Viral Infection Can Induce the Production of Autoantibodies

Ori Barzilai; Maya Ram; Yehuda Shoenfeld

Curr Opin Rheumatol.  2007;19(6):636-643.  ?2007 Lippincott Williams & Wilkins
Posted 10/31/2007

Abstract and Introduction

Abstract

Purpose of Review: To review the current literature and summarize the main principles found between viral infections and the subsequent production of autoantibodies.
Recent Findings: We concentrate on recent findings involving three viral agents, one of which is Epstein-Barr virus, which has been associated with many autoimmune diseases and is classically considered to induce systemic lupus erythematosus. As we will discuss, this occurs through molecular mimicry between Epstein-Barr virus nuclear antigen 1 and lupus-specific antigens such as Ro, La or dsDNA, through induction of Toll-like receptor hypersensitivity by Epstein-Barr virus latent membrane protein 2A or by creating immortal B and T cells by loss of apoptosis. Hepatitis B virus was found to share amino acid sequences with different autoantigens. Tissue damage and the release of intracellular components is just another example of the autoantibody production caused by this virus. Cytomegalovirus has often been controversially associated with several autoimmune diseases and, although is the least understood viral infection of the three, appears to be somewhat suspicious.
Summary: Understanding the infectious origin of autoimmune diseases is important as we aim to identify high-risk patients and disrupt this process with vaccines or other medications, ultimately delaying or even preventing the evolution of autoimmune diseases.

Introduction

The immune system's ability to distinguish self from nonself is essential for both host defense against microbial antigens and protection of self-antigens from autoimmune destruction.[1]

Autoantibodies have been defined as an aberration of an essentially physiological and protective process, representing immunoglobulins reacting against self-molecules.[2?]

Three major mechanisms have been shown to govern B-cell tolerance: deletion, anergy, and receptor editing. Deletion is a process in which autoreactive B cells are eliminated from the repertoire, whereas in anergy, the B cells are rendered unresponsive to stimulation. Receptor editing involves secondary rearrangements to replace an autoreactive receptor with another substituting a new immunoglobulin gene. A breakdown of B-cell tolerance could result in the production of autoantibodies.[3,4]

More theories have been suggested for the generation of autoreactivity. For example, if a physiologically inaccessible target tissue that was not presented for B- and T-cell selection suddenly becomes available, the immune system will not recognize it as self and production of autoantibodies may occur.[2?] This is the case when autoantigens are released by both necrotic and apoptotic cells. Moreover, defects in the clearance of apoptotic cell debris may lead to aberrant uptake by macrophages, which will then present the previously intracellular antigens to T and B cells, thus driving the autoimmune process.[5]

Acute viral infections in children and adults have long been suggested to induce transient autoimmune responses, including generation of autoantibodies in which their titers are typically low and the autoimmune course transient. It is important to note that progression into an established autoimmune disease is rare.[6?,7]

The mechanisms by which viruses cause the generation of autoantibodies are still obscure, although it has been suggested that cross-reactivity between autoantigens and viral proteins play an important role.[3] Another important finding is the ability of viruses to induce apoptosis[8] and, in accordance with the above description, also cause the production of autoantibodies.

Although there are autoantibodies that do not induce tissue damage,[3] most of them do have a pathogenic effect[9?] as seen in the work of Katzav et al.,[10??] in which a depression-like behavior developed in mice following brain injection of autoantibodies against ribosomal P protein. The pathogenic mechanisms vary from modulation of the biological activities, generation of immune complexes, to lysis of the cell.[9?] A more descriptive mechanism of the pathogenic effect is shown in Table 1 .

Since these pathogenic effects could lead to an autoimmune phenomenon, finding a way to prevent them from occurring could be a great achievement in the field of autoimmunity in general, and autoimmune phenomena produced by viruses in particular.

Although a cause and effect relationship between viruses and the development of autoantibodies are still linked in a mysterious way, we attempt to show the most recent data on this subject by focusing on three different viruses that appear to be associated with autoimmunity more commonly than other viruses:[11] Epstein-Barr virus (EBV), hepatitis B virus (HBV), and cytomegalovirus (CMV).

