HPV and Systemic Lupus Erythematosus: a Mosaic of Potential Crossreactions

Immunol Res (2017) 65:564–571 DOI 10.1007/s12026-016-8890-y

NOVEL ASPECTS IN LUPUS, 2017

HPV and systemic lupus erythematosus: a mosaic of potential crossreactions

Yahel Segal1 & Shani Dahan1 & Michele Calabrò2 & Darja Kanduc3 & Yehuda Shoenfeld 1,4,5

Published online: 23 January 2017 # Springer Science+Business Media New York 2017 Yehuda Shoenfeld

Abstract Etiology, pathogenesis, and immunology of systemic lupus erythematosus (SLE) form a complex, still undeciphered picture that recently has been further made complicated by a new factor of morbidity: human papillomaviruses (HPVs). Indeed, a prevalence of HPV infections has been reported among SLE patients. Searching for molecular mechanisms that might underlie and explain the relationship between HPV infection and SLE, we explored the hypothesis that immune responses following HPV infection may crossreact with proteins that, when altered, associate with SLE. Analyzing HPV L1 proteins and using Epstein- Barr virus (EBV) and human retrovirus (HERV) as controls, we found a vast peptide overlap with human proteins comprehending lupus Ku autoantigen proteins p86 and p70, lupus brain antigen 1 homolog, lupus antigen expressed in neurons and muscles, natural killer cell IgG-like receptors, complement proteins C4-A and C4-B, complement receptor CD19, and others. The multitude and heterogeneity of peptide overlaps not only further support the hypothesis that crossreactivity can represent a primum movens in SLE onset, but also provide a molecular framework to the concept of SLE as Ban autoimmune mosaic syndrome.^ Finally, once more, it emerges the need of using the principle of peptide uniqueness as a new paradigm for safe and efficacious vaccinology.

Keywords HPV . EBV . HERV . SLE . Crossreactivity SLE: autoantibodies and autoantigens

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by an extremely heterogeneous population of autoantibodies (AAbs) [1–5]. The numerous SLE AAbs mirror the wide spectrum of clinical manifestations and the Electronic supplementary material The online version of this article variety of organs involved in the disease, i.e., the kidneys, (doi:10.1007/s12026-016-8890-y) contains supplementary material, skin, joints, blood vessel walls, mucous membranes, muscu- which is available to authorized users. loskeletal system, reproductive apparatus, and nervous system. * Yehuda Shoenfeld [email protected] Accordingly, to such immunological complexity, distinct pathological entities have been defined (lupus nephritis, neu- 1 Zabludowicz Center for Autoimmune Diseases, Sheba Medical ropsychiatric SLE, pediatric SLE, cutaneous discoid LE; Center (Tel-Hashomer), Sackler Faculty of Medicine, Tel Aviv drug-induced lupus, etc.) [1, 2] and, pari passu, a remarkably University, Tel Aviv, Israel vast number of autoantigens has been identified. The multi- 2 Department of Emergency and Organ Transplantation, University of tude of autoantigens targeted by SLE AAbs includes amino Bari, Bari, Italy acyl-tRNA synthetases, centromeric proteins, complement 3 Department of Biosciences, Biotechnologies and Biopharmaceutics, proteins, phospholipids (complexed to β2 glycoprotein 1), University of Bari, Bari, Italy nucleic acids, N-methyl-D-aspartate receptors, and others. 4 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Following remarkable scientific efforts in numerous laborato- 5 Department of Medicine B, Chaim Sheba Medical Center, Tel ries worldwide, today, we have a clear biochemical scenario of Hashomer, 52621 Ramat Gan, Israel SLE [1–5]. SLE Research and Clinical Update (2017) 65:564–571 565

Table 1 Pentapeptide sharing between HPV L1s (strains 6, 11, 16, and 18) and SLE-related proteins

Peptidea,b HPV SLE-associated proteins involved in Pathology involvemente Refse strainc the peptide sharingd

