Environmental factors are capable of triggering the expression of human endogenous retroviruses and induce an autoimmune response. Infection can promote the expression of human endogenous retroviruses by molecular mimicry or by functional mimicry. There are additional mechanisms which may control the expression of human endogenous retroviruses, such as epigenetic status of the genome (hypomethylation, histone deacetylation). Ultraviolet exposure, chemicals/drugs, injury/stress, hormones, all as a single cause or in a concert, may modulate the involvement of human endogenous retroviruses in pathogenic processes. In the current review we summarize the current knowledge on infections, molecular mimicry, cross-reactivity and epigenetics contribution for trigger human endogenous retroviruses expression and pathogenesis in lupus patients. Lupus (2009) 18, 1136—1143.
Sherer Y., Gorstein A., Fritzler MJ, Shoenfeld Y.Autoantibody explosion in systemic lupus erythematosus: more than 100 different Abs found in SLE patients. Semin Arthritis Rheum2004; 34: 501-537.
3.
Atassi MZ, Casali P.Molecular mechanisms of autoimmunity. Autoimmunity2008; 41: 123-132.
4.
Hewagama A., Richardson B.The genetics and epigenetics of autoimmune diseases. J Autoimmun2009; 33: 3-11.
5.
Pan Y., Sawalha AHEpigenetic regulation and the pathogenesis of systemic lupus erythematosus . Transl Res2009; 153: 4-10.
6.
Münz C. , Lünemann JD, Getts MT, Miller SDAntiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol2009; 9: 246-258.
7.
Su BY, Su CY, Yu SF, Chen CJIncidental discovery of high systemic lupus erythematosus disease activity associated with cytomegalovirus viral activity. Med Microbiol Immunol2007; 196: 165-170.
8.
Yoshiki T., Mellors RC, Strand M., August JTThe viral envelope glycoprotein of murine leukemia virus and the pathogenesis of immune complex glomerulonephritis of New Zealand mice. J Exp Med1974; 140: 1011-1027.
9.
Rich SAHuman lupus inclusions and interferon. Science1981; 213: 772-775.
10.
Krieg AM, Steinberg ADAnalysis of thymic endogenous retroviral expression in murine lupus. Genetic and immune studies. J Clin Invest1990; 86: 809-816.
11.
Talal N., Dauphinee MJ, Dang H., Alexander S., Hart DJ, Garry RFDetection of serum antibodies to retroviral proteins in patients with primary Sjogren’s syndrome (autoimmune exocrinopathy). Arthritis Rheum1990; 33: 774-781.
12.
Brookes SM, Pandolfino YA, Mitchell TJ, et al. The immune response to and expression of cross-reactive retroviral gag sequences in autoimmune disease. Brit J Rheum1992; 31: 735-742.
13.
Hermann M., Hagenhofer M., Kalden JRRetroviruses and systemic lupus erythematosus. Immunol Rev1996; 152: 145-156.
14.
Deas JE, Liu LG, Thompson JJ, et al. Reactivity of sera from systemic lupus erythematosus and Sjogren’s syndrome patients with peptides derived from human immunodeficiency virus p24 capsid antigen. Clin Diagn La Immunol1989; 5: 181-185.
15.
Shih A., Misra R., Rush MGDetection of multiple, novel reverse transcriptase coding sequences in human nucleic acids: Relation to primate retroviruses. J Virol1989; 63: 64-75.
16.
Griffiths DJ, Cooke SP, Herve C., et al. Detection of human retrovirus 5 in patients with arthritis and systemic lupus erythematosus. Arthritis Rheum1999; 42: 448-454.
Baltimore D.Retroviruses and retrotransposons: the role of reverse transcription in shaping the eukaryotic genome. Cell1985; 40: 481-482.
19.
Löwer R. , Löwer J., Kurth R.The viruses in all of us: characteristics and biological significance of human endogenous retrovirus sequences. Proc Natl Acad Sci USA1996; 93: 5177-5184.
20.
Krieg AM, Gourley MF, Perl A.Endogenous retroviruses: potential etiologic agents in autoimmunity. FASEB J1992; 6: 2537-2544.
21.
Perl A., Banki K.Human endogenous retroviral elements and autoimmunity: data and concepts. Trends Microbiol1993; 1: 153-156.