Epstein-Barr Virus

EBV is a member of the herpesvirus family and is known for causing acute infectious mononucleosis and various lymphoproliferative diseases. The story of the relationship between EBV infection and systemic autoimmune diseases has evolved into a rather interesting 'love affair'. EBV is known as an infamous viral agent that may, in the right circumstances, encourage the development of many different autoimmune diseases. The best-known and most profoundly understood relationship between this infecting agent and an autoimmune disease is that of EBV and systemic lupus erythematosus (SLE).

The association between SLE and EBV was first noted in 1971, when Evans[12] described a high prevalence of the virus in the sera of patients with SLE. This serological correlation has been established over the years and has previously been reviewed.[13] It is not surprising that even the most modern diagnostic methods are producing similar results.[14] Interestingly, it was not until 1997 that EBV was proposed as an etiological cause for SLE in susceptible patients,[15] rather than as an incidental finding. In the past decade, this association has been a 'hot' topic for inquiry and investigators have come a long way in understanding this connection. Finding the specific viral antigen that induces production of SLE-specific autoantibodies is particularly difficult when considering the fact that there are more than 100 different autoantibodies that may appear in the sera of patients with SLE.[16] The most well-substantiated method by which EBV infection may cause SLE is via molecular mimicry. The immune response against EBV and EBV nuclear antigen 1 (EBNA-1), in particular, is different between patients with SLE and healthy controls. Unlike patients with SLE, controls maintain a partial humoral response and do not generally produce long-standing cross-reactive antibodies. Hence, the humoral immune response to EBNA-1 leads to the generation of cross-reactive antibodies only in susceptible individuals.[17?] Harley et al.[18,19??] propose a sequence whereby the introduction of EBNA-1 to a host causes the creation of anti-EBNA-1 antibodies. Circulating anti-EBNA-1 antibodies are also capable of binding to SLE-specific autoantigens, namely Sm and Ro, due to the structural similarity between them. Accumulation of such autoantibody complexes through epitope spreading will, in turn, cause an overt clinical illness. In addition to Ro and Sm, it has been shown that EBNA-1 may elicit creation of anti-dsDNA, another SLE associated autoantibody, also via molecular mimicry.[20]

The hypothesis that EBV causes autoimmunity by cross-reacting viral and endogenous proteins is not the only explanation offered. Recent research using transgenic mouse models suggests that B cells expressing the EBV-encoded protein latent membrane protein 2A bypasses normal tolerance checkpoints and enhances the development of autoimmune diseases, thus providing another model attempting to explain the link between EBV and SLE, and may perhaps be considered in other autoimmune diseases.[21] This model is based on the fact that EBV latent protein 2A induces hypersensitivity to Toll-like-receptor stimulation, which leads to the activation of anti-Sm B cells through the B-cell receptor/Toll-like receptor pathway. The end result is increased proliferation or differentiation of antibody secreting cells or both.[22?]

A third hypothesis, proposed by Pender et al.[23], offers another explanation that may be considered regarding EBV infection and autoimmune diseases. According to this theory, during primary infection, autoreactive B cells are infected by EBV, proliferate, and become latently infected memory B cells, which are resistant to the apoptosis that occurs during normal B-cell homeostasis, since they express virus-encoded antiapoptotic molecules. At the end of a chain of events, autoreactive T cells, which were activated by the impaired B cells, also fail to undergo apoptosis because they receive a costimulatory survival signal from the infected B cells. The autoreactive T cells proliferate and produce cytokines, which recruit other inflammatory cells, with resultant target-organ damage and chronic autoimmune disease.

The case of rheumatoid arthritis is less clear than that of SLE. The association between EBV and rheumatoid arthritis has been explored for more than 25 years. As previously reviewed,[24] patients with RA have higher levels of anti-EBV antibodies than healthy controls, EBV-specific suppressor T-cell function is defective in rheumatoid arthritis and patients with rheumatoid arthritis have a higher EBV load in peripheral blood lymphocytes. When it comes to the creation of autoantibodies, however, there is no clear-cut evidence showing that EBV induces the creation of rheumatoid arthritis-specific autoantibodies. It has been proposed that EBV can, perhaps, play a role in the citrullination of autoantigens or formation of autoantibodies such as anticyclic citrullinated peptide, but this theory has yet to be proven.[25]

Similarly, recent studies confirm the belief that EBV plays a critical role in the etiology of multiple sclerosis,[26] via the hypothesis similar to those discussed previously.[27,28] Molecular mimicry may play a critical role again, as it has been shown that Toll-like receptors may recognize an EBV peptide as well as a myelin basic protein peptid.e[29] Yet, to our knowledge, it is still difficult to associate a specific multiple sclerosis autoantibody produced due to EBV infection.

