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Human parvovirus B19, autoimmunity and systemic lupus erythematosus
Tsai-Ching Hsu1, Bor-Show Tzang1,2,3
1Professor, Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung40201, Taiwan.
2Consultant, Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan, 40201.
3Professor, Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung40201, Taiwan.

Article ID: 100002B01TH2015

Address correspondence to:
Bor-Show Tzang
PhD., Department of Biochemistry, School of Medicine, Chung Shan Medical University, No. 110
Section 1, Jianguo N. Road
Taichung 40201
Taiwan, Republic of China

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Tsai-Ching H, Bor-Show T. Human parvovirus B19, autoimmunity and systemic lupus erythematosus. Edorium J Biochem 2015;1:4–7.


Imbalance of autoimmunity is a significant issue worldwide, which results in autoimmune disorders. To date, more than eighty autoimmune diseases are identified [1]. An autoimmune disorder may cause diverse impacts such as destruction of body tissue, abnormal growth of an organ, and organ dysfunction [2]. Various factors are strongly associated with the development of autoimmunity such as genetics, age and environment. Among environmental factors, viruses, bacteria and other infectious pathogens are the major postulated triggers of autoimmune diseases including systemic lupus erythematosus (SLE) [3] [4], which is known as a prototypic autoimmune disease with unknown etiology [5]. Notably, human parvovirus B19 has been suspected as contributors to human autoimmune diseases, especially SLE [6].

B19 virus induces autoimmunity and mimics SLE manifestations

Human parvovirus B19 (B19) is known as the cause of fifth disease in childhood, and the possible trigger in the spectrum of autoimmune diseases in adults [7]. B19 is a linear, non-segmented single-stranded DNA virus that belongs to the large Parvoviridae family. B19 consists a nonstructural protein (NS1) and two capsid proteins, VP1 (83 kDa) and VP2 (58 kDa) [8]. These two capsid proteins of B19 are identical except for 227 amino acids at the amino-terminal end of the VP1-protein, the so called VP1-unique region (VP1u) [9]. Notably, B19 VP1u has been linked to the phospholipase A2 (PLA2)-like activity, which is essential for parvovirus B19 infectivity [10].

B19 infection has been recognized as a cause or trigger of autoimmune diseases [11] [12] and associated with the production of various autoantibodies against beta2-glycoprotein I (β2GPI), and cardiolipin (aCL) [13] [14]. Accumulating evidences have indicated that human parvovirus B19 infection is highly associated with the onset and exacerbations of SLE [15]. B19 infection may present a clinical and serological tableau like the episode of SLE such as cytopenia, hypocomplementemia and generation of autoantibodies [16][17]. An in vitro study has indicated that B19-NS1 proteins enhanced the expression of cleavage of 70 kDa U1-snRNP autoantigen, suggesting a role of B19-NS1 on autoantibody induction [18]. In addition, a previous study has also demonstrated the induction of autoimmunity by antibodies against B19-VP1u in naïve mice. In BALB/c mice infused with recombinant B19-VP1u proteins through tail vein, thrombocytopenia, prolongation of aPTT, and autoantibody against β2GPI and PhL were detected [19].

B19 infection and anti-phospholipid syndrome (APS) have been reported to show similar symptoms leading to the hypothesis of a common pathogenetic background [13]. Remarkable similarity exists in the specificity of anti-phospholipid antibody (APhL) between patients with B19 infection or SLE [13][14] [20]. The APS is an autoimmune disease characterized by the persistent presence of APhL and by the occurrence of thrombosis, fetal loss and thrombocytopenia [21]. An APhL is a pathogenic antibody mainly directed against the phospholipid-binding protein β2GPI [22] [23] [24]. The β2GPI is an abundant plasma phospholipid-binding protein and has been demonstrated binding to human endothelial cells via annexin II, resulting in activation of human endothelial cells [25]. The activated endothelial cells induce the pro-coagulant and pro-inflammatory phenotype with adhesion molecule such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin [26] [27] and pro-inflammatory cytokines and chemokines [28] [29], which is regarded to be involved in the generation of autoimmunity. Notably, autoantibodies against CL, β2GPI, and phospholipid (PhL) in sera from patients with B19 infection were cross-reactive with B19-VP1u [19]. In animal experiments, sera from rabbits immunized with recombinant B19-VP1u protein displayed raised detectable immunoglobulins against B19-VP1u, CL, β2GPI and PhL. Moreover, the mice immunized with anti-B19-VP1u IgG developed thrombocytopenia, prolongation of aPTT, and autoantibody against β2GPI and PhL [30]. These experiments provided rational evidences of B19 on inducing autoimmunity.