22.
de Parseval N., Heidmann T.Human endogenous retroviruses: from infectious elements to human genes. Cytogenet Genome Res2005; 110: 318-332.
23.
Martin MA, Bryan T., Rasheed S., Khan ASIdentification and cloning of endogenous retroviral sequences present in human DNA. Proc Natl Acad Sci USA1981; 78: 4892-4896.
24.
Perl A.Mechanisms of viral pathogenesis in rheumatic disease. Ann Rheum Dis1999; 58: 454-461.
25.
Fujinami RS , von Herrath MG, Christen U., Whitton JLMolecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev2006; 19: 80-94.
26.
Poole BD, Scofield RH, Harley JB, James JAEpstein-Barr virus and molecular mimicry in systemic lupus erythematosus. Autoimmunity2006; 39: 63-70.
27.
Poole BD, Gross T., Maier S., Harley JB, James JALupus-like autoantibody development in rabbits and mice after immunization with EBNA-1 fragments. J Autoimmun2008; 31: 362-371.
28.
Sutkowski N. , Chen G., Calderon G., Huber BTEpstein-Barr virus latent membrane protein LMP-2A is sufficient for transactivation of the human endogenous retrovirus HERV-K18 superantigen. J Virol2004; 78: 7852-7860.
29.
Pender MPInfection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol2003; 24: 584-588.
30.
Hsiao FC, Lin M., Tai A., Chen G., Huber BTCutting edge: Epstein-Barr virus transactivates the HERV-K18 superantigen by docking to the human complement receptor 2 (CD21) on primary B cells. J Immunol2006; 177: 2056-2060.
31.
Hsiao FC, Tai AK, Deglon A., Sutkowski N., Longnecker R., Huber BT. EBV LMP-2A employs a novel mechanism to trans-activate the HERV-K18 superantigen through its ITAM. Virology2009 ; 385: 261-266.
32.
Herve CA, Lugli EB, Brand A., Griffiths DJ, Venables PJAutoantibodies to human endogenous retrovirus- K are frequently detected in health and disease and react with multiple epitopes. Clin Exp Immunol2002; 128: 75-82.
33.
Perl A., Nagy G., Koncz A., et al. Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE. Autoimmunity2008; 41: 287-297.
34.
Banki K., Maceda J., Hurley E., et al. Human T-cell lymphotropic virus (HTLV)-related endogenous sequence, HRES-1, encodes a 28-kDa protein: a possible autoantigen for HTLV-I gag-reactive autoantibodies. Proc Natl Acad Sci USA1992 ; 89: 1939-1943.
35.
Perl A., Colombo E., Dai H., et al. Antibody reactivity to the HRES-1 endogenous retroviral element identifies a subset of patients with systemic lupus erythematosus and overlap syndromes. Correlation with antinuclear antibodies and HLA class II alleles . Arthritis Rheum1995; 38: 1660-1671.
36.
Gergely P. Jr , Pullmann R., Stancato C., et al. Increased prevalence of transfusion-transmitted virus and cross-reactivity with immunodominant epitopes of the HRES-1/p28 endogenous retroviral autoantigen in patients with systemic lupus erythematosus . Clin Immunol2005; 116: 124-134.
37.
Perl A.Role of endogenous retroviruses in autoimmune diseases. Rheum Dis Clin North Am2003; 29: 123-143.
38.
Gergely P. Jr , Perl A. , Poor G.Possible pathogenic nature of the recently discovered TT virus: does it play a role in autoimmune rheumatic diseases?Autoimmun Rev2006; 6: 5-9.
39.
Abrams MT, Robertson NM, Yoon K., Wickstrom E.Inhibition of glucocorticoid-induced apoptosis by targeting the major splice variants of BIM mRNA with small interfering RNA and short hairpin RNA. J Biol Chem2004; 279: 55809-55817.
40.
Garbuglia AR , Iezzi T., Capobianchi MR, et al. Detection of TT virus in lymph node biopsies of B-cell lymphoma and Hodgkin’s disease, and its association with EBV infection. Int J Immunopathol Pharmacol2003; 16: 109-118.
41.