EBV has also been associated with Sjögren's syndrome,[30,31] autoimmune thyroiditis,[32] autoimmune hepatitis,[33] and Kawasaki disease.[34] In our recent study,[35] we observed a higher prevalence of EBV antibodies in patients with polymyositis than in healthy controls, thus raising the possibility that EBV plays a role in the pathogenesis of polymyositis as well. In these cases, the role of EBV remains unclear and future research will determine whether this notorious virus causes the creation of autoantibodies and, if so, which ones.

Hepatitis B Virus

HBV is a small partially double-stranded circular DNA virus that favors its replication in the liver cell. Therefore, it is defined as a hepatotropic virus classified in the hepadnaviridae family. HBV represents one of the major causes of liver disease, which vary in severity from person to person.[36-38]

HBV evades the innate response but appears to employ active evasion strategies that target the adaptive immune response, which is responsible for the elimination of HBV infection.[37,39] CD4 T cells, classically referred to as helper T cells, are robust producers of cytokines and are required for the efficient development of effector cytotoxic CD8 T-cell antibody production by B cells. CD8 T cells go on to clear HBV-infected hepatocytes through cytolytic and noncytolytic mechanisms, reducing the levels of circulating virus, while B-cell antibody production neutralizes free viral particles and can prevent (re)infection.[37]

T-cell responses are responsible for the liver injury during the acute and chronic phases of viral hepatitis. It is believed that HBV-specific CD8+ T cells function as a double-edged sword. These T cells play a critical role in the control and clearance of the viruses; on the other hand, when overall antiviral immunity is not vigorous enough to clear the viruses, they may also cause sustained liver tissue damage through different pathways, including perforin-mediated cytotoxicity and Fas ligand/Fas-mediated apoptosis.[40,41]

Autoreactivity might also contribute to liver damage in patients with chronic HBV infections that present with histological features of chronic active hepatitis (portal and periportal lymphoplasmacytic infiltrates and piecemeal necrosis of periportal hepatocytes). As HBV-infected cells are not predominantly concentrated in the periportal areas of the liver lobules, it is unlikely that a virus-directed T-cell cytotoxic reaction alone can account for this histological picture. Similar histological features are seen in autoimmune hepatitis, in which the hepatocyte-specific asialoglycoprotein receptor has been shown to be a major target of humoral and cellular autoreactions. McFarlane et al.[41] found antibodies against the asialoglycoprotein receptor-R in 31 of 42 (73.8%) patients with chronic HBV with histological features of chronic active hepatitis. The very marked association of anti-asialoglycoprotein receptor-R antibodies with moderate and severe chronic active hepatitis suggests that these antibodies are in some way related to the development of liver damage in patients with HBV infection and not simply the response to tissue damage.

The liver cell damage could be the consequence of the host's immune response to virus-infected hepatocytes[42] or, as shown by some researchers,[8] it could be that the virus induces apoptosis. As a result of this damage, autoantibody production may occur.[42] The autoantibodies associated with HBV infection are shown in Table 2 .[1,7,41-58]

One study detected the presence of antinuclear antibodies, smooth muscle antibodies, parietal cell antibodies, antimitochondrial antibody and liver kidney microsome antibody in 10 of 61 (16.3%) children with chronic hepatitis B.[59] A different study[7] detected significant titers of antinuclear antibodies, smooth muscle antibodies, or liver kidney microsome antibody in 42 of 306 (14%) patients with hepatitis B.

