EBV Causes Lupus

Smokers are more likely to have been infected by EBV, and at younger ages, for socioeconomic reasons. The Surgeon General report of 2014 makes no mention at all of EBV in lupus, therefore it is a deliberate act of scientific fraud.

An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. JA James, KM Kaufman, AD Farris, E Taylor-Albert, TJA Lehman, JB Harley. J Clin Invest 1997 Dec;100(12):3019-3026. "Virtually all (116 of 117, or 99%) of these young patients had seroconverted against Epstein-Barr virus, as compared with only 70% (107 of 153) of their controls (odds ratio 49.9, 95% confidence interval 9.3-1025, P<0.00000000001)... An assay for Epstein-Barr virus DNA in peripheral blood lymphocytes established Epstein-Barr infection in the peripheral blood of all 32 of the lupus patients tested, while only 23 of the 32 matched controls were infected (odds ratio >10, 95% confidence interval 2.53-[infinity], P<0.002)."

James / J Clin Invest 1997 full article

Editorial. The Epstein-Barr virus and systemic lupus erythematosus. JH Vaughan. J Clin Invest 1997 Dec;100(12):2939-2940. Re James et al: "As they note, this suggests either that EBV predisposes to the development of SLE or, conversely, that SLE predisposes to EBV. As there has been nothing during decades of intense clinical interest in SLE to suggest that SLE patients are hypersusceptible to EBV infection... the former interpretation is preferred."

Vaughan / J Clin Invest 1997 full article

Potential role of the Epstein-Barr virus in systemic lupus erythematosus autoimmunity. M Incaprera, L Rindi, A Bazzichi, C Garzelli. Clin Exp Rheumatol 1998 May-Jun;16(3):289-294. "50% of the patients with SLE and 100% of the patients in the acute phase of IM, but none of the seropositive normal individuals, produced IgG antibodies to the EBNA-2-derived synthetic peptide," which has a region resembling SmD1, a common target of autoantibodies. "We suggest the possibility that EBV may establish a persistent infection in at least a certain number of SLE patients."

Incaprera - Clin Exp Rheumatol 1998 abstract / PubMed

Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. JA James, BR Neas, KL Moser, T Hall, GR Bruner, AL Sestak, JB Harley. Arthritis Rheum 2001 May;44(5):1122-1126. "Of the 196 lupus patients tested, all but 1 had been exposed to EBV, while 22 of the 392 controls did not have antibodies consistent with previous EBV exposure (OR 9.35, 95% CI 1.45-infinity, P=0.014)."

James / Arthritis Rheum 2001 full article

Epstein-barr virus-associated non-Hodgkin's lymphoma of B-cell origin, Hodgkin's disease, acute leukemia, and systemic lupus erythematosus: a serologic and molecular analysis. W Mitarnun, J Pradutkanchana, S Takao, V Saechan, S Suwiwat, T Ishida. J Med Assoc Thai. 2002 May;85(5):552-9. In 58 patients, "EBV internal repeat-1 region (IR-1) in peripheral blood CD3+ cells was detected in 10 of 14 patients (71.5%) with NHL-B, 3 of 8 patients (37.5%) with Hodgkin's disease, 1 of 6 patients (16.7%) with acute leukemia, 4 of 9 patients (44.5%) with SLE, and was not detected in any of the 21 patients with other diseases."

Mitarnun J Med Assoc Thai 2002 abstract / PubMed

Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus. I Kang, T Quan, H Nolasco, SH Park, MS Hong, J Crouch, EG Pamer, JG Howe, J Craft. J Immunol 2004 Jan 15;172(2):1287-1294. 42 patients, 32 healthy controls. "Patients with SLE had an approximately 40-fold increase in EBV viral loads compared with controls, a finding not explained by disease activity or immunosuppressive medications. The frequency of EBV-specific CD69+ CD4+ T cells producing IFN-gamma was higher in patients with SLE than in controls. By contrast, the frequency of EBV-specific CD69+ CD8+ T cells producing IFN-gamma in patients with SLE appeared lower than that in healthy controls, although this difference was not statistically significant... EBV viral loads were inversely correlated with the frequency of EBV-specific CD69+ CD4+ T cells producing IFN-gamma and were positively correlated with the frequencies of CD69+ CD8+ T cells producing IFN-gamma and with EBV-specific, HLA-A2 tetramer-positive CD8+ T cells."

Kang / J Immunol 2004 full article

Patients with systemic lupus erythematosus have abnormally elevated Epstein-Barr virus load in blood. UY Moon, SJ Park, ST Oh, WU Kim, SH Park, SH Lee, CS Cho, HY Kim, WK Lee, SK Lee. Arthritis Res Ther 2004;6(4):R295-302. 66 patients, 63 controls. "The number of infections and EBV type distribution were similar between adult SLE patients and healthy control individuals (98.5% versus 94%). Interestingly, the EBV burden in peripheral blood mononuclear cells (PBMCs) was over 15-fold greater in SLE patients than in healthy control individuals (mean +/- standard deviation: 463 +/- 570 EBV genome copies/3 microg PBMC DNA versus 30 +/- 29 EBV genome copies/3 microg PBMC DNA; P = 0.001), suggesting that EBV infection is abnormally regulated in SLE."

Moon - Arthritis Res Ther 2004 full article / PubMed Central
Moon / Arthritis Res Ther 2004 full article

High prevalence of immunoglobulin A antibody against Epstein-Barr virus capsid antigen in adult patients with lupus with disease flare: case control studies. CJ Chen, KH Lin, SC Lin, WC Tsai, JH Yen, SJ Chang, SN Lu, HW Liu. J Rheumatol 2005 Jan;32(1):44-47. "In the first study, IgA antibody against EBV-VCA was the only marker with significantly higher prevalence in adults with SLE compared to healthy adults (36.1% vs 5.6%; p < 0.005). In the second study, we confirmed that the prevalence of IgA antibody against EBV-VCA was indeed higher in adults with SLE (38.9% vs 2.8%; p < 0.001)... SLE patients with flare showed much higher prevalence of IgA antibody against EBV-VCA compared to those without flare (81.3% vs 25.0%; p < 0.001)."

Chen - J Rheumatol 2005 abstract / PubMed

Elevated immunoglobulin G antibodies to the proline-rich amino-terminal region of Epstein-Barr virus nuclear antigen-2 in sera from patients with systemic connective tissue diseases and from a subgroup of Sjogren's syndrome patients with pulmonary involvements. M Yamazaki, R Kitamura, S Kusano, H Eda, S Sato, M Okawa-Takatsuji, S Aotsuka, K Yanagi. Clin Exp Immunol 2005 Mar;139(3):558-568. 102 SLE, 74 primary SS, 70 RA, 15 SSc, 51 secondary SS, seven PM/DM, nine MCTD patients and 120 healthy controls. "The specific levels of IgG antibodies to the amino-terminal region of EBNA-2 were elevated in patients with SLE, primary SS or RA, as well as those with secondary SS complicated with SLE or RA."