Gharavi AE, Pierangeli SS, Espinola RG, Liu X., Colden-Stanfield M., Harris ENAntiphospholipid antibodies induced in mice by immunization with a cytomegalovirus-derived peptide cause thrombosis and activation of endothelial cells in-vivo. Arthritis Rheum2002; 46: 545-552.
42.
Blank M., Asherson RA, Cervera R., Shoenfeld Y.Antiphospholipid syndrome infectious origin. J Clin Immunol2004; 24: 12-23.
43.
Bonfa E., Golombek SJ, Kaufman LD, et al. Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med1987; 217: 265-271.
44.
Reichlin M.Ribosomal P antibodies and CNS lupus. Lupus2003; 12: 916-918.
45.
Mahler M., Kessenbrock K., Szmyrka M., et al. International multi-center evaluation of autoantibodies to ribosomal P proteins. Clin Vaccine Immunol2006; 13: 77-83.
46.
Brey RL, Holliday SL, Saklad AR, et al. Neuropsychiatric syndromes in lupus: Prevalence using standardized definitions. Neurology2002; 58: 1214-1220.
47.
Katzav A., Solodeev I., Brodsky O., et al. Induction of autoimmune depression in mice by anti-ribosomal P antibodies via the limbic system. Arthritis Rheum2007; 56: 938-948.
48.
Mahler M., Kessenbrock K., Raats J., Williams R., Fritzler MJ, Bluthner M.Characterization of the human autoimmune response to the major C-terminal epitope of the ribosomal P proteins. J Mol Med2003; 81: 194-204.
Li JM, Fan WS, Horsfall AC, et al. The expression of human endogenous retrovirus-3 in fetal cardiac tissue and antibodies in congenital heart block. Clin Exp Immunol1996; 104: 388-393.
52.
Cervera R., Piette JC, Font J., et al. Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum2002; 46: 1019-1027.
Blank M., Cohen J., Toder V., Shoenfeld Y.Induction of primary anti-phospholipid syndrome in mice by passive transfer of anticardiolipin antibodies. Proc Natl Acad Sci USA1991; 88: 3069-3073.
55.
Blank M., Shoenfeld Y., Cabilli S., Heldman Y., Fridkin M., Katchalski-Katzir E.Prevention of experimental antiphospholipid syndrome and endothelial cell activation by synthetic peptides. Proc Natl Acad Sci USA1999; 96: 5164-5168.
56.
Pierangeli SS, Liu X., Espinola R., et al. Functional analyses of patient-derived IgG monoclonal anticardiolipin antibodies using in vivo thrombosis and in vivo microcirculation models. Thromb Haemost2000; 84: 388-395.
57.
Ogasawara H. , Naito T., Kaneko H., et al. Quantitative analyses of messenger RNA of human endogenous retrovirus in patients with systemic lupus erythematosus . J Rheumatol2001; 28: 533-538.
58.
Javierre BM , Esteller M., Ballestar E.Epigenetic connections between autoimmune disorders and haematological malignancies. Trends Immunol2008; 29: 616-623.
59.
Ballestar E. , Esteller M., Richardson BCThe epigenetic face of systemic lupus erythematosus . J Immunol2006; 176: 7143-7147.
60.
Okada M., Ogasawara H., Kaneko H., et al. Role of DNA methylation in transcription of human endogenous retrovirus in the pathogenesis of systemic lupus erythematosus. J Rheumatol2002; 29: 1678-1682.
61.
Ogasawara H., Hishikawa T., Sekigawa I., Hashimoto H., Yamamoto N., Maruyama M.Sequence analysis of human endogenous retrovirus clone 4-1in systemic lupus erythematosus. Autoimmunity2001; 33: 15-21.
62.
Nagy G., Ward J., Mosser DDRegulation of CD4 expression via recycling by HRES-1/RAB4 controls susceptibility to HIV infection. J Biol Chem2006; 281: 34574-34591.
63.
Fernandez DR , Telarico T., Bonilla E., et al. Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. J Immunol2009; 182: 2063-2073.
64.
Pullmann R. Jr, Bonilla E., Phillips PE, Middleton FA, Perl A.Haplotypes of the HRES-1 endogenous retrovirus are associated with development and disease manifestations of systemic lupus erythematosus. Arthritis Rheum2008; 58: 532-540.
65.
Tsao BPLupus susceptibility genes on human chromosome 1. Int Rev Immunol2000; 19: 319-334.