B19 infection aggravated liver injuries in SLE

B19 infection has been associated with liver abnormality in SLE [31]. The liver is such an important organ that plays important role in the metabolism of various substances. It is also involved in the induction of immune tolerance and recognized as a target for immune-mediated injuries [32]. Notably, the liver involvement in SLE, recently gained extensive attention worldwide. Although further hepatic inspection is not a routinely diagnostic criterion [33], accumulating studies have indicated that more than 50% of SLE patients reveal various liver abnormalities during the course of their illness [34] [35] [36]. To investigate whether B19 infection induces liver injury and contributes to induction of autoimmunity, experiments of passive transfer of B19 viral proteins or antibodies against B19 viral proteins were performed. Likewise, significantly aggravated liver inflammation was observed in liver of the lupus-prone mice receiving antibodies against B19-VP1u [37]. Additionally, significantly aggravated liver damage indices, including elevated MMP-9 activity and expressions of iNOS, COX-2 and TNF-α were detected in lupus-prone mice that were treated with B19-NS1 proteins [38] as well as liver fibrosis through TGF-b/Smad signaling [39].

Numerous studies have recognized that virus-induced liver damage is involved in generation of autoimmunity. For instance, chronic viral hepatitis induced by HCV or HDV is usually accompanied by production of autoantibodies, particularly liver/kidney microsomal (LKM) antibodies [40]. Although direct evidence of B19 infection for the development of SLE is lacking, these studies indicated that B19 aggravated liver injury in SLE could be a potential impact for autoimmunity. Whether B19-aggravated liver injuries induce autoimmunity in SLE needs further investigations to clarify the precise mechanism.