Yamazaki - Clin Exp Immunol 2005 full article / PubMed Central
Yamazaki / Clin Exp Immunol 2005 full article

Association of Epstein-Barr virus with systemic lupus erythematosus: effect modification by race, age, and cytotoxic T lymphocyte-associated antigen 4 genotype. CG Parks, GS Cooper, LL Hudson, MA Dooley, EL Treadwell, EW St Clair, GS Gilkeson, JP Pandey. Arthritis Rheum 2005 Apr;52(4):1148-1159. 144 African American and 86 white SLE patients, 276 controls. "In African Americans, EBV-IgA seroprevalence was strongly associated with SLE (odds ratio [OR] 5.6, 95% confidence interval [95% CI] 3.0-10.6). In whites, the modest association of SLE with EBV-IgA (OR 1.6) was modified by age, in that the strongest association was observed in those older than age 50 years (OR 4.1, 95% CI 1.6-10.4)."

Parks / Arthritis Rheum 2005 full article

Reactivation of Epstein-Barr virus in patients with systemic lupus erythematosus. ML Huggins, I Todd, RJ Powell. Rheumatol Int 2005 Apr;25(3):183-187. "Sera from SLE patients were tested for antibodies to several EBV antigens and had a significantly higher prevalence of immunoglobulin G antibodies against EBV early antigens than in normal or disease controls. This suggests that recent EBV infection or virus reactivation was occurring in these patients."

Huggins - Rheumatol Int 2005 abstract / PubMed

Phenotypic and functional analysis of EBV-specific memory CD8 cells in SLE. BR Berner, M Tary-Lehmann, NL Yonkers, AD Askari, PV Lehmann, DD Anthony. Cell Immunol 2005 May;235(1):29-38. 6 SLE patients, 5 controls. "Frequencies of EBV-specific CD8 cells tended to be greater in SLE subjects than in healthy control subjects (p=0.07). While over 10% of EBV-specific CD8 cells were capable of producing IFN-gamma in four out of five healthy control subjects, such proportions of EBV-specific CD8 cells capable of IFN-gamma production were observed in only one out of six SLE subjects (p=0.04). In contrast, viral peptide pool-specific and mitogen-induced IFN-gamma-producing T cell function was intact in SLE subjects. Phenotypic analysis revealed EBV-specific CD8 cells to be in an early to intermediate differentiation and resting memory state in both groups. While EBV-specific CD8 cells are similar in phenotype, their frequency tends to be increased, and function appears to be decreased in SLE."

Berner - Cell Immunol 2005 abstract / PubMed

Detecting Epstein-Barr virus DNA from peripheral blood mononuclear cells in adult patients with systemic lupus erythematosus in Taiwan. SF Yu, HC Wu, WC Tsai, JH Yen, W Chiang, CY Yuo, SN Lu, LC Chiang, CJ Chen. Med Microbiol Immunol 2005 May;194(3):115-120. "Of the 87 SLE patients, 71 (81.6%) were found to be positive for EBV DNA, while 85 (48.9%) of the 174 controls (odds ratio 4.64, 95% confidence interval 2.50-8.62, P < 0.0001) were positive. While the EBV DNA-positive rate did not decline with age in SLE patients (P > 0.05), it did decline with age in controls (P < 0.05). Furthermore, based on a real-time quantitative PCR study, we have found a significant difference between EBV viral load in SLE and controls (P = 0.008)."

Yu - Med Microbiol Immunol 2005 abstract / PubMed

EBV and systemic lupus erythematosus: a new perspective. AJ Gross, D Hochberg, WM Rand, DA Thorley-Lawson. J Immunol 2005 Jun 1;174(11):6599-6607. 35 SLE patients, 44 healthy volunteers, 17 other disease controls. "We show that patients with SLE have abnormally high frequencies of EBV-infected cells in their blood, and this is associated with the occurrence of SLE disease flares. Although patients with SLE have frequencies of infected cells comparable to those seen in immunosuppressed patients, in SLE the effect was independent of immunosuppressive therapy. Aberrant expression of viral lytic (BZLF1) and latency (latency membrane proteins 1 and 2a) genes was also detected in the blood of SLE patients."

Gross / J Immunol 2005 full article

An altered immune response to Epstein-Barr nuclear antigen 1 in pediatric systemic lupus erythematosus. MT McClain, BD Poole, BF Bruner, KM Kaufman, JB Harley, JA James. Arthritis Rheum 2006 Jan;54(1):360-368. 36 patients, 36 controls. "All 36 pediatric SLE patient sera tested recognized EBNA-1, while sera from only 25 of 36 matched EBV-positive controls targeted EBNA-1 (P < 0.005). Epitope mapping revealed that the humoral anti-EBNA-1 response in pediatric SLE was distinct from and less restricted than that in matched normal individuals. Meanwhile, no significant differences between SLE patient sera and control sera were observed in the responses to other herpesviruses or in binding to sequential epitopes from cytomegalovirus immediate-early antigen or EBNA-2."

McClain / Arthritis Rheum 2006 full article

Association of Epstein-Barr virus infection with systemic lupus erythematosus in Taiwan. JJ Lu, DY Chen, CW Hsieh, JL Lan, FJ Lin, SH Lin. Lupus 2007;16(3):168-175. 93 adult SLE patients and 370 matched controls. "Our results show that IgA anti-EBV EBNA1 antibodies were detectable in 31.2% SLE patients but only in 4.1% of controls (odds ratio [OR] = 10.72, 95% confidence interval [CI] = 5.19-22.35; P < 10(-7)), IgG anti-EBV DNase antibodies were detected in 53.8% SLE patients but only in 12.2% controls (OR = 8.40, 95% CI = 4.87-14.51; P < 10(-7)). EBV DNA was amplifiable from the sera of 41.9% SLE patients but from only 3.24% controls (P < 0.05). A significant association of IgG anti-EBV DNase antibodies with anti-Sm/RNP antibodies was observed (P < 0.005)."

Lu - Lupus 2007 abstract / PubMed

Aberrant Epstein-Barr viral infection in systemic lupus erythematosus. BD Poole, AK Templeton, JM Guthridge, EJ Brown, JB Harley, JA James. Autoimmun Rev 2009 Feb;8(4):337-342. 10 SLE patients and 10 controls. "Expression levels of mRNA were significantly greater by Wilcoxen signed rank test in the ex vivo-infected SLE patient-derived cells for 4 of 8 EBV genes, including BLLF1, 3.2-fold (p<0.004); LMP-2, 1.7-fold (p<0.008); EBNA-1, 1.7-fold (p<0.01); and BcRF1, a proposed DNA binding protein, 1.7-fold (p<0.02). The frequency of LMP-1 gene expression was significantly greater by Chi square analysis in the peripheral blood from SLE patients than controls (44% of patients, 10% of controls p<0.05). PBMCs from SLE patients had greater expression of latent genes as well as increased expression of both latent and lytic genes after infection, suggesting that EBV may participate in SLE etiology through several mechanisms."

Poole - Autoimmun Rev 2009 full article / PubMed Central

Exposure to Epstein-Barr virus infection is associated with mild systemic lupus erythematosus disease. G Zandman-Goddard, Y Berkun, O Barzilai, M Boaz, M Blank, M Ram, Y Sherer, JM Anaya, Y Shoenfeld. Ann N Y Acad Sci 2009 Sep;1173:658-663. In 120 SLE patients and 140 controls, "EAG titers were significantly elevated (P < 0.024) in patients with cutaneous symptoms and increased anti-Ro antibody titers (P < 0.005). VCA IgG titers were significantly elevated (P < 0.003) in patients with joint involvement. None of the titers differed by central nervous system or renal involvement or antiphospholipid syndrome."