SVLED 6, 11 BLK. Tyrosine-protein kinase Blk Disseminated lupus erythematosus [46] MSLWL 16 CD22. B cell receptor CD22. B lymphocyte cell adhesion SLE [47] molecule. Sialic acid-binding Ig-like lectin 2 SRLLA 6, 11, CO4A. Complement C4-A. Cleaved into: Complement C4 Complement component 4A deficiency. A rare defect of the [48] 16 β chain; Complement C4-A α chain; C4a anaphylatoxin; complement classical pathway associated with FLLQA 16 C4b-A; C4d-A; Complement C4 γ chain autoimmune disorders, mainly systemic lupus with/out VGLSG 18 glomerulonephritis FSLDL 18 SRLLA 6, 11, CO4B. Complement C4-B. Cleaved into: Complement C4 Complement component 4B deficiency. A rare defect of the [48] 16 β chain; Complement C4-B α chain; C4a anaphylatoxin; complement classical pathway associated with the FLLQA 16 C4b-B; C4d-B; Complement C4 γ chain development of autoimmune disorders, mainly systemic VGLSG 18 lupus with/out associated glomerulonephritis FSLDL 18 RVNVG 6, 11 CO2. Complement C2 Complement component 2 deficiency, associated with [49] LQDTK 18 autoimmune disorders, mainly SLE LQSGY 6, 11 CO3. Complement C3 Complement component 3 deficiency. Patients develop [50] PLLNK 11,16 pyogenic infections and may develop arthralgia and PVPGQ 18 vasculitic rashes, lupus-like syndrome and glomerulonephritis YHASS 6, 11 C1QB. Complement C1q subcomponent subunit B Complement component C1q deficiency. It leads to immune [51] complex disease with features of SLE and glomerulonephritis LYTRV 18 C1S. Complement C1s subcomponent Complement component C1s deficiency that generally leads [52] to immune complex disease with features of SLE and glomerulonephritis. GSIVT 18 CR2. Complement receptor type 2. CD19. SLE 9 [53] TTPST 18 DNAS1. Deoxyribonuclease-1 SLE [54] TVIQD 16 EEA1. Early endosome antigen 1 Subacute cutaneous lupus erythematosus [55] STTAK ASSIY 11 GRP1. RAS guanyl-releasing protein 1. Calcium and SLE [56] DAG-regulated guanine nucleotide exchange factor II DTENA 16 ITAM. Integrin α-M SLE 6 [57, 58] GDCPP 6, 11, KPCD (isoform 2). Protein kinase C δ type. SLE [59] 16, Tyrosine-protein kinase PRKCD 18 LFFFL 6 KI2LA. Killer cell IgG-like receptor 2DL5A Receptor on natural killer (NK) cells for HLA-C alleles in- [60–63] LFFFL 6 KI2LB. Killer cell IgG-like receptor 2DL5B hibits the activity of NK cells thus preventing cell lysis. SKVVS 16 KI2L1. Killer cell IgG-like receptor 2DL1 Disturbance between activating and inhibitory killer cell IgG-like receptors may be one of the key factors under- SKVVS 16 KI2L2. Killer cell IgG-like receptor 2DL2 lying the pathogenesis of SLE SKVVS 16 KI3L1. Killer cell IgG-like receptor 3DL1 SKVVS 16 KI3L2. Killer cell IgG-like receptor 3DL2 LASSN 16 KI2L4. Killer cell IgG-like receptor 2DL4 TPSGS 6, 11, LARP6. La-related protein 6. Acheron. Lupus antigen Lupus [64] 16 expressed in neurons and muscles NRSSV 11 PSTAP 11 SGSLV 6, 11 MAGB2. Melanoma-associated antigen B2 SLE [65] SKVVS 16 NLRP1. NACHT, LRR, and PYD domains containing Vitiligo-associated multiple autoimmune disease 1. [66] LPDTS 18 protein 1 Characterized by the association of vitiligo with several diseases including SLE NTPSG 6 PSME3 (isoform 2). Ki nuclear autoantigen Lupus [67] TSSTS 16 PTN22. Tyrosine-protein phosphatase non-receptor type 22 SLE. Diabetes mellitus, insulin dependent (IDDM) [68, 69] TSVQN 11 SAMH1. Deoxynucleoside Chilblain lupus 2. A rare cutaneous form of lupus [70] triphosphatetriphosphohydrolase SAMHD1 erythematosus, with painful papular or nodular lesions of the skin precipitated by cold 566 SLE Research and Clinical Update (2017) 65:564–571