Those findings are supported by the work of Bogdanos et al.,[1] which showed that autoimmunity is a common feature of HBV infection, with more than 50% of the infected patients being seropositive for autoantibodies such as antinuclear antibodies and smooth muscle antibodies. Six human proteins were identified with a high local sequence similar to the HBV-DNA polymerase; four were nuclear proteins and two were smooth muscle proteins. Nuclear proteins are key proteins involved in structural and regulatory functions, while smooth muscle proteins are involved in muscle contraction. From these findings, these autoantibodies may have arisen as an inappropriate evolution of the anti-HBV-poly immune response to include antigenically similar nuclear and smooth muscle proteins. Thus, 'mimicry' between viral and 'self' antigens may lead to failure of tolerance to the self-components, resulting in autoimmunity. It should be noted that the cross-reactive antibodies detected are of the immunoglobulin G (IgG) isotype, implicating T-cell help in the generation of these autoantibodies.[1,60]

Kansu et al.[59] also showed the presence of antinuclear antibodies, antimitochondrial antibodies, and smooth muscle antibodies in patients with HBV before and after the use of treatment with interferon-α. These authors[59] found that the autoantibody prevalence was highly affected by the use of interferon, however.

Zachou et al.[43] investigated 50 patients with HBV for the presence of the IgG isotype of anticardiolipins (aCLs) antibodies and antibodies against b2-glycoprotein I. The results showed that 14% of the patients with HBV tested positive for IgG aCL antibody, which was significantly higher than the healthy controls (P < 0.0001). Only 2% of the patients with HBV tested positive for anti-b2-glycoprotein I antibodies. These researchers[43] concluded that low to medium titers of aCLs antibodies are frequently detected in patients with HBV. aCLs appear to be of the nonpathogenic type, however, as b2-glycoprotein I dependency was not shown.

Guglielmone et al.[44] report the occurrence of b2-glycoprotein I-dependent and b2-glycoprotein I-independent aCL isotypes in a number of patients with various infections, including HBV. It was found that 17 of 40 (42%) patients with acute and chronic HBV were positive for aCL and that the most prevalent isotypes in this population were IgM and IgA. The mean cofactor-dependent titer was low in all groups. Moreover, it was found that there was no correlation between disease activity (acute or chronic hepatitis B) and increased aCL levels.

Rheumatoid factor, especially the IgA isotype, may be present in 20-75% of patients with chronic HBV, but they rarely have anticyclic citrullinated peptide. This indicates that, despite the presence of rheumatoid factor, arthralgia, or arthritis related to chronic hepatitis B, patients do not develop rheumatoid arthritis.[45]

Autoantibodies to proliferating-cell nuclear antigen are detected in the sera of 3-5% of patients with SLE. These antibodies were not detected in other autoimmune diseases and were thought to be a specific and useful serological marker for SLE.[42] Tzang et al.[42] have shown that the prevalence of anti-proliferating-cell nuclear antigen in 243 patient with chronic HBV was approximately 12%. The isotype distribution of anti-proliferating-cell nuclear antigen was predominantly IgG (80%) with a small amount of IgM (20%). These are similar results to the reported spontaneously arising autoantibodies in SLE that were predominantly IgG with a low level of IgM. Moreover, none of these patients exhibited clinical manifestations of SLE. It is still unknown how long this antibody will persist in patients with chronic HBV and if these patients will subsequently develop SLE manifestations.[11]

Despite the insufficient data, it is apparent that HBV and autoantibodies are associated with each other in a way that remains unclear. In the future, it will be interesting to further investigate this topic and to find the cause and effect relationship between HBV and the generation of autoantibodies.

Cytomegalovirus

CMV is another member of the herpesvirus family, which is known to be a leading factor in the causation of mental retardation and congenital hearing loss. CMV has been associated with various autoimmune diseases, yet data regarding these associations are much less clear and remain mostly theoretical. CMV infection is known to induce several autoimmune abnormalities in mice that resemble those found in SLE.[46] In addition, a potential role for CMV in the development and/or progression of SLE has been suggested.[61] CMV has also been associated with antiphospholipid syndrome,[62,63] systemic sclerosis[64] inflammatory bowel disease,[65] and diabetes mellitus.[66,67] Conflicting data exist regarding the relationship between CMV infection and accelerated atherosclerosis.[68,69]

Review of the current literature and updating information about this intriguing relationship is a difficult task, simply because there are not much available data. To our knowledge, a cause and effect relationship between CMV infection and the creation of autoantibodies has yet to be discovered. In our recent study,[35] we noticed that there seems to be a higher prevalence of CMV IgG antibodies in patients with SLE, and we discovered a high prevalence of CMV IgM antibodies in association with many autoimmune diseases, including SLE, antiphospholipid syndrome, primary biliary cirrhosis, systemic sclerosis, polymyositis, Sjögren's syndrome, and different types of vasculitis. We believe that although deciphering the role of CMV in autoimmune diseases appears to be a difficult task, and although it remains uncertain whether or not this virus plays a role in such pathogenesis, this will be a matter worth investigating in the future.