Zandman-Goddard - Ann N Y Acad Sci 2009 abstract / PubMed

Everyone comes from somewhere: systemic lupus erythematosus and Epstein-Barr virus induction of host interferon and humoral anti-Epstein-Barr nuclear antigen 1 immunity. JB Harley, JA James. Arthritis Rheum 2010 Jun;62(6):1571-1575. Review. "EBV has many properties that make it an ideal etiologic agent for SLE. EBV is ubiquitous in the human population which is required based upon the wide-spread occurrence of lupus. EBV makes its own version of IL-10, which would be expected to encourage TH2 responses, perhaps influencing the course of humoral autoimmunity in SLE. EBV produces BHRF1 (which has a protein structure similar to Bcl2) and inhibits apoptosis which could allow continued life of cells that should die in order to avoid autoimmunity. Clearly, the presence of increased levels of IFNα in sera from SLE patients and the induction of SLE by interferon treatment leads to the expectation that a virus causing lupus would be expected to induce interferon. (To complicate these issues CD21 the major receptor for EBV has been also shown to be a receptor binding IFNα.) EBV induces lupus-oriented humoral autoimmunity as part of its natural history of disease of infection, making the idea that it might be involved in generating the autoimmunity of lupus seem less far-fetched."

Harley - Arthritis Rheum 2010 full article / PubMed Central

Exhausted cytotoxic control of epstein-barr virus in human lupus. M Larsen, D Sauce, C Deback, L Arnaud, A Mathian, M Miyara, D Boutolleau, C Parizot, K Dorgham, L Papagno, V Appay, Z Amoura, G Gorochov. PLoS Pathog 2011 Oct;7(10):e1002328. "Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8(+) T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8(+) T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8(+) T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8(+) T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients."

Larsen / PLoS Pathog 2011 full article

Serologic response to Epstein-Barr virus antigens in patients with systemic lupus erythematosus: a controlled study. BA Esen, G Yılmaz, S Uzun, M Ozdamar, A Aksözek, S Kamalı, S Türkoğlu, A Gül, L Ocal, O Aral, M Inanç. Rheumatol Int 2012 Jan;32(1):79-83. 198 consecutive SLE patients, 46 systemic sclerosis (SSc) patients, 38 primary antiphospholipid syndrome (PAPS) patients, 65 healthy controls. "Significantly more SLE (54%, P = 0.001, OR 5.77, 95% CI 2.8-11.6), SSc (41.3%, P = 0.005, OR 3.4, 95% CI 1.4-8.2) and PAPS sera (36.8%, P = 0.023, OR 2.86, 95% CI 1.14-7.22) reacted against EA/D than healthy controls (16.9%). The mean age of anti-EA/D-positive SLE patients was significantly higher, and their disease duration was longer compared to anti-EA/D-negative SLE patients (41 ± 14 vs. 33.8 ± 10.8 years, P < 0.001 and 100 ± 73 vs. 71 ± 62 months, P = 0.003). In SLE patients, EA/D reactivity was associated with Raynaud's phenomenon and the presence of any anti-ENA antibodies. Although it did not reach a statistical significance, anti-EBNA-1 reactivity was slightly lower in patients with SLE. The frequency of anti-CMV Ig G positivity was found significantly higher in SLE patients (100%) when compared to patients with SSc (95.7%), PAPS (94.7%) and healthy controls (95.4%) (P = 0.035, P = 0.025 and P = 0.015 respectively)."

Esen - Rheumatol Int 2012 abstract / PubMed

Epstein-barr virus and systemic lupus erythematosus. AH Draborg, K Duus, G Houen. Clin Dev Immunol 2012;2012:370516. Review.

Draborg - Clin Dev Immunol 2012 full article / PubMed Central
Draborg / Clin Dev Immunol 2012 full article

Toll-like receptor 7 stimulates the expression of epstein-barr virus latent membrane protein 1. RM Valente, E Ehlers, D Xu, H Ahmad, A Steadman, L Blasnitz, Y Zhou, L Kastanek, B Meng, L Zhang. PLoS One 2012;7(8):e43317. "Type I interferons (IFN) are apparently driving forces for lupus pathogenesis... We find that TLR7 activation increases the expression of EBV LMP1, and IFN regulatory factor 7 (IRF7) is involved in the stimulation process. TLR7 activation did not induce IFNs from EBV-infected cells, but potentiates those cells for IFN production by TLR3 or TLR9 activation. In addition, we find that LMP1 and IFNs are co-expressed in the same cells in some lupus patients."

Valente - PLoS One 2012 full article / PubMed CentralValente / PLoS One 2012 full article

Epstein-Barr virus early antigen diffuse (EBV-EA/D)-directed immunoglobulin A antibodies in systemic lupus erythematosus patients. AH Draborg, JM Jřrgensen, H Müller, CT Nielsen, S Jacobsen, LV Iversen, E Theander, LP Nielsen, G Houen, K Duus. Scand J Rheumatol 2012 Aug;41(4):280-289. 60 patients with SLE, 40 with scleroderma (SSc), 20 with primary Sjögren's syndrome (pSS), 20 with rheumatoid arthritis (RA), 20 healthy controls, and also subjects with various circulating autoantibodies. "A significant elevated titre of immunoglobulin (Ig)A, IgG, and IgM EBV-EA/D antibodies was found in SLE patients compared to healthy controls, a finding not explained by immunosuppressive treatment or disease activity. The largest difference was observed for IgA EBV-EA/D antibodies (p = 0.0013) with a seropositive rate of 58% in SLE patients and 0% in healthy controls. RA and SSc patients and individuals seropositive for anti-Scl-70 were additionally found to have elevated titres of IgA EBV-EA/D antibodies (40%, p = 0.014; 60%, p = 0.015; and 38.5%, p = 0.045, respectively). However, the titres were generally lower than in SLE patients."

Draborg - Scand J Rheumatol 2012 abstract / PubMed

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein-Barr nuclear antigen 1 and its aa35-58 or aa398-404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis. D Csuka, D Simon, R Hóbor, K Uray, Z Prohászka, Z Bánlaki, PK Jani, A Szilágyi, F Hudecz, K Rajczy, G Beke, A Boros Major, A Tordai, Z Illés, T Berki, L Czirják, G Füst. Clin Exp Immunol 2013 Mar;171(3):255-262. 301 SLE patients, 135 MS patients and 345 healthy controls. "The serum concentration of anti-EBNA-1 antibodies was significantly (P < 0·001) higher both in MS and SLE patients than in controls. Similar significant differences were found both in HLA-DRB1*15:01 carriers and non-carriers. Furthermore, titres of antibodies against the aa35-58 EBNA-1 fragment were elevated both in MS and SLE patients. By contrast, the levels of aa398-404 EBNA-1 antibodies were elevated significantly only in the SLE patients."

Csuka - Clin Exp Immunol 2013 abstract / PubMed

Evidence of dynamically dysregulated gene expression pathways in hyperresponsive B cells from african american lupus patients. I Dozmorov, N Dominguez, AL Sestak, JM Robertson, JB Harley, JA James, JM Guthridge. PLoS One 2013 Aug 15;8(8):e71397. 20 African-American female lupus patients and 20 African-American female controls. Average response [amount of phospho-ERK1/2 generated] was significantly higher in the EBV transformed cells from the lupus cases. Some genes were only activated in normal responsive B cells, while GPR137B, NAB1, and TCIRG1 were only expressed in hyperresponsive B cells from SLE patients.