Table 1 (continued)

Peptidea,b HPV SLE-associated proteins involved in Pathology involvemente Refse strainc the peptide sharingd

PLYHP 18 SIAE. Sialate O-acetylesterase precursor Autoimmune disease 6: individuals can suffer from [71] rheumatoid arthritis, multiple sclerosis, Sjogren syndrome, SLE, diabetes, etc. SGLQY 16 TNAP3. Tumor necrosis factor α-induced protein 3. Disseminated lupus erythematosus [72] Cleaved into: A20p50; A20p37 LPPPS 18 TNIP1. TNFAIP3-interacting protein 1. A20-binding SLE [73] inhibitor of NFκB activation 1 DLLVK 11 TRNK1. TPR and ankyrin repeat-containing protein 1. Psychotic bipolar disorder. Neuropsychiatric lupus [74] EVPLD 16,18 Lupus brain antigen 1 homolog LDICT 16 TSVGS 6 XRCC5. X-ray repair cross-complementing protein 5. SLE [75] AENKD 18 Lupus Ku autoantigen protein p86. Thyroid-lupus autoantigen ELDQF 11 XRCC6. X-ray repair cross-complementing protein 6. SLE [76] Lupus Ku autoantigen protein p70. Ku70. Thyroid-lupus autoantigen a Shared pentapeptides are given in one letter code b Pentapeptide matches were used as probes since a pentapeptide is a minimal immune-biological determinant [77]. Pentapeptide sharing analyses were conducted as already described in detail [78–80] c HPV L1 proteins are from the following strains: 6 (P69899, VL1_HPV6B, 500 aa); 11 (P04012, VL1_HPV11, 501 aa); 16 (P03101, VL1_HPV16, 531 aa); and 18 (P06794, VL1_HPV18, 568 aa) d Using the keyword Blupus,^ an unbiased set of 97 human SLE-associated proteins was retrieved from UniProt protein resource (http://www.uniprot. org/) [45] (see Supplemental Table 1). SLE antigens are reported as UniProtKB entry names. Only reviewed entries were analyzed e Further references and details for protein involvement in SLE can be found at http://www.ncbi.nlm.nih.gov/omim/; http://www.uniprot.org/

SLE etiopathogenesis: viral infections These clinical data raise a crucial question— could HPV infection be the primary event that leads to SLE onset? What However, while the clinical-pathological-immunological are the molecules and mechanisms that link HPV and SLE? complexity of SLE has been analytically fathomed during the last decades [1–5], SLE etiopathogenesis is not yet clearly defined. Among the many genetic and environmental risk factors, viral infections appear to contribute the most to the path- Analyzing HPV for peptide sharing with SLE ogenesis of SLE. antigens Actually, the concept that viral infections may be involved in the etiopathogenesis of SLE has been repeatedly explored Searching for molecular links between HPV infection (or [6–13] and Epstein-Barr virus (EBV) [14–23] and human ret- vaccination) and SLE onset, the present study explored roviruses (HERVs) [24–31] are the main candidates currently HPV for peptide sharing with SLE autoantigens and used implicated in peptide sequence sharing in lupus [13]. EBV and HERV as controls. The rationale is that host im- Recently, a further factor of complexity in the study of SLE mune responses following HPV infection (or vaccination) etiopathogenesis has been the finding of a high incidence of might crossreact with SLE autoantigens, thus, damaging human papillomaviruses (HPV) infection among SLE pa- functions and structures in the cell. Indeed, several publica- tients. In particular, one study demonstrated a threefold in- tions draw attention to the molecular similarity of HPV to crease in HPV prevalence among SLE patients as compared the human proteome. Since 2000 [39–44], data were report- to controls. The higher rate of HPV infection was found in ed on the exact definition of the phenetic sequence similarity SLE patients with mild or no use of immunosuppressive drugs between onco-proteins of HPV to the human proteome. when compared to controls [32] and with a significantly lower While theoretically the mathematical probability of a number of classical risk factors, such as early sexual activity penta- or hexapeptide occurrence in two proteins is minis- and number of sexual partners [33]. These findings are cule, actually, a massive peptide overlap between HPV and flanked by additional reports documenting a link between lu- human proteins was found. This intense peptide sharing be- pus and HPV infection [34, 35] and, in some cases, a lupus tween HPV and human proteomes appears of relevance and pathologic sequela to HPV vaccination [36–38]. strongly supports the hypothesis that immune crossreactivity SLE Research and Clinical Update (2017) 65:564–571 567