Conclusions

The etiology for development of an autoimmune disease is multifactorial in nature and requires many pieces of a puzzle to fall into place. Of this puzzle, one of the most dominant pieces appears to be the environmental factor, and infection in particular. There are five main mechanisms proposed[70] by which an infecting agent can induce an autoimmune reaction. Molecular mimicry has been discussed previously.[71] Polyclonal activation occurs when lymphotrophic viruses infect B cells. This infection will lead to B-cell proliferation causing enhanced antibody production, resulting in the accumulation of circulating immune complexes that may cause damage to self tissues.[72] Viral superantigens cause autoimmune reactions as they activate an array of T cells, irrespective of their specificity. This occurs due to their ability to bind to the T-cell receptor beta chain variable domain, as well as their ability to bind to a variety of major histocompatability complex class 2 molecules.[73] Epitope spreading occurs when, in an inflammatory state, there is strong local activation of antigen-presenting cells. Such an activation may result in overprocessing and overpresentation of antigens, thus priming large numbers of T cells with broad specificities, possibly against self antigens.[74] Lastly, bystander activation occurs when, following infection, enhanced cytokine production induces the expansion of autoreactive T cells that were already present within the self tissue but, due to their prior low number, were unable to cause an overt autoimmune disease.[75]

We strongly believe that what we see as clinicians at the endpoint of an autoimmune disease is only 'the tip of the iceberg' (Fig. 1). Numerous biological events, and perhaps the most interesting events, in the pathogenesis of autoimmune diseases take place before this tip is revealed. There are a few key steps in the development of an autoimmune disease. Firstly, an individual is born with a genetic susceptibility and develops a normal immune system. Somewhere along the way, this individual encounters different environmental factors, in this case viral infection. This encounter will set off a chain of events via the mechanisms mentioned above, and will result in the development of a defective immune system. As time goes by, damage caused by this defective immune system accumulates and an overt clinical illness is revealed. The study of the infectious agents that play a role in this process is therefore important as we aim to identify high-risk patients and disrupt this process with vaccines or other medications, ultimately delaying or preventing the evolution of autoimmune diseases.



References

Papers of particular interest, published within the annual period of review, have been highlighted as:
? of special interest:
?? of outstanding interest