Keywords:Autoimmunity, Fetal loss, Thrombocytopenia, Liver injury, Infection

  1. Selgrade MK, Cooper GS, Germolec DR, Heindel JJ. Linking environmental agents and autoimmune disease: an agenda for future research. Environ Health Perspect 1999 Oct;107 Suppl 5:811–3.   [CrossRef]   [Pubmed]    Back to citation no. 1
  2. Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 2013 Aug 31;382(9894):819–31.   [CrossRef]   [Pubmed]    Back to citation no. 2
  3. Danzer C, Mattner J. Impact of microbes on autoimmune diseases. Arch Immunol Ther Exp (Warsz) 2013 Jun;61(3):175–86.   [CrossRef]   [Pubmed]    Back to citation no. 3
  4. Smilek DE, Ehlers MR, Nepom GT. Restoring the balance: immunotherapeutic combinations for autoimmune disease. Dis Model Mech 2014 May;7(5):503–13.   [CrossRef]   [Pubmed]    Back to citation no. 4
  5. Hahn BH. An overview of the pathogenesis of systemic lupus erythematosus In: Wallace DJ, Hahn BH eds. Dubois' lupus erythematosus. Philadelphia: Williams & Wilkins; 1993. p. 69–76.    Back to citation no. 5
  6. Pavlovic M, Kats A, Cavallo M, Shoenfeld Y. Clinical and molecular evidence for association of SLE with parvovirus B19. Lupus 2010 Jun;19(7):783–92.   [CrossRef]   [Pubmed]    Back to citation no. 6
  7. Young NS. B19 parvovirus. Baillieres Clin Haematol 1995 Mar;8(1):25–56.   [CrossRef]   [Pubmed]    Back to citation no. 7
  8. Young NS, Brown KE. Parvovirus B19. N Engl J Med 2004 Feb 5;350(6):586–97.   [CrossRef]   [Pubmed]    Back to citation no. 8
  9. Rayment FB, Crosdale E, Morris DJ, Pattison JR, Talbot P, Clare JJ. The production of human parvovirus capsid proteins in Escherichia coli and their potential as diagnostic antigens. J Gen Virol 1990 Nov;71 (Pt 11):2665–72.   [CrossRef]   [Pubmed]    Back to citation no. 9
  10. Zádori Z, Szelei J, Lacoste MC, et al. A viral phospholipase A2 is required for parvovirus infectivity. Dev Cell 2001 Aug;1(2):291–302.   [CrossRef]   [Pubmed]    Back to citation no. 10
  11. Hsu TC, Tsay GJ. Human parvovirus B19 infection in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2001 Feb;40(2):152–7.   [CrossRef]   [Pubmed]    Back to citation no. 11
  12. Lehmann HW, von Landenberg P, Modrow S. Parvovirus B19 infection and autoimmune disease. Autoimmun Rev 2003 Jun;2(4):218–23.   [CrossRef]   [Pubmed]    Back to citation no. 12
  13. Loizou S, Cazabon JK, Walport MJ, Tait D, So AK. Similarities of specificity and cofactor dependence in serum antiphospholipid antibodies from patients with human parvovirus B19 infection and from those with systemic lupus erythematosus. Arthritis Rheum 1997 Jan;40(1):103–8.   [CrossRef]   [Pubmed]    Back to citation no. 13
  14. Kalt M, Gertner E. Antibodies to beta 2-glycoprotein I and cardiolipin with symptoms suggestive of systemic lupus erythematosus in parvovirus B19 infection. J Rheumatol 2001 Oct;28(10):2335–6.   [Pubmed]    Back to citation no. 14
  15. Esposito S, Bosis S, Semino M, Rigante D. Infections and systemic lupus erythematosus. Eur J Clin Microbiol Infect Dis 2014 Sep;33(9):1467–75.   [CrossRef]   [Pubmed]    Back to citation no. 15
  16. Nesher G, Osborn TG, Moore TL. Parvovirus infection mimicking systemic lupus erythematosus. Semin Arthritis Rheum 1995 Apr;24(5):297–303.   [Pubmed]    Back to citation no. 16
  17. Sève P, Ferry T, Koenig M, Cathebras P, Rousset H, Broussolle C. Lupus-like presentation of parvovirus B19 infection. Semin Arthritis Rheum 2005 Feb;34(4):642–8.   [Pubmed]    Back to citation no. 17
  18. Tzang BS, Chen DY, Tsai CC, Chiang SY, Lin TM, Hsu TC. Human parvovirus B19 nonstructural protein NS1 enhanced the expression of cleavage of 70 kDa U1-snRNP autoantigen. J Biomed Sci 2010 May 25;17:40.   [CrossRef]   [Pubmed]    Back to citation no. 18
  19. Tzang BS, Tsay GJ, Lee YJ, Li C, Sun YS, Hsu TC. The association of VP1 unique region protein in acute parvovirus B19 infection and anti-phospholipid antibody production. Clin Chim Acta 2007 Mar;378(1-2):59–65.   [CrossRef]   [Pubmed]    Back to citation no. 19
  20. von Landenberg P, Lehmann HW, Modrow S. Human parvovirus B19 infection and antiphospholipid antibodies. Autoimmun Rev 2007 Apr;6(5):278–85.   [CrossRef]   [Pubmed]    Back to citation no. 20
  21. Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid antibody syndrome: a systematic review. JAMA 2006 Mar 1;295(9):1050–7.   [CrossRef]   [Pubmed]    Back to citation no. 21
  22. Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci U S A 1991 Apr 15;88(8):3069–73.   [CrossRef]   [Pubmed]    Back to citation no. 22
