Epstein-Barr virus and molecular mimicry in systemic lupus
BRIAN D. POOLE1, R. HAL SCOFIELD1,2,3, JOHN B. HARLEY1,2,3, & JUDITH A. JAMES1,2
1Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma, OK 73104, USA,2Oklahoma Health Sciences
Center, 825 NE 13th Street, Oklahoma, OK 73104, USA, and3Veterans Affairs Medical Center, 825 NE 13th Street,
Oklahoma, OK 73104, USA
Systemic lupus erythematosus (SLE or lupus) is a complex disease with a multifactoral etiology, with genetic, hormonal, and
environmental influences. Molecular mimicry as a result of viral infection may contribute to the development of lupus. The
pattern of autoantibody development in lupus is consistent with initiation through molecular mimicry, as the initial
autoantigenic epitopes that have been observed are limited and cross-reactive with viral proteins. Autoantibody specificity may
then later diversify to other autoantigens through B-cell epitope spreading. Epstein-Barr virus (EBV) is an excellent candidate
to be involved in molecular mimicry in lupus. EBV infection has been associated with lupus through serological and DNA
studies. Infection with EBV results in the production of the viral protein Epstein-Barr virus nuclear antigen-1 (EBNA-1),
antibodies against which cross-react withlupus-associated autoantigens, including Ro, SmB/B0,and SmD1, in lupus patients.
The immune response against EBV, and EBNA-1 in particular, differs among lupus patients and healthy controls, with
controls maintaining a limited humoral response and failing to produce long-standing cross-reactive antibodies. We
hypothesize that the humoral immune response to EBNA-1 in susceptible individuals leads to the generation of cross-reactive
antibodies. Through the process of epitope spreading, these cross-reactive antibodies target additional, non-cross reactive
autoepitopes, spread to additional autoantigens, and become pathogenic, leading eventually to clinical lupus. This paper
reviews some of the current literature supporting roles for EBVexposure and epitope spreading in SLE.
Keywords: Systemic lupus erythematosus, Epstein-Barr virus, cross-reactivity, autoimmunity, epitope spreading,
Systemic lupus erythematosus (SLE or lupus) is a
complex systemic autoimmune disease. Clinical
presentation of lupus varies among patients, including
a wide range of possible organ system damage .
Autoantibodies serve as the most common and
unifying characteristic of lupus. These antibodies are
directed against a large but limited collection of
autoantigenic targets, including DNA chromatin and
its component histones, components of the spliceo-
some, the Ro/La complex, among others [2,3]. This
complexity has made the complete understanding of
lupus etiology and pathogenesis difficult. No factor,
either genetic or environmental, appears to be solely
causal for most of the patients. Therefore, most
investigators strongly suspect that lupus has a multi-
The available immunochemical evidence is consist-
ent with a mechanism of lupus autoantibody
generation through molecular mimicry. A molecular
mimicry mechanism is possible