ANCA myeloperoxidaseADAMTS13
Tobacco mosaic virus
Human parvovirus B19FEQVMALVRP
Dengue virus 1ARASF, SGSASAGEKA, TLRVL AGILA, GAGLA, GANAS, SLRTT,
Influenza A virus, H1N1GDMLL, GHADL, GILHL, LESSL, PGHAD
Influenza A virus, H5N1ALTED, GDMLL, GHADL GILHL, PGHAD
Influenza A virus, H3N8ALTED, PGHAD, ELLVA, QGSLL GDMLL, GHADL, GILHL,
Influenza A virus, H10N7ALTED, PGHAD ELLVA, GDMLL, GHADL, GILHL,
Influenza B virusVTVVT, TVVTFLERKL, RLATEGGVLL, RQRQR, TGTID
Influenza C virus
  1. –•On the whole, the viral vs human peptide overlap consists of 24 pentapeptide matches, 17 of which occur in ADAMTS13 and mainly involve influenza A and dengue viruses.
  2. –•The viral peptide sharing with the two ANCA autoantigens amounts to seven pentamers and is restricted to influenza B, B19, and dengue viruses.
  3. –•Influenza C virus and the negative control tobacco mosaic virus have no pentapeptide sequences in common with any of the three analyzed human proteins.

In commenting data from Table 1, two further observations merit notice. First, the extent of the viral vs human peptide overlap is mathematically unexpected since the probability that two proteins may share a pentapeptide is equal to 20˗5 (ie, probability 1 out of 3,200,000 or 0.0000003125). Second, the present study examines only reference influenza proteomes, ie, selected proteomes that cover well-studied model organisms [30, 31], and neglects the hundreds of existing influenza subtypes and variants. That is to say that the cross-reactivity scenario between influenza infection and ADAMTS13 might be more intense and varied than that summarized in Table 1. As an example, the influenza A virus, H5N1 (NCBI:txid176674) shares the additional pentapeptide SLEPC with ADAMTS13 when compared to the, here, analyzed influenza A virus, H5N1 (NCBI:txid93838).

5 Immunologic potential of the peptide sharing between influenza viruses and ADAMTS13

The peptide sharing as summarized in Table 1 has a high immunologic potential. In fact, using IEDB [33], a catalog of experimentally validated epitopes, and searching within IEDB epitopes, it was found that almost all of the shared pentapeptides described in Table 1 repeatedly occur in immunoreactive epitopic sequences. Table 2 lists the immunopositive epitopes containing sequences shared between B19, dengue, and influenza proteomes and the ANCA and ADAMTS13 autoantigens and highlights the disproportionately high number of epitopes containing ADAMTS13 pentapeptides.

Tab. 2

Epitopes containing peptides shared between B19, dengue, and influenza proteomes and ANCA and ADAMTS13 autoantigens