Dozmorov - PLoS One 2013 full article / PubMed Central
Dozmorov - PLoS One 2013 full article

Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and systemic lupus erythematosus. P Hanlon, A Avenell, L Aucott, MA Vickers. Arthritis Res Ther 2014 Jan 6;16(1):R3. 25 case-control studies, between 1996 and 2012. "There was a statistically significant higher seroprevalence of anti-viral capsid antigen (VCA) IgG (OR 2.08; 95% confidence interval (CI) 1.15 - 3.76, p = 0.007) but not anti-EBV-nuclear antigen1 (EBNA1) (OR 1.45; 95% CI 0.7 to 2.98, p = 0.32) in cases compared to controls. The meta-analyses for anti-early antigen (EA) /D IgG and anti-VCA IgA also showed significantly high ORs (4.5; 95% CI 3.00 to 11.06, p < 0.00001 and 5.05 (95% CI 1.95 - 13.13), p = 0.0009 respectively). However, funnel plot examination suggested publication bias."

Hanlon - Arthritis Res Ther 2014 abstract / PubMed

EBV Antibodies Mark SLE and Scleroderma Patients Negative for Anti-DNA. I Fattal, N Shental, Y Molad, A Gabrielli, E Pokroy-Shapira, S Oren, A Livneh, P Langevitz, R Pauzner, O Sarig, U Gafter, E Domany, IR Cohen. Immunology 2014 Feb;141(2):276-285. 49 SLEpatients, 24 SSc patients, and 23 healthy controls. "[T]wo-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr Virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond... SSc patients shared many of these serologic abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to Topoisomerase and Centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV."

Fattal - Immunology 2014 abstract / PubMed
Fattal / Immunology 2014 full article

Reduced response to Epstein-Barr virus antigens by T-cells in systemic lupus erythematosus patients. AH Draborg, S Jacobsen, M Westergaard, S Mortensen, JL Larsen, G Houen, K Duus. Lupus Sci Med 2014 Apr 1;1(1):e000015. 27 SLE patients, 27 controls. "SLE patients showed a significantly reduced number of activated (CD69) T-cells upon ex vivo stimulation with EBV nuclear antigen (EBNA) 1 or EBV early antigen diffuse (EBV-EA/D) in whole blood samples compared with healthy controls. Also, a reduced number of T-cells from SLE patients were found to produce interferon-γ upon stimulation with these antigens. Importantly, responses to a superantigen were normal in SLE patients. Compared with healthy controls, SLE patients had fewer EBV-specific T-cells but higher titres of antibodies against EBV. Furthermore, an inverse correlation was revealed between the number of lytic antigen EBV-specific T-cells and disease activity of the SLE patients, with high-activity SLE patients having fewer T-cells than low-activity SLE patients."

Draborg - Lupus Sci Med 2014 full article / PubMed Central

The expression of renal Epstein-Barr virus markers in patients with lupus nephritis. XX Yu, CW Yao, JL Tao, C Yang, MN Luo, SM Li, HF Liu. Exp Ther Med 2014 May;7(5):1135-1140. 58 patients with lupus nephritis, 7 atients with non-glomerular hematuria, and 37 with minimal change nephropathy. "An equivalence test showed that the results from the IHC and the ISH analyses had strong agreement. The positive rates of renal EBER-1 and EBV-LMP1 in the LN patients were significantly higher than those of the normal and minimal change nephropathy patients (P<0.001), while no significant difference was identified between those of the normal and minimal change nephropathy groups (P>0.05)... The proportion of LN patients positive for anti-Sm antibody was significantly higher in the renal EBV-positive group than in the EBV-negative group (P<0.05), while the proportions of LN patients positive for the other autoantibodies that were examined were not identified to be significantly different between these two groups (P>0.05). The present study shows that renal EBV infection may contribute to the pathogenesis of LN by inducing anti-Sm antibody production."

Yu - Exp Ther Med 2014 full article / PubMed Central

Elevated antinuclear antibodies and altered anti-Epstein-Barr virus immune responses. L Cuomo, M Cirone, AO Gregorio, M Vitillo, M Cattivelli, V Magliocca, S Maiorano, M Meledandri, C Scagnolari, SL Rocca, P Trivedi. Virus Res 2015 Jan 2;195:95-99. 92 patients, 146 controls. "We found that anti-EBV-VCA and EA IgG concentrations were significantly higher in ANA-positive patients in comparison to the controls (VCA P<0.0001 and EA P<0,03) as well as in those ANA-positive patients that showed a concomitant ENA positivity (P=0.0002). Interestingly, elevated anti-EBNA-1 IgG was found in a group of patients who had anti SSA/Ro antibodies. Anti-VCA IgM Abs were more frequently found in those patients with a very high titer of ANA (P=0.06); moreover detection of anti-VCA IgM/IgG in absence of anti-EBNA-1 IgG was more frequent in the patient than in the control group. Both these conditions correlate with a recent EBV infection or reactivation. The data suggest that EBV, particularly during acute infection or in its reactivation phase, could be involved in the ANA and ENA autoantibody formation."

Cuomo - Virus Res 2015 abstract / PubMed

Antibodies to early EBV, CMV, and HHV6 antigens in systemic lupus erythematosus patients. N Rasmussen, A Draborg, C Nielsen, S Jacobsen, G Houen. Scand J Rheumatol 2015;44(2):143-149. 77 lupus patients, 29 healthy controls. "IgM, IgG, and IgA levels against EBV EA/D, and IgG and IgA levels against CMV pp52, were significantly higher in SLE patients compared with healthy controls. Furthermore, EBV EA/D- and CMV pp52-directed IgG levels were inversely and positively associated, respectively, with lymphocyte counts in SLE patients. None of the findings seemed to be associated with use of immunosuppressive medication."

Rasmussen - Scand J Rheumatol 2015 abstract / PubMed

Isotypes of epstein-barr virus antibodies in rheumatoid arthritis: association with rheumatoid factors and citrulline-dependent antibodies. MW Westergaard, AH Draborg, L Troelsen, S Jacobsen, G Houen. Biomed Res Int 2015;2015:472174. 77 RA patients, 28 patients with systemic lupus erythematosus (SLE), and 28 healthy controls. "Increased percentages of positives and concentrations of IgG/IgA/IgM antibodies against the latent EBV nuclear antigen-1 (EBNA-1) were observed in RA patients compared to SLE patients and HCs. Increased concentrations and percentages of positives of IgG/IgA/IgM against the early lytic EBV antigen diffuse (EAD) were also found in RA patients compared to HCs but were highest in SLE patients. Furthermore, associations between the elevated EBNA-1 IgA and EBNA-1 IgM levels and the presence of IgM and IgA rheumatoid factors (RFs) and anti-citrullinated protein antibodies (ACPAs, IgG) and between elevated IgA concentrations against EAD and the presence of RFs and ACPAs in RA patients were found. Thus, RA patients had elevated antibodies of all isotypes characteristic of latent EBV infection (whereas SLE patients had elevated antibodies characteristic of lytic EBV infection)."

Westergaard - Biomed Res Int 2015 full article / PubMed Central
Westergaard / Biomed Res Int 2015 full article

Real-Time PCR of cytomegalovirus and Epstein-Barr virus in adult Egyptian patients with systemic lupus erythematosus. AE Mohamed, AM Hasen, GF Mohammed, NN Elmaraghy. Int J Rheum Dis 2015 May;18(4):452-458. "Almost all SLE patients 32/33 (96.9%) were positive for IgG anti-CMV antibodies versus 20/30 in the control group (66.6%) (P = 0.002). All SLE patients were positive for IgG anti-EBV antibodies compared to 25 in the control group (100% vs. 83.3%, P = 0.02). CMV and EBV DNA were detected by PCR in 30.3% and 51.5% of SLE patients, respectively. A statistically significant lower SLEDAI was found in PCR positive patients for EBV compared to negative patients (9.6 ± 5.2 vs. 13.1 ± 3.1, respectively P = 0.041)."