Table 2 Immunological potential of the pentapeptides shared between Table 2 (continued) HPV L1 proteins and human proteins associated with lupus IEDB IDa Epitope sequenceb IEDB IDa Epitope sequenceb 153467 SSSYSKQFTSSTSYN 2009 AILTPTPVNPSTAPA 163452 SLNSKVVSQY 16854 FLPSPLFFFL 175631 PLGVGISGHPLLNKLDDTEN 17353 FPPSPLFFFL 177534 QFTSSTSYNRGDSTFESKSY 22873 GTVCKRDQSDRGWGNHAGLFGKGSIVTCVKA 181924 KNINVNMKKNNDNIWTDLLVKNSSDINK 40130 LTPTPVNPSTAPAPA 191701 QYQENRSSV 40131 LTPTPVNPSTAP 199073 AENKDEIAL 49756 PTPVNPSTAPAPAPT 201618 APASRLLAL 49920 PVNPSTAPAPAPTPT 219685 SVLSPLLNK 63039 TAVSTLLESGSLVTVAEQHP 224967 SFDLLVKNL 65790 TPTPVNPSTAPAPAPTPTFA 113838 SADLDQFPLGRKFLLQAGLK 65791 TPTPVNPSTAPAPAPTPTFAC 117593 NTPSGTTTQSRL 71222 VSYGSIVTY 117928 ILELDQFKGQQGQKRFQDMMGHGSDYSLSEVLW 75031 YLYYLSRTNTPSGTTTQSRL 118104 RILELDQFKGQQGQKRFQDMMGHGSDYSLSEVL 90882 YNKLTEDKKEPLLNKFQITTSPGSTQKILTA 225798 LQDTKISEW 109478 LGKRKATPTTSSTSTTAKRKKRKL 229931 SKQFTSSTSYNRGDSTFESKS 109716 PPVPVSKVVSTDEYVARTNIYYHA 232123 MPVPGQQSM 110343 NLASSNYFPTPSGSM 241658 CYRWPSTAPSCAAPRATVAL 110724 TNIYYHAGTSRLLAVGHPYF 241957 MRTADGLELACYRWPSTAPS 110872 GSGSTANLASSNYFP 242401 CVSPSTAPARAHQMSP 110916 KLDDTENASAYAANA 243003 NDLLVKVLEKH 110938 LYIKGSGSTANLASSNYFPT 418832 HAFILQDTKALHQV 110980 QPLGVGISGHPLLNKLDDTE 418833 HAFILQDTKALHQVFE 111110 ANKSEVPLDICTSIC 425900 KVADLLVKY 111175 CTNVAVNPGDCPPLE 429431 ATTSLNSKVVSQY 111183 CYGMLGNNLPPPSEV 431524 NMDEDLLVKY 111219 DVNVYHIFFQMSLWLPSEAT 431525 NMDEDLLVKY 111450 KGSPCTNVAVNPGDCPPLEL 432788 TTSLNSKVVSQY 111555 MLGNNLPPPSEVVSL 435133 GRLKGPLLNKF 111585 NKSEVPLDICTSICKYPDYI 441136 TPSGSREGSL 111595 NNLPPPSEVVSLYKS 441545 VSGDTENAKGQGEQGSTGGTN 111653 PVPVSKVVSTDGYVA 442677 APSKSRLLATL 111733 RKATPTTSSTSTTAK 447018 NRSSVEVRM 111911 VGISGHPLLNKLDDT 450351 YRLPPPSDPQY 111960 YHAGTSRLLAVGHPY 111962 YHIFFQMSLWLPSEA a Epitopes listed according to increasing IEDB ID number. Epitope refer- 112317 SIYVNTPSGSLVSS ences at www.immuneepitope.org/[81] 112317 SIYVNTPSGSLVSS b Peptide sequences shared between HPV L1 and human proteins related 112479 DNRVNVGMDYKQTQL to SLE are given in bold 112499 EQMFARHFFNRAGTVGEPVPDDLLVKGGNNRS 112527 GLEVGRGQPLGVGVSGHPLLNKYDDVENSGGY 112613 NKYDDVENSGGYGGNPGQDNRVNVGMDYKQTQL 112625 PSEATVYLPPVPVSKVVSTD may have a role in the pathogenesis of SLE among HPV 112648 RLFFFLRKEQMFARHFFNRA carriers. 