Do Viruses Cause Lupus?

ACR Special Report

Michael D. Lockshin, MD
Michael D. Lockshin, MD
Attending Rheumatologist, Hospital for Special Surgery
Director, Barbara Volcker Center for Women and Rheumatic Disease

The question of whether viruses play a causative role in lupus has been around for a number of years, most prominently asked by Thomas Lehman, MD, of Hospital for Special Surgery, in a 1997 paper pointing out the high frequency antibody to Epstein Barr virus (EBV, mononucleosis virus) in children with lupus[1]. The idea, although attractive on clinical grounds, has not been widely accepted because EBV infection is ubiquitous and, on the face of it, not a likely explanation for a rare disease.

However, at the 2003 American College of Rheumatology (ACR) meeting in Orlando, several papers bring the concept of viral causation of lupus to the forefront. The group at Oklahoma Medical Research Foundation, led by Dr. John Harley, one of Dr. Lehman's initial co-authors, pointed out in a series of presentations that serological evidence of lupus is apparent years before the clinical onset of illness, and that serological abnormalities progress in a defined way until the disease appears. These results were recently published in the New England Journal of Medicine[2]. In abstracts presented in Orlando, they now show that the appearance of antibody response indicating EBV infection occurs near the onset of clinical lupus[3],[4]. This evidence is epidemiological, hence circumstantial, in support of the concept that EBV has something to do with the development, or at least the appearance, of lupus.

The work from Harley's group received new and substantial support from two additional lines of investigation. Perhaps most importantly, investigators from Yale, led by Dr. Joseph Craft, looking at cellular dysregulation, concluded that lupus patients do not handle EBV well[5]. At the same time, a group from Case Western Reserve, approaching functional capacity of memory cells, also concluded that lupus patients have defective responses to EBV[6]. These latter studies are important confirmations, in particular because they come from basic science laboratories interested in cellular immunology rather than from people interested in viruses or etiology of lupus itself. While none of these papers definitively states that EBV causes lupus, they certainly lead a great deal in the direction of the idea that a virus, possibly EBV, is a possible cause.

Along the same line, two papers suggested that other viruses may be implicated in the formation of antiphospholipid, an antibody that commonly occurs in patients with lupus and sometimes on its own. The group led by Harris, Gharavi and Pierangeli suggested CMV[7], and a German group proposed parvovirus[8].

All these papers together give new life to the idea that viruses are important in the development of autoimmune disease. This is more than an intellectual exercise. If the virus is critical to the beginning or the clinical development of lupus, then a new focus for prevention or treatment intervention becomes available. We already know, from the work of Harley and others, that there are indicators of lupus decades before the disease actually occurs. Rather than focusing on changing the way the immune system works, after clinical symptoms begin, as we do now, we might be able to provide vaccinations before the onset of the disease or chemical treatments very much like antibiotics after symptoms occur. Even more important, the implications of these findings go well beyond lupus to all inflammatory disease.

[1] James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman TJ, Harley JB. J Clin Invest. 1997 Dec 15;100(12):3019-26. An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus.

[2] Arbuckle MR, McClain MT, Rubertone MV, Scofield H, Dennis GJ, James JA, Harley JB. New Engl J. Med 2003 October 16 (16);349:1526-33 Development of autoantibodies before the clinical onset and systemic lupus erythematosus.

[3] Heinlen LD, McClain MT, Dennis GJ, Rubertone MV, Harley JB, James JA. The Development of Antibodies Targeting Epstein-Barr Virus Closely Parallels Autoimmune Progression Near the Onset of SLE. Arthritis Rheum. 2003 Sep;48(9):S662-3. (Abstract #1733)

[4] McClain MT, Bruner TL. Dennis, GJ, Harley JB, James JA. The Temporal Relationship Between the Onset of Anti-EBNA-1 and Lupus Autoimmunity Supports a Role for EBV in the Development of SLE. Arthritis Rheum. 2003 Sep;48(9):S674. (Abstract # 1764)

[5] Kang I, Quan T, Park S, Nolasco H, Hong MS, Howe JG, Craft J. Defective Control of Latent Epstein-Barr Virus (EBV) Infection in Systemic Lupus Erythematosus (SLE) Arthritis Rheum. 2003 Sep;48(9):S194. (Abstract # 412)

[6] Berner BR, Ott PA, Lehmann PV, Tary Lehmann M, Anthony DD. Phenotypic and Functional Analysis of EBV-specific Memory CD8 T-cells in SLE Patients. Arthritis Rheum. 2003 Sep;48(9):S196. (Abstract # 416)

[7] Labat K, Pierangeli SS, Cox T, Osula O, Gharavi AE. High Levels Of Antibodies To Cytomegalovirus And To CMV-Peptide Are Found In Sera Of Antiphospholipid Syndrome Patients. Arthritis Rheum. 2003 Sep;48(9):S164. (Abstract # 326)

[8] von Landenberg P, Hartwig W. Lehmann W, Lackner KJ, Modrow S.Parvovirus B19 Infection in Pediatric and Adult Patients with Rheumatic Disease is Associated with Antiphospholipid-Antibodies Arthritis Rheum. 2003 Sep;48(9):S165. (Abstract # 331)


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