  1. Bogdanos DP, Mieli-Vergani G, Vergani D. Virus, liver and autoimmunity. Dig Liver Dis 2000; 32:440-446.
  2. ? Oertelt S, Invernizzi P, Podda M, Gershwin ME. What is an autoantibody. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Amsterdam: Elsevier; 2007. pp. 3-6. A basic chapter on the characteristics and definition of autoantibody.
  3. Yamamoto K. Possible mechanisms of autoantibody production and the connection of viral infections in human autoimmune diseases. Tohoku J Exp Med 1994; 173:75-82.
  4. Pisetsky DS. Anti-DNA and autoantibodies. Curr Opin Rheumatol 2000; 12:364-368.
  5. D'Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet 2007; 369:587-596.
  6. ? Denman AM, Rager-Zisman B. Viruses: The culprits of autoimmune diseases? In: Shoenfeld Y, Rose NR, editors. Infection and Autoimmunity. Amsterdam: Elsevier; 2004. pp. 123-153. A basic chapter on the role of various viruses in different autoimmune diseases, delineating the different viruses involved in each one of the diseases.
  7. Hansen KE, Arnason J, Bridges AJ. Autoantibodies and common viral illnesses. Semin Arthritis Rheum 1998; 27:263-271.
  8. Baumert TF, Thimme R, von Weizsacker F. Pathogenesis of hepatitis B virus infection. World J Gastroenterol 2007; 13:82-90.
  9. ? Cervera R, Shoenfeld Y. Pathogenic mechanisms and clinical relevance of autoantibodies. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Amsterdam: Elsevier; 2007. pp. 29-35.
  10. ?? Katzav A, Solodeev I, Brodsky O, et al. Induction of autoimmune depression in mice by antiribosomal P antibodies via the limbic system. Arthritis Rheum 2007; 56:938-948. A cornerstone study in which a specific autoantibody, anti p ribosomal, was injected into the brain ventricle of mice and induced a psychiatric condition such as depression.
  11. Hsu TC, Tsay GJ, Chen TY, et al. Anti-PCNA autoantibodies preferentially recognize C-terminal of PCNA in patients with chronic hepatitis B virus infection. Clin Exp Immunol 2006; 144:110-116.
  12. Evans AS. E.B. virus antibody in systemic lupus erythematosus. Lancet 1971; 1:1023-1024.
  13. McClain MT, Harley JB, James JA. The role of Epstein-Barr virus in systemic lupus erythematosus. Front Biosci 2001; 6:E137-E147.
  14. Lu JJ, Chen DY, Hsieh CW, et al. Association of Epstein-Barr virus infection with systemic lupus erythematosus in Taiwan. Lupus 2007; 16:168-175.
  15. James JA, Kaufman KM, Farris AD, et al. An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J Clin Invest 1997; 100:3019-3026.
  16. Sherer Y, Gorstein A, Fritzler MJ, Shoenfeld Y. Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum 2004; 34:501-537.
  17. ? Poole BD, Scofield RH, Harley JB, James JA. Epstein-Barr virus and molecular mimicry in systemic lupus erythematosus. Autoimmunity 2006; 39:63-70.
  18. Harley JB, James JA. Epstein-Barr virus infection induces lupus autoimmunity. Bull NYU Hosp Jt Dis 2006; 64:45-50.
  19. ?? Harley JB, Harley IT, Guthridge JM, James JA. The curiously suspicious: a role for Epstein-Barr virus in lupus. Lupus 2006; 15:768-777.
  20. Sundar K, Jacques S, Gottlieb P, et al. Expression of the Epstein-Barr virus nuclear antigen-1 (EBNA-1) in the mouse can elicit the production of antidsDNA and anti-Sm antibodies. J Autoimmun 2004; 23:127-140.
  21. Swanson-Mungerson M, Longnecker R. Epstein-Barr virus latent membrane protein 2A and autoimmunity. Trends Immunol 2007; 28:213-218.
  22. ? Wang H, Nicholas MW, Conway KL, et al. EBV latent membrane protein 2A induces autoreactive B cell activation and TLR hypersensitivity. J Immunol 2006; 177:2793-2802. An experimental model by which a specific protein derived from EBV was shown to induce autoreactive B cells in Toll-like receptors.
  23. Pender MP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol 2003; 24:584-588.
  24. Balandraud N, Roudier J, Roudier C. Epstein-Barr virus and rheumatoid arthritis. Autoimmun Rev 2004; 3:362-367.
  25. Costenbader KH, Karlson EW. Epstein-Barr virus and rheumatoid arthritis: is there a link? Arthritis Res Ther 2006; 8:204.
  26. Nielsen TR, Pedersen M, Rostgaard K, et al. Correlations between Epstein-Barr virus antibody levels and risk factors for multiple sclerosis in healthy individuals. Mult Scler 2007; 13:420-423.