112659 SGGNPGQDNRVNVGMDYKQT 112663 SIYVHTPSGSLVSSE In order to accurately estimate the crossreactivity hypothe- 112676 TNIFYHASSSRLLAV sis, here, we examined the peptide sharing between HPV L1 112677 TNIYYHAGTSRLLAV proteins and human proteins that when altered, are associated 112683 TPSGSLVSSEAQLFN 112728 YIKGSGSTANLASSNYFPTP with SLE. L1 proteins of HPV (strains 6, 11, 16, and 18) were 113838 SADLDQFPLGRKFLLQAGLK analyzed using public database resources [45]. Table 1 shows 117593 NTPSGTTTQSRL that 40 pentapeptide matches are distributed throughout 33 117928 ILELDQFKGQQGQKRFQDMMGHGSDYSLSEVLW 118104 RILELDQFKGQQGQKRFQDMMGHGSDYSLSEVLW human proteins that when altered, are associated with SLE 133612 KCCSGSLVERRPCFS and different lupus-like diseases [46–76]. 145283 KQFTSSTSYNRGDSTFES The pentapeptide sharing illustrated in Table 1 is also im- 145284 KQFTSSTSYNRGDSTFESKSY 145447 QFTSSTSYNRGDSTFESK munologically relevant. In fact, many of the pentapeptides 145580 TSSTSYNRGDSTF shared between HPV L1 proteins and human proteins associ- 148558 DDSKLPIVKVEDKSKLQDTKDKKR ated with lupus are present, too, in immunopositive epitopes 148562 DDSKLPVVKVEDKSKLQDTKDKKR 148647 IVKVEDKSKLQDTKDKKR (Table 2) 148971 VIKVEDKSKLQDTKDKKR Analysis of Tables 1 and 2 outlines an intricate and inho- 148982 VVKVEDKSKLQDTKDKKR mogeneous peptide sharing. It has to be noted that the HPV L1 149948 SPSGSLVSTDNQIFN versus human protein overlap is massive and, in addition, 568 SLE Research and Clinical Update (2017) 65:564–571 complex. For example, Table 1 shows that complement C4-A, complement C1q subcomponent subunit B and the pentapep- alterations of which may cause systemic lupus with/out glo- tide SRLLA from complement C4-A and complement C4-B merulonephritis, shares pentapeptides with the four HPV L1 (shared fragments marked in bold). In the end, immune reac- proteins under study. The peptide sharing is highly inhomo- tions against the L1 epitope TNIFYHASSSRLLAV can poten- geneous. As a paradigmatic example, complement C4-A tially crossreact with three human complement proteins, in this shares SRLLA with L1 from strains 6, 11, and 16; FLLQA way possibly causing the well-known hypocomplementemia with L1 from strain 16 and VGLSG and FSLDL with L1 from that characterizes lupus. strain 18. In this way, from an immunological point of view, In the end, Tables 1 and 2 provide evidence to the pathologic potential as well as the possible crossreactivity crossreactivity as a possible mechanism by which im- is amplified. mune responses following HPV infection (or, as well A further note of importance is the co-existence of many as vaccination) can trigger autoimmunity and contribute pentapeptides in the same epitope. This, too, can amplify im- to the development of SLE through different munological crossreactivity. An example is the HPV L1 crossreactions, thus, leading to a possible overlap of epitopic sequence TNIFYHASSSRLLAV (IEDB ID 112676, lupus symptoms or, in other words, a potential Blupus Table 2) that contains the pentapeptide YHASS from mosaic^ disease.