Mohamed - Int J Rheum Dis 2015 abstract / PubMed

The expression of EBV-encoded LMP1 in young patients with lupus nephritis. Y Ding, X He, W Liao, Z Yi, H Yang, W Xiang. Int J Clin Exp Med 2015 Apr 15;8(4):6073-6078. 51 SLE patients, 21 normal controls. "We found that the positive rate of LMP1 in the renal tissues was significantly higher in patients with LN compared with control (P<0.001), which is consistent with the previous reports... The proportion of young patients positive for anti‑Sm antibody was significantly higher in the LMP1 positive group compared with the LMP1 negative control (P>0.05)."

Ding - Int J Clin Exp Med 2015 full article / PubMed Central

Infections and Systemic Lupus Erythematosus: Binding or Sparring Partners? D Rigante, S Esposito. Int J Mol Sci 2015 Jul 29;16(8):17331-17343. REVIEW.

Rigante & Esposito / Int J Mol Sci 2015 full article landing

Sensing of latent EBV infection through exosomal transfer of 5'pppRNA. SR Baglio, MA van Eijndhoven, D Koppers-Lalic, J Berenguer, SM Lougheed, S Gibbs, N Léveillé, RN Rinkel, ES Hopmans, S Swaminathan, SA Verkuijlen, GL Scheffer, FJ van Kuppeveld, TD de Gruijl, IE Bultink, ES Jordanova, M Hackenberg, SR Piersma, JC Knol, AE Voskuyl, T Wurdinger, CR Jiménez, JM Middeldorp, DM Pegtel. Proc Natl Acad Sci USA 2016 Feb 2;113(5):E587-596. "Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non-cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host-pathogen stand-off and may promote inflammatory disease."

Baglio - Proc Natl Acad Sci USA 2016 abstract / PubMed

Senescent profile of angiogenic T cells from systemic lupus erythematosus patients. P López, J Rodríguez-Carrio, A Martínez-Zapico, L Caminal-Montero, A Suarez. J Leukoc Biol 2016 Mar;99(3):405-412. 84 lupus patients and 46 healthy controls, plus 48 rheumatoid arthritis patients and 72 "with traditional cardiovascular risk factors" as disease controls. "CD4+CD28null cells were notably increased in the systemic lupus erythematosus patients and disease controls compared with healthy controls. In contrast, angiogenic T cells were only reduced in the disease controls (those with rheumatoid arthritis or traditional cardiovascular risk factors). Nevertheless, an anomalous presence of CD28null-angiogenic T cells, with cytotoxic and senescent characteristics, was noted in systemic lupus erythematosus patients in association with anti-dsDNA titer, anti-SSA/Ro antibodies and circulating TNF-α, IL-8, IFN-α, and B lymphocyte stimulator amounts. This subset was also detected in those with traditional cardiovascular risk factors but not in the rheumatoid arthritis patients. In contrast, CD28+-angiogenic T cells were reduced in the systemic lupus erythematosus patients with cardiovascular disorders. In conclusion, CD28 expression must be used to redefine the angiogenic T cell population, because in pathologic conditions, a senescent CD28null-angiogenic T cell subset with inflammatory, rather than protective, effects could be present."

López - J Leukoc Biol 2016 abstract / PubMed

Humoral markers of active Epstein-Barr virus infection associate with anti-extractable nuclear antigen autoantibodies and plasma galectin-3 binding protein in systemic lupus erythematosus. NS Rasmussen, CT Nielsen, G Houen, S Jacobsen. Lupus 2016 Dec;25(14):1567-1576. 57 patients, 29 controls. "Plasma galectin-3 binding protein concentrations were significantly higher in systemic lupus erythematosus patients (P = 0.009) and associated positively with Epstein-Barr virus early antigen diffuse-directed antibodies and the presence of autoantibodies against extractable nuclear antigens in adjusted linear regressions (B = 2.02 and 2.02,P = 0.02 andP = 0.002, respectively). Furthermore, systemic lupus erythematosus patients with anti-extractable nuclear antigens had significantly higher antibody levels against Epstein-Barr virus early antigen diffuse (P = 0.02)."

Rasmussen - Lupus 2016 abstract / PubMed

Correlation between Epstein-Barr Virus Infection and Disease Activity of Systemic Lupus Erythematosus: a Cross-Sectional Study. A Piroozmand, H Haddad Kashani, B Zamani. Asian Pac J Cancer Prev 2017 Feb 1;18(2):523-527. 40 patients. "The EBV test was positive in 67.5% and mean viral load was 5396 ± 1891.9 copy/ml. Twenty of forty patients had active and 50% inactive disease, mean EBV viral loads being 6798 and 28.25 copy/ml, respectively (P-value = 0.003). In terms of the severity of disease activity, 17.5 % of female patients had mild to moderate activity, whilst 32.5% of them had severe activity, with respective viral loads of 5,803.3 and 29.73 copy/ml (P-value = 0.003)."

Piroozmand / Asian Pac J Cancer Prev 2017 full article (pdf)

Strong viral associations with SLE among Filipinos. ES Vista, MH Weisman, ML Ishimori, H Chen, RL Bourn, BF Bruner, L Hamijoyo, RD Tanangunan, NJ Gal, JM Robertson, JB Harley, JM Guthridge, SV Navarra, JA James. Lupus Sci Med 2017 Jul 28;4(1):e000214. 233 patients, 543 relatives, 221 unrelated controls. "Filipino patients with SLE had increased seroprevalence and elevated antibody concentrations against EBV viral capsid antigen (EBV-VCA), CMV, HSV-1 and HSV-2 compared with unrelated controls (p<0.05). Seropositivity for anti-EBV early antigen (EA), a marker of EBV reactivation, was dramatically increased in patients with SLE compared with unrelated controls (92.3% vs 40.4%; OR 17.15(95% CI 10.10, 30.66), p<0.0001) or unaffected FDRs (49.4%; OR 12.04(7.42, 20.74), p<0.0001), despite similar seroprevalence of EBV-VCA in patients and FDRs."

Vista - Lupus Sci Med 2017 full article / PubMed Central
Vista / Lupus Sci Med 2017 full article

The interaction between anti-Ro/SSA and anti-La/SSB autoantibodies and anti-infectious antibodies in a wide spectrum of auto-immune diseases: another angle of the autoimmune mosaic. N Agmon-Levin, A Dagan, Y Peri, JM Anaya, C Selmi, A Tincani, N Bizzaro, L Stojanovich, J Damoiseaux, JW Cohen Tervaert, M Mosca, R Cervera, Y Shoenfeld. Clin Exp Rheumatol 2017 Nov-Dec;35(6):929-935. "Additionally, we found a correlation between anti-Ro/SSA antibodies and antibodies of the IgM and IgG subtypes directed at cytomegalovirus as well as IgG-antibodies directed at Epstein-Barr virus (EBV) and toxoplasma (p<0.001). Anti-La/SSB antibodies correlated with the presence of IgG antibodies against EBV early antigen (p<0.001)."

Agmon-Levin - Clin Exp Rheumatol 2017 abstract / PubMed

Epstein-Barr virus infection and type I interferon signature in patients with systemic lupus erythematosus. L Han, Y Zhang, Q Wang, M Xin, K Yang, K Lei, M Sun. Lupus 2018 Jan 1:961203317753069 [Epub ahead of print]. 116 SLE patients and 76 healthy controls. "SLE patients had a higher rate of lytic infection defined as positive EBV-VCA IgM antibody (39.66% vs 10.53%, p = 0.027), but not the EB virus DNA load. Patients with lytic EB virus infection had higher SLEDAI scores than patients with non-lytic infection (15.24 ± 2.63 vs 13.79 ± 3.24, p = 0.012). LMP1 was the only EBV gene that had a higher expression level in SLE patients than in healthy controls (3.26 ± 2.95 vs 1.00 ± 2.89, p = 0.000)."

Han - Lupus 2018 abstract / PubMed

Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at-risk individuals. NR Jog, KA Young, ME Munroe, MT Harmon, JM Guthridge, JA Kelly, DL Kamen, GS Gilkeson, MH Weisman, DR Karp, PM Gaffney, JB Harley, DJ Wallace, JM Norris, JA James. Ann Rheum Dis 2019 Jun 19 [Epub ahead of print]. 56 SLE patient relatives without SLE who later developed it, versus 380 who did not. "Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95% CI 1.07 to 1.53, p=0.007, OR 1.43 95% CI 1.06 to 1.93, p=0.02, respectively)."

Jog - Ann Rheum Dis 2019 abstract / PubMed

HHV-6A can reactivate EBV infection

Isolation of human herpesvirus-6 (HHV-6) from patients with collagen-vascular diseases. GR Krueger, C Sander, A Hoffman, A Barth, B Koch, M Braun. In Vivo 1991 May-Jun;5(3):217-225. "Fifty-five percent of the SLE patients, 6.5% of the RA patients and both patients with Sharp's syndrome or with APL had antibody titers indicative of active HHV-6 infection."

Krueger - In Vivo 1991 abstract / PubMed

Other studies implicating EBV infection

CD4 positive peripheral T cells from patients with systemic lupus erythematosus (SLE) are clonally expanded. W Kolowos, US Gaipi, RE Voll, C Frank, JP Haas, TD Beyer, JR Kalden, M Herrmann. Lupus 2001;10(5):321-331. "We observed a restricted CDR3 length polymorphism in peripheral CD4+ T cells from SLE patients compared with NHD, more pronounced in patients with high disease activity. Furthermore, in some Vbeta families single peaks in the histogram indicated nearly monoclonal T cell expansion. Sequencing of selected TCR beta-chains revealed a increased content of acidic amino acids in the CDR3 encoded by either proximal Jbeta elements or N nucleotides."

Kolowos - Lupus 2001 abstract / PubMed

Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. L Farkas, K Beiske, F Lund-Johansen, P Brandtzaeg, FL Jahnsen. Am J Pathol 2001 Jul;159(1):237-243. "Our results showed that P-DCs were present in 14 out of 15 tissue specimens of cutaneous LE lesions, but not in normal skin. Importantly, the density of P-DCs in affected skin correlated well (r(s) = 0.79,P < 0.0005) with the high number of cells expressing the IFN-alpha/beta-inducible protein MxA, suggesting that P-DCs produce IFN-alpha/beta locally. Accumulation of P-DCs coincided also with the expression of L-selectin ligand peripheral lymph node addressin on dermal vascular endothelium, adding further support to the notion that these adhesion molecules are important in P-DC extravasation to peripheral tissue sites."

Farkas - Am J Pathol 2001 abstract / PubMed
Farkas - Am J Pathol 2001 Full Article

An etiopathogenic role for the type I IFN system in SLE. L Ronnblom, GV Alm. Trends Immunol 2001 Aug;22(8):427-431. "The type I interferon (IFN) system plays a pivotal role in the etiopathogenesis of systemic lupus erythematosus (SLE). The initial appearance of autoantibody-producing B cells can be precipitated by infection-induced type I IFNs, but the further, significant generation of autoimmune T and B cells is caused by the prolonged production of IFN-alpha, which is maintained by a vicious circle mechanism. This involves the activation of immature dendritic cells, known as natural IFN-producing cells, by continuously formed endogenous IFN-alpha inducers. These IFN-alpha inducers consist of complexes of autoantibodies with nucleic-acid-containing autoantigens derived from apoptotic cells."

Ronnblom - Trends Immunol 2001 abstract / PubMed

EBV stimulates TLR- and autophagy-dependent pathways and impairs maturation in plasmacytoid dendritic cells: Implications for viral immune escape. M Severa, E Giacomini, V Gafa, E Anastasiadou, F Rizzo, M Corazzari, A Romagnoli, P Trivedi, GM Fimia, EM Coccia. Eur J Immunol 2013 Jan;43(1):147-158. "We show that high amounts of type I IFNs were released from isolated pDCs after exposure to EBV by a mechanism requiring TLRs and a functional autophagic machinery. We next demonstrate that EBV can infect pDCs via viral binding to MHC class II molecule HLA-DR and that pDCs express EBV-induced latency genes. Furthermore, we observe that EBV is able to induce activation but not maturation of pDCs, which correlates with an impaired TNF-α release. Accordingly, EBV-infected pDCs are unable to mount a full T-cell response, suggesting that impaired pDC maturation, combined with a concomitant EBV-mediated upregulation of the T-cell inhibitory molecules B7-H1 and ICOS-L, could represent an immune-evasion strategy promoted by the virus. These mechanisms might lead to persistence in immunocompetent hosts or to dysregulated immune responses linked to EBV-associated diseases."

Severa - Eur J Immunol 2013 abstract / PubMed

Epitope distribution in ordered and disordered protein regions. Part B -- Ordered regions and disordered binding sites are targets of T- and B- cell immunity. MD Pavlović, DR Jandrlić, NS Mitić. J Immunol Methods 2014 May;407:90-107. "Two minor antigenic regions within EBNA-1, mapped to the residues 58-85 and 398-458, encompassing putative disordered binding sites, contain epitopes connected with anti-Ro 60 KDa and anti-Sm B/B' autoimmunity in systemic lupus erythematosus. One of these regions overlaps residues 395-450, identified as the binding site of USP7 (HAUSP), which regulates the EBNA-1 replication function. In Sm-B/B', one of the putative disordered binding sites (residues 114-165) encompasses the T-cell epitope 136-153, while another, residues 200-216, flanks two proline-rich B-cell epitopes (residues 190-198 and 216-222), overlapping the preferred CD2BP2-GYF-binding motif (R/K/G)XXPPGX(R/K), characteristic of splicosomal proteins. We have noticed that the same motif (residues 397-403) is mimicked in EBNA-1 and overlaps epitope 398-404, involved in anti-Sm B/B' autoimmunity."

Pavlović - J Immunol Methods 2014 abstract / PubMed

Impaired Cytokine Responses to Epstein-Barr Virus Antigens in Systemic Lupus Erythematosus Patients. AH Draborg, N Sandhu, N Larsen, J Lisander Larsen, S Jacobsen, G Houen. J Immunol Res 2016;2016:6473204. 27 patients, 27 controls. "Decreased induction of IL12, IFNγ, IL17, and IL6 upon EBNA1 stimulation and that of IFNγ, IL6, TNFβ, IL1β, and GM-CSF upon EBV-EA/D stimulation were detected in SLE patients compared to HCs. IFNγ responses, especially, were shown to be reduced. Induction of several cytokines was furthermore impaired in SLE patients upon SEB stimulation, but no difference was observed in basic levels."