  27. Lunemann JD, Munz C. Epstein-Barr virus and multiple sclerosis. Curr Neurol Neurosci Rep 2007; 7:253-258.
  28. Haahr S, Hollsberg P. Multiple sclerosis is linked to Epstein-Barr virus infection. Rev Med Virol 2006; 16:297-310.
  29. Lang HL, Jacobsen H, Ikemizu S, et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 2002; 3:940-943.
  30. Padalko EY, Bossuyt X. AntidsDNA antibodies associated with acute EBV infection in Sjogren's syndrome. Ann Rheum Dis 2001; 60:992.
  31. Trimeche M, Ziadi S, Amara K, et al. Prevalence of Epstein-Barr virus in Sjogren's syndrome in Tunisia. Rev Med Interne 2006; 27:519-523. Article in French.
  32. Vrbikova J, Janatkova I, Zamrazil V, et al. Epstein-Barr virus serology in patients with autoimmune thyroiditis. Exp Clin Endocrinol Diabetes 1996; 104:89-92.
  33. Vento S, Guella L, Mirandola F, et al. Epstein-Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet 1995; 346:608-609.
  34. Lee SJ, Lee KY, Han JW, et al. Epstein-Barr virus antibodies in Kawasaki disease. Yonsei Med J 2006; 47:475-479.
  35. Barzilai O, Sherer Y, Ram M, Izhaky D, Anaya J, Shoenfeld Y. EBV and CMV in autoimmune diseases. Are they truly notorious? A preliminary report. Ann NY Acad Sci 2007;1108:567-577.
  36. Shepard CW, Simard EP, Finelli L, et al. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev 2006; 28:112-125.
  37. Bertoletti A, Gehring AJ. The immune response during hepatitis B virus infection. J Gen Virol 2006; 87:1439-1449.
  38. Huang CF, Lin SS, Ho YC, et al. The immune response induced by hepatitis B virus principal antigens. Cell Mol Immunol 2006; 3:97-106.
  39. Wieland SF, Chisari FV. Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol 2005; 79:9369-9380.
  40. Ichiki Y, He XS, Shimoda S, et al. T cell immunity in hepatitis B and hepatitis C virus infection: implications for autoimmunity. Autoimmun Rev 2005; 4:82-95.
  41. McFarlane BM, Bridger CB, Smith HM, et al. Autoimmune mechanisms in chronic hepatitis B and delta virus infections. Eur J Gastroenterol Hepatol 1995; 7:615-621.
  42. Tzang BS, Chen TY, Hsu TC, et al. Presentation of autoantibody to proliferating cell nuclear antigen in patients with chronic hepatitis B and C virus infection. Ann Rheum Dis 1999; 58:630-634.
  43. Zachou K, Liaskos C, Christodoulou DK, et al. Anticardiolipin antibodies in patients with chronic viral hepatitis are independent of beta2-glycoprotein I cofactor or features of antiphospholipid syndrome. Eur J Clin Invest 2003; 33:161-168.
  44. Guglielmone H, Vitozzi S, Elbarcha O, Fernandez E. Cofactor dependence and isotype distribution of anticardiolipin antibodies in viral infections. Ann Rheum Dis 2001; 60:500-504.
  45. Lee SI, Yoo WH, Yun HJ, Kim DS, Lee HS, Choi SI, Hur JA, Cho YG. Absence of antibody to cyclic citrullinated peptide in sera of nonarthritic patients with chronic hepatitis B virus infection. Clin Rheumatol 2006; 26:1079-1082.
  46. Sekigawa I, Nawata M, Seta N, et al. Cytomegalovirus infection in patients with systemic lupus erythematosus. Clin Exp Rheumatol 2002; 20:559-564.
  47. Owada T, Matsubayashi K, Sakata H, et al. Interaction between desialylated hepatitis B virus and asialoglycoprotein receptor on hepatocytes may be indispensable for viral binding and entry. J Viral Hepat 2006; 13:11-18.
  48. Doniach D. The relationship between the viruses causing hepatitis and autoimmunity in liver disease. Int Arch Allergy Appl Immunol 1973; 45:214-215.
  49. Invernizzi P. Antinuclear antibodies: general introduction. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Amsterdam: Elsevier; 2007. pp. 129-133.
  50. Selmi C, Muratori P, Podda M, Bianchi FB. Smooth muscle antibodies. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Amsterdam: Elsevier; 2007. pp. 487-491.
  51. Toh B-H, Alderuccio F. Parietal cell and intrinsic factor autoantibodies. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Elsevier: Amsterdam; 2007. pp. 479-486.
  52. Invernizzi P, Selmi C, Gershwin ME. Antimitochondrial antibodies. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Amsterdam: Elsevier; 2007. pp. 473-477.