Table 3 EBV and HERV-W pentapeptide occurrences in human proteins associated with SLE

EBV shared pentapeptidesa,b,c Human proteins associated HERV-W shared Human proteins with SLEe,f pentapeptidesa,b,d associated with SLEe,f

PGAPG; GRRGR C1QA RSLSK; AIILL CO2 PGAPG; RGRER; GRERA C1QB LDLSK CO4A GRGGG C1R LDLSK CO4B GSGPQ; GGGGR CR2 YVISK CR2 AGGGG; PVGDA CO4A AAIIL ITAM AGGGG; PVGDA CO4B TTSTQ MECP2 GSGGR; GPDGE CR1 GTSSP PDCD1 GQKED CR2 VISQL PK3CG SSQSS ETS1 NSAGS PXK GAGEE IRF5 GTSSP SC5AB LRVLL ITAM IILLL; ILLLL SLAF6 NPKFE KPCD LVSNL THOC4 GRGRG; RGRGR; RGRGG; GAGGA; GAGGG; LARP1 LDLSK; LFLGE TLR5 AGGGA; AGGGG; SQSSS AGGGG; GGGGR; SGGRG LTK LQDQL TNIP1 GRGRG; RGRGR MECP2 FSNTT TNR1B KRPRS PSME3 KTKIY UB2L3 RERAR; RSRER; SRERA; EGGDG RU17 AAVVL XRCC5 GRGRG; RGRGR; RGRGG; SMD1 GRGRG; RGRGR; ARGRG SMD3 GRGRG; RGRGR; GRGGG; RGGGR; GGGAG; THOC4 AGGGG; GGGGR; GGGRG; ARGRG RRPPP TNFL6 GEKRP UB2L3 a Shared pentapeptides are given in a one-letter code b Pentapeptide matches were used as probes since a pentapeptide is a minimal immune-biological determinant [77]. Pentapeptide sharing analyses were conducted as already described in detail [78–80] c Analyses were conducted on EBV EBNA1 protein (UniProtKB ID: Q3KSS4, 641 aa) from EBV strain GD1, GenBank: AY961628.3 d Analyses were conducted on HERV-W or endogenous retrovirus group W member 1 (or Syncytin-1 or Envelope polyprotein gPr73, UniProtKB ID: Q9UQF0, 538 aa) e Using the keyword Blupus,^ an unbiased set of 97 human SLE-associated proteins was retrieved from UniProt protein resource (http://www.uniprot. org/) [45] (see Supplemental Table 1). SLE antigens are reported as UniProtKB entry names. Only reviewed entries were analyzed f Further references and details for protein involvement in SLE can be found at http://www.ncbi.nlm.nih.gov/omim/http://www.uniprot.org/ SLE Research and Clinical Update (2017) 65:564–571 569

EBV, HERV, and HPV versus SLE: a mosaic In conclusion, this study may contribute to an exact defini- of potential overlapping crossreactions tion of the etiologies and pathogenic mechanism of the currently still elusive SLE and SLE-like diseases. In the need of controls to validate our hypothesis and in light of the extensive scientific data that relate SLE to herpesviruses Acknowledgements We apologize to the many authors whose works [14–23, 82, 83] and retroviruses [24–31], we searched the set we have used but not discussed and cited because of space limitations. of human proteins related to SLE (Supplemental Table 1)for matches with EBVand HERV-W. Table 3 documents that both Compliance with ethical standards EBV and HERV-W share pentapeptides with SLE-associated antigens. Conflict of interest Yehuda Shoenfeld appears as a medical consultant in vaccine compensation court, USA. 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