c-ANCA myeloblastinp-ANCA myeloperoxidaseADAMTS13
IEDB ID1Epitope sequence2,3IEDB ID1Epitope sequence2,3IEDB ID1Epitope sequence2,3
71568VTVVTtsgs36432lhtdFEQVM358aapgaatafvGAGLAgaaig
173682vlqelnVTVVTFfcr37398llhtdFEQVM391aaqlaapgaatafvGAGLAg
175507tlvvnklqgllqVTVVTipq49778ptstfllhtdFEQVMc1565AGILArnlvpmvatv
118332epgegpvllVTVVTggevkkl65519tpcilSGSAS4870atafvGAGLAgaaigsvglgk
132262elnVTVVTFfcrphn171363hdldftpepaARASF18173fvGAGLAgaaigsv
715422langTVVTF171908kqrlrSGSASpmell21783gpSLRTTtv
730502vhaVTVVTl173480tlllrehnRLATElk31200kidlwsynaELLVAle
175982kaleLERKL31201kidlwsynaELLVAlenqhti
195579knetwklARASFiev35002lavGGVLLflsvnvha
195784netwklARASFievk48949ppwqAGILArnlvpm
219932teLERKLtf48950ppwqAGILArnlvpmv
236113lFEQVMr50046pwqAGILArnlvpmv
435362kRLATEfel53178raprtgrrlmALTEDtssds
490162ARASFpdqay62654synaELLVAlenqhti
534632sldangvSGSASyyevkfsd72977wqAGILArnlvpmva
539401ieseknetwklARASFi74558ylaGAGLAf
628468ylnpLERKL95135qAGILArnlvpmvat
655819arlaeLERKL102905vlgGGVLLlrvipaldsltpaned
725289shssSGSASl113533idlwsynaELLVAl
753847kgttvtvsSGSASaptlf129078kidlwsynaELLVAlen
754288wgqgtlvtvsSGSASastlfp130384ynaELLVAlenqhtidl
795873grlelSGSASgaagr131309rvALTEDrlp
803192kaSGSASgfwps143423kidlwsynaELLVAlenqht
810555qlSGSASnyavs180774TLRVLnlvenwlnnn
188763TLRVLqdql
190640aGDMLLlwgrltwrk
190646asyilirdthSLRTT
190647asyilirdthSLRTTa
190648asyilirdthSLRTTaf
190680rpgGGVLLrygsqlape
190682rqhlepTGTIDmrgpg
190687syilirdthSLRTT
195114aGAGLAfslmkslgg
195117AGILArwssfkknga
195346GAGLAfsimksvgtg
222546geshiGGVLL
228201GGVLLlenvrfykee
422312ELLVAmenqhtidlads
422725sitevwsynaELLVAme
422849wsynaELLVAmenqhti
430467htdcPGHADy
448746sqypELLVAsy
459203slvGILHL
466503iiyAGEKAqf
466967iyAGEKAqf
474578aaniiGILHLilwildrl
478472geltQGSLL
491545griepGDMLL
534840eGANASyilirdthSLRTTa
539613lrflaipptAGILAr
541068alLESSLrqa
559187drsiGGVLLdsklvl
564437lelepGAGLAl
576396redTLRVLaa
582709fGGVLLplly.
585298krkSLRTTgf
587265prgGGVLLfi.
588256reqGAGLAl
593918aALTEDgrlfmw
594947dTLRVLtlw
595352fsgQGSLLqpfiyyrf
598639lALTEDsevhsw
602194sTLRVLynlf
605046grlgrGAGLAk
615393eiiAGILAy
621328lredTLRVL
638082ttAGILAtl
643987gqnepELLVAhay
697198GDMLLlwgrltwrkm
710401iatGILHLl
716337lpnQGSLLr
724737seqGGVLLl
738679dlirlcimvGANASd
738927flrflaipptAGILA
740498TLRVLlvgrdgavyvhhm
753010ypELLVAsy
766470vtttildreiqevfTLRVLvrdgg
768115asyilirdthSLRTTafhg
768265rpgGGVLLrygsqlapet
773323gvagvGAGLAy
776377pvELLVAes
781091aeGGVLLpvdrr
782476alahGGVLLfpk
787546dpmaELLVAsrt
790759eyTGTIDgltqa
792564GGVLLirclllg
806468ltGANASgepht
822504ssspGAGLAfgi
838772vALTEDqvpalk
1Epitope IEDB ID number. Details and references: www.iedb.org 2Peptides shared between viruses and human autoantigens (Table 1) in capital letters.

6 Conclusion

Numerous pentapeptides are shared between influenza A and B viruses and ADAMTS13, the autoantigen of TTP (Table 1). The peptide sharing is higher than expected by being very low the chance for two proteins to share a pentapeptide. Moreover, the peptide sharing is immunologically significant by being most of the shared peptides also part of experimentally validated epitopes (Table 2). Hence, the present study substantiates the hypothesis of cross-reactivity involvement in the generation of anti-ADAMTS13 AAbs following influenza infection, in this way flanking previous findings [53, 54, 55, 56, 57] that indicate autoimmune cross-reactions as a basic mechanism in the generation of autoimmune diseases following infections.

The data warrant further collaborative research efforts, especially in light of the fact that low levels of ADAMTS13 protease are a risk factor for the development of myocardial infarction [58,59], stroke [59, 60, 61], preeclampsia [61], disseminated intravascular coagulation [62], cerebrovascular disease [63], etc.

Acknowledgment

This research received no specific grants from any funding agency in public, commercial, or not-for-profit sectors.

Competing interests: The author declares no conflicts.

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