  53. Strassburg CP, Manns MP. Liver cytosol antigen type I autoantibodies, liver kidney microsomal autoantibodies, and liver microsomal autoantibodies. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Amsterdam: Elsevier; 2007. pp. 463-471.
  54. Khamashta MA, Bertolaccini ML. Anticardiolipin antibodies. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Amsterdam: Elsevier; 2007. pp. 741-745.
  55. Harada M, Fujisawa Y, Sakisaka S, et al. High prevalence of anticardiolipin antibodies in hepatitis C virus infection: lack of effects on thrombocytopenia and thrombotic complications. J Gastroenterol 2000; 35:272-277.
  56. Angelis VD, Meroni PL. Rheumatoid factors. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Amsterdam: Elsevier; 2007. pp. 755-762.
  57. Mccarty GA. Proliferating cell nuclear antigen autoantibodies. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Amsterdam: Elsevier; 2007. pp. 205-210.
  58. Mccarty GA. Proliferating cell nuclear antigen autoantibodies. In: Shoenfeld Y, Gershwin ME, Meroni PL, editors. Autoantibodies. Amsterdam: Elsevier; 2007. pp. 205-210.
  59. Kansu A, Kuloglu Z, Demirceken F, Girgin N. Autoantibodies in children with chronic hepatitis B infection and the influence of interferon alpha. Turk J Gastroenterol 2004; 15:213-218.
  60. Gregorio GV, Choudhuri K, Ma Y, et al. Mimicry between the hepatitis B virus DNA polymerase and the antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis B virus infection. J Immunol 1999; 162:1802-1810.
  61. Su BY, Su CY, Yu SF, Chen CJ. Incidental discovery of high systemic lupus erythematosus disease activity associated with cytomegalovirus viral activity. Med Microbiol Immunol 2007; 196:165-170.
  62. Blank M, Asherson RA, Cervera R, Shoenfeld Y. Antiphospholipid syndrome infectious origin. J Clin Immunol 2004; 24:12-23.
  63. Uthman I, Tabbarah Z, Gharavi AE. Hughes syndrome associated with cytomegalovirus infection. Lupus 1999; 8:775-777.
  64. Guiducci S, Giacomelli R, Tyndall A, Cerinic MM. Infection and systemic sclerosis. In: Shoenfeld Y, Rose NR, editors. Infection and Autoimmunity. Amsterdam: Elsevier; 2004. pp. 613-622.
  65. Criscuoli V, Rizzuto MR, Cottone M. Cytomegalovirus and inflammatory bowel disease: is there a link? World J Gastroenterol 2006; 12:4813-4818.
  66. Filippi C, von Herrath M. How viral infections affect the autoimmune process leading to type 1 diabetes. Cell Immunol 2005; 233:125-132.
  67. Roberts BW, Cech I. Association of type 2 diabetes mellitus and seroprevalence for cytomegalovirus. South Med J 2005; 98:686-692.
  68. Nerheim PL, Meier JL, Vasef MA, et al. Enhanced cytomegalovirus infection in atherosclerotic human blood vessels. Am J Pathol 2004; 164:589-600.
  69. Degre M. Has cytomegalovirus infection any role in the development of atherosclerosis? Clin Microbiol Infect 2002; 8:191-195.
  70. Wucherpfennig KW. Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest 2001; 108:1097-1104.
  71. Wucherpfennig KW. Structural basis of molecular mimicry. J Autoimmun 2001; 16:293-302.
  72. Ferri C, Zignego AL. Relation between infection and autoimmunity in mixed cryoglobulinemia. Curr Opin Rheumatol 2000; 12:53-60.
  73. Scherer MT, Ignatowicz L, Winslow GM, et al. Superantigens: bacterial and viral proteins that manipulate the immune system. Annu Rev Cell Biol 1993; 9:101-128.
  74. Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 1992; 358:155-157.
  75. Murali-Krishna K, Altman JD, Suresh M, et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 1998; 8:177-187.

Abbreviation Notes

aCL = anticardiolipin; CMV = cytomegalovirus; EBV = Epstein-Barr virus; EBNA-1 = Epstein-Barr virus nuclear antigen 1; HBV = hepatitis B virus; Ig = immunoglobulin; SLE = systemic lupus erythematosus

Reprint Address

Correspondence to Yehuda Shoenfeld, MD, FRCP, Head, Department of Medicine 'B' Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel Tel: +972 3 530 2652; fax: +972 3 535 2855; e-mail: shoenfel@post.tau.ac.il


Ori Barzilai,a,* Maya Ram,a,* and Yehuda Shoenfelda,b

aCenter for Autoimmune Diseases, Department of Medicine 'B', Sheba Medical Center, Israel
bSackler Faculty of Medicine, Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel
*The first two authors contributed equally to the article.