Draborg - J Immunol Res 2016 full article / PubMed Central
Draborg / J Immunol Res 2016 full article

A Possible Role of Polyoma Viruses

According to the health establishment's ideology of infection-denial, systemic lupus erythematosus (SLE) is a non-infectious, inflammatory, so-called "autoimmune" disorder. According to this delusional mode of thought, some peoples' immune systems are genetically programmed to attack their own bodies. What sets of this attack is a complete mystery, and "treatments" consist mainly of anti-inflammatory, immunosuppressive, and/or cytotoxic drugs.

The symptoms of lupus are diverse. These include a "butterfly" rash across the nose and cheeks, ulcers in the mouth or nose, and hair loss; painful joints; kidney disease; pleurisy, pericarditis and/or peritonitis; vasculitis; abnormalities in the blood cells, including anemia, low white blood cell or platelet count; and nervous system symptoms such as convulsions, psychosis, abnormal sensations, and muscular weakness or lack of coordination.

Commonly used laboratory tests for lupus include the anti-nuclear antibody test (ANA), to determine if there are "autoantibodies" to the cell nuclei; the anti-DNA antibody test; and the anti-Sm antibody test, for antibodies to a protein found in the cell nucleus. According to conventional thinking, these purported antigens are released into the bloodstream due to "aberrant apoptosis" (programmed cell death), of unknown cause, in patients with SLE.

But there are gaping holes in this hypothesis. "Free, naked DNA is not present in the circulation. The existence of DNA/antiDNA complexes is highly questionable and injection of these complexes hardly leads to glomerular localization" in the kidney. Also, "Immunization with DNA in general fails to induce pathogenic anti-dsDNA antibodies" (Autoimmunity against nucleosomes and lupus nephritis. MC Van Bruggen, C Kramers, JH Berden. Ann Med Interne (Paris) 1996;147(7):485-489).

Van Bruggen - Ann Med Interne (Paris) 1996 abstract / PubMed

In fact, all of these variety of symptoms are consistent with what has long been known about the effects of human polyomavirus infections. The BK virus and JC virus were both discovered long ago, in 1971. BKV was isolated from a kidney transplant patient (among whom the virus causes tubulonephritis and ureteral stenosis), and JCV from an AIDS patient with progressive multifocal leukoencephalopathy, a demyelinating brain disease. Most of the population worldwide is infected with one or both of these viruses during childhood, and they remain latent in the kidneys (although with occasional reactivations) for life. Reactivations are more common in immunosuppressed persons, such as transplant, cancer chemotherapy, lymphoma, and AIDS patients, but they also occur very frequently during pregnancy (10-37%). And, polyomavirus reactivations have been demonstrated in patients with "noninfectious" diseases including several forms of anemia, nephrotic syndrome, Guillain-Barre syndrome, and in lupus, dating from the latter 1970s. JCV and BKV persistently infect the central nervous system and B lymphocytes, with JCV more neurotropic than BKV, and are also able to persistently infect CD34+ hematopoietic precursor cells, while BKV also infects connective tissue and endothelial cells, causing vasculitis.

A recent study in Norway has directly addressed the role of polyomaviruses BK and JC in SLE. First, in experiments in laboratory mice, they observed that antibodies to DNA and transcription proteins developed only after exposure to polyomavirus T-antigens. Then, over a period of a year, they collected sera monthly, and urine samples every other week, from 20 SLE patients, 6 rheumatoid arthritis patients, and 10 normal controls. None of the normal controls and only one of the six RA patients became PCR-positive for JC or BK polyomavirus, but 16 of the 20 SLE patients did. Their antibody levels to T-antigen and to DNA correlated with the frequency of reactivations. 12 of the 16 were positive for BK virus, 3 for JC, and for one no sequence was obtained. Finally, in a prevalence study, polyoma DNA was found in only one out of 36 RA patients and none of 32 healthy controls, while 43% of SLE patients were positive by PCR. (Experimental expression in mice and spontaneous expression in human SLE of polyomavirus T-antigen. OP Rekvig et al. J Clin Invest 1997 Apr 15;99(8):2045-2054.)

Rekvig / J Clin Invest 1997 full article

Further evidence that a virus is involved is that T cells did not proliferate in response to histones or nucleosomes, except after this was initiated by T-antigen or T-antigen complexes. (Termination of human T cell tolerance to histones by presentation of histones and polyomavirus T antigen provided that T antigen is complexed with nucleosomes. K Andreassen et al. Arthritis Rheum 1999 Nov;42(11):2449-2460.)

Andreassen - Arthritis Rheum 1999 abstract / PubMed

And, cells that are stimulated by certain viral infections synthesize alpha/beta interferons, which induce MxA protein. MxA protein is found in skin lesions with known viral causes, such as chickenpox, herpes zoster, and herpes simplex. It is also found in skin lesions of unknown cause, including lupus erythematosus, lichen planus, Schoenlein-Hennoch's anaphylactoid purpura, and psoriasis. It is not found in non-viral skin infections or certain other skin lesions of unknown cause. (J Fah et al. Expression of MxA protein in inflammatory lesions. J Histochem 1995 Jan;43(1):47-52.)

Fah - Histochem Cytochem 1995 abstract / PubMed

BK and JC viruses in patients with systemic lupus erythematosus: prevalent and persistent BK viruria, sequence stability of the viral regulatory regions, and nondetectable viremia. A Sundsfjord, A Osei, H Rosenqvist, M Van Ghelue, Y Silsand, HJ Haga, OP Rekvig, U Moens. J Infect Dis 1999 Jul;180(1):1-9. 44 SLE patients, 88 controls. BKV and JCV were found in urine specimens from 7 (16%) of 44 and 5 (11%) of 44 patients with SLE and 0/88 and 18 (21%) of 88 matched healthy controls. "During a 1-year follow-up study, episodes of polyomaviruria were detected in 16 (80%) of 20 patients, BKV in 13, and JCV in 3 patients. A group of 12 (60%) of 20 patients demonstrated persistent or recurrent polyomaviruria, BKV viruria (n=9), or JCV viruria (n=3) in 180 (70%) of 256 specimens. Polyomaviruria was not significantly associated with immunosuppressive therapy."

Sundsfjord / J Infect Dis 1999 full article

Human polyomavirus BK in patients with lupus nephritis: clinical and histological correlations. L Colla, P Mesiano, V Morellini, L Besso, R Cavallo, M Bergallo, C Costa, C Merlino, C Marcuccio, F Fop, G Lanfranco, GP Segoloni, C Canavese, P Stratta. Lupus 2007;16(11):881-886. 40 patients with SLE nephritis and 29 healthy controls. "sBKV was present in 15% of SLE patients and in 13.8% of controls; uBKV in 32% of SLE patients and in 17.2% of controls. There was no significant difference in terms of kidney function, urinary activity, SLEDAI score, presence of anti-dsDNA antibodies, CD4+/CD8+ ratio and BKV viremia and/viruria, as well as there was no significant correlation between SLEDAI score, anti-dsDNA antibodies titers and median viral load."

Colla - Lupus 2007 abstract / PubMed

Increased prevalence of polyomavirus BK viruria that correlates with thrombocytopenia in patients with systemic lupus erythematosus on intensive immunosuppressive therapy. MC Lu, CL Yu, WY Yin, CH Tung, KY Huang, SQ Liu, NS Lai. Autoimmunity 2009 Mar;42(3):216-223. 95 patients with SLE and 32 healthy volunteers. "We found that the prevalence rate of BKV viruria in SLE patients was significantly higher than normal group (71.6% vs. 18.6%, p < 0.001) as well as the urine BKV DNA viral load (4.74 +/- 3.17 vs. 1.08 +/- 2.33 by log scale, p < 0.001). Interestingly, BKV viruria (+) SLE patients had more thrombocytopenic events than BKV viruria ( - ) group (32.4% vs. 3.7%, p = 0.008 after adjustment by age and sex)."

Lu - Autoimmunity 2009 abstract / PubMed

Polyomavirus reactivation in pediatric patients with systemic lupus erythematosus. P Rianthavorn, N Posuwan, S Payungporn, A Theamboonlers, Y Poovorawan. Tohoku J Exp Med 2012;228(3):197-204. 50 SLE patients <18 y. The prevalence of JC and BK viruria was 16% and 32%, respectively. WU, KI, MC and TS were not isolated from any urine specimens. Co-reactivation of 2 PyV was not detected. Urine TGF-β1 levels in patients with JC viruria, with BK viruria and without PyV viruria were 0.27 ± 0.09, 0.10 ± 0.05 and 0.13 ± 0.09 ng/mg of urine creatinine, respectively. Cumulative doses of cyclophosphamide per body weight and urine TGF-β1 levels were higher in JC viruria than in other groups (p < 0.05)."

Rianthavorn / Tohoku J Exp Med 2012 full article landing page

Increased prevalence of JC polyomavirus viruria was associated with arthritis/arthralgia in patients with systemic lupus erythematosus. MC Lu, WY Yin, SQ Liu, M Koo, CH Tung, KY Huang, NS Lai. Lupus 2015 Jun;24(7):687-694. Sixty-one patients with SLE and 22 controls. "The prevalence of JCV viruria (63.9% vs. 18.2%, p < 0.001) and urine JCV viral load (2.92 ± 2.76 vs. 0.81 ± 1.85 copies/ml by log10 scale, p < 0.001) were significantly higher in patients with SLE compared with controls. JCV viruria (+) SLE patients had a higher occurrence of arthritis/arthralgia compared with JCV viruria (-) SLE patients (64.1% vs. 22.7%, p = 0.003). In SLE patients, the urine JCV viral load was significantly associated with the occurrence of arthritis/arthralgia. SLE patients with urine JCV viral load >10,000 copies/ml exhibited a 12.75-fold (95% confidence interval 2.88-56.40) risk in clinical arthritis/arthralgia, 18.90-fold (95% confidence interval 2.10-170.39) risk in persistent arthritis, and significantly greater number of length variants in the VP1 gene of JCV compared with JCV viruria (-) SLE patients."

Lu - Lupus 2015 abstract / PubMed

Review article: BK virus in systemic lupus erythematosus. N Gupta, RM Lawrence, C Nguyen, RF Modica. Pediatr Rheumatol Online J 2015 Aug 21;13(1):34.

Gupta - Pediatr Rheumatol Online J 2015 full article / PubMed Central
Gupta / Pediatr Rheumatol Online J 2015 full article

Why some non-immunosuppressed, non-pregnant people have frequent reactivations while others do not is still unknown. But it could be as simple as that those with frequent recurrences were infected with the virus earlier in life. For example, nearly everyone who has had chickenpox has been latently infected by the varicella-zoster virus, and reactivations, producing shingles, are rare in people under 50 years old. However, shingles occurs much earlier in life in people who had chickenpox before they were two years old. Interestingly, outbreaks of shingles are more frequent in people with lupus than in the general population, so there may be some kind of interaction between these viruses. Unfortunately, there is no drug to treat the polyomaviruses that is like acyclovir for the herpes viruses (although new acyclic nucleoside phosphonates have recently been proved effective in clinical trials). This has not been a priority for the health establishment, which has seen the pathogenic effects in animals while they played with these viruses in the laboratory for nearly 30 years, but denies that they cause disease in people other than AIDS and transplant patients. And they left the human epidemiology to human garbage who ignore infections and the socioeconomic linkages to them, and do surveys of peoples' smoking habits instead.

Polyomaviruses and autoimmunity

Inoculation with BK virus may break immunological tolerance to histone and DNA antigens. T Flaegstad, K Fredriksen, B Dahl, T Traavik, OP Rekvig. Proc Natl Acad Sci U S A 1988 Nov;85(21):8171-8175.

Flaegstad / PNAS 1988 full article
Flaegstad PNAS 1988 full article / PubMed Central

BK virus terminates tolerance to dsDNA and histone antigens in vivo. T Fredriksen, T Traavik, T Flaegstad, OP Rekvig. Immunol Invest 1990 Apr;19(2):133-151. "Antibodies to BK virus structural proteins were detected in all rabbits. Two out of five rabbits produced antibodies to dsDNA, ssDNA, nucleosomes and histones H1 and H3. Even a weak reactivity to H2B was detected in one serum. The autoantibody response was transient as it declined after a few weeks, but it reappeared after a second boost in one of the rabbits."

Fredriksen - Immunol Invest 1990 abstract / PubMed

Antibodies to dsDNA are produced during primary BK virus infection in man, indicating that anti-dsDNA antibodies may be related to virus replication in vivo. K Fredriksen, A Skogsholm, T Flaegstad, T Traavik, OP Rekvig. Scand J Immunol 1993 Oct;38(4):401-406. 8 of 59 children experienced primary BK virus infection; anti-BK dsDNA antibodies appeared in all 8.

Fredriksen - Scand J Immunol 1993 abstract / PubMed

Autoimmunity to DNA and nucleosomes in binary tetracycline-regulated polyomavirus T-Ag transgenic mice. S Bendiksen, M Van Ghelue, T Winkler, U Moens, OP Rekvig. J Immunol 2004 Dec 15;173(12):7630-40.

Bendiksen / J Immunol 2004 full article

Acyclic nucleoside phosphonates (acyclovir)

Acyclic nucleoside phosphonates in the chemotherapy of DNA virus and retrovirus infections. E De Clercq. Intervirology 1997;40(5-6):295-303.

DeClercq - Intervirology 1997 abstract / PubMed

Intracellular metabolism of the N7-substituted acyclic nucleoside analog 2-amino-7-(1,3-dihydroxy-2-propoxymethyl) purine, a potent inhibitor of herpesvirus replication. J Neyts, J Balzarini, G Andrei, Z Chaoyong, R Snoeck, A Zimmermann, T Mertens, A Karlsson, E De Clercq. Mol Pharmacol 1998 Jan;53(1):157-165.

Neyts - Mol Pharmacol 1998 abstract / PubMed
Neyts / Mol Pharmacol 1998 full article

Antitumor potential of acyclic nucleoside phosphonates. F De Clercq, G Andrei, J Balzarini, S Hatse, S Liekens, L Naesens, J Neyts, R Snoeck. Nucleosides Nucleotides 1999 Apr-May;18(4-5):759-771.

De Clercq - Nucleosides Nucleotides 1999 abstract / PubMed

See Also:

EBV Causes Multiple Sclerosis
Epstein-Barr Virus Causes Sjogren’s Syndrome


cast 06-27-19