  23. Bas de Laat H, Derksen RH, de Groot PG. beta2-glycoprotein I, the playmaker of the antiphospholipid syndrome. Clin Immunol 2004 Aug;112(2):161–8.   [CrossRef]   [Pubmed]    Back to citation no. 23
  24. Pierangeli SS, Harris EN. Clinical laboratory testing for the antiphospholipid syndrome. Clin Chim Acta 2005 Jul 1;357(1):17–33.   [CrossRef]   [Pubmed]    Back to citation no. 24
  25. Ma K, Simantov R, Zhang JC, Silverstein R, Hajjar KA, McCrae KR. High affinity binding of beta 2-glycoprotein I to human endothelial cells is mediated by annexin II. J Biol Chem 2000 May 19;275(20):15541–8.   [CrossRef]   [Pubmed]    Back to citation no. 25
  26. George J, Blank M, Levy Y, et al. Differential effects of anti-beta2-glycoprotein I antibodies on endothelial cells and on the manifestations of experimental antiphospholipid syndrome. Circulation 1998 Mar 10;97(9):900–6.   [Pubmed]    Back to citation no. 26
  27. Raschi E, Testoni C, Borghi MO, Fineschi S, Meroni PL. Endothelium activation in the anti-phospholipid syndrome. Biomed Pharmacother 2003 Sep;57(7):282–6.   [CrossRef]   [Pubmed]    Back to citation no. 27
  28. Cho CS, Cho ML, Chen PP, et al. Antiphospholipid antibodies induce monocyte chemoattractant protein-1 in endothelial cells. J Immunol 2002 Apr 15;168(8):4209–15.   [CrossRef]   [Pubmed]    Back to citation no. 28
  29. Meroni PL, Ronda N, De Angelis V, Grossi C, Raschi E, Borghi MO. Role of anti-beta2 glycoprotein I antibodies in antiphospholipid syndrome: in vitro and in vivo studies. Clin Rev Allergy Immunol 2007 Feb;32(1):67–74.   [Pubmed]    Back to citation no. 29
  30. Tzang BS, Lee YJ, Yang TP, et al. Induction of antiphospholipid antibodies and antiphospholipid syndrome-like autoimmunity in naive mice with antibody against human parvovirus B19 VP1 unique region protein. Clin Chim Acta 2007 Jul;382(1-2):31–6.   [CrossRef]   [Pubmed]    Back to citation no. 30
  31. Barash J, Dushnitzky D, Sthoeger D, Bardenstein R, Barak Y. Human parvovirus B19 infection in children: uncommon clinical presentations. Isr Med Assoc J 2002 Oct;4(10):763–5.   [Pubmed]    Back to citation no. 31
  32. Malnick S, Melzer E, Sokolowski N, Basevitz A. The involvement of the liver in systemic diseases. J Clin Gastroenterol 2008 Jan;42(1):69–80.   [CrossRef]   [Pubmed]    Back to citation no. 32
  33. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982 Nov;25(11):1271–7.   [CrossRef]   [Pubmed]    Back to citation no. 33
  34. Harvey AM, Shulman LE, Tumulty PA, Conley CL, Schoenrich EH. et al. Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine (Baltimore) 1954 Dec;33(4):291–437.   [CrossRef]   [Pubmed]    Back to citation no. 34
  35. Abraham S, Begum S, Isenberg D. Hepatic manifestations of autoimmune rheumatic diseases. Ann Rheum Dis 2004 Feb;63(2):123–9.   [CrossRef]   [Pubmed]    Back to citation no. 35
  36. Takahashi A, Abe K, Saito R, et al. Liver dysfunction in patients with systemic lupus erythematosus. Intern Med 2013;52(13):1461–5.   [CrossRef]   [Pubmed]    Back to citation no. 36
  37. Tsai CC, Tzang BS, Chiang SY, Hsu GJ, Hsu TC. Increased expression of Matrix Metalloproteinase 9 in liver from NZB/W F1 mice received antibody against human parvovirus B19 VP1 unique region protein. J Biomed Sci 2009 Jan 26;16:14.   [CrossRef]   [Pubmed]    Back to citation no. 37
  38. Tsai CC, Chiu CC, Hsu JD, Hsu HS, Tzang BS, Hsu TC. Human parvovirus B19 NS1 protein aggravates liver injury in NZB/W F1 mice. PLoS One 2013;8(3):e59724.   [CrossRef]   [Pubmed]    Back to citation no. 38
  39. Hsu TC, Tsai CC, Chiu CC, Hsu JD, Tzang BS. Exacerbating effects of human parvovirus B19 NS1 on liver fibrosis in NZB/W F1 mice. PLoS One 2013 Jun 28;8(6):e68393.   [CrossRef]   [Pubmed]    Back to citation no. 39
  40. Manns MP, Obermayer-Straub P. Viral induction of autoimmunity: mechanisms and examples in hepatology. J Viral Hepat 1997;4 Suppl 2:42–7.   [CrossRef]   [Pubmed]    Back to citation no. 40

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Author Contributions:
Tsai-Ching Hsu – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Bor-Show Tzang – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Guarantor of submission
The corresponding author is the guarantor of submission.
Source of support
Conflict of interest
Authors declare no conflict of interest.
© 2015 Tsai-Ching Hsu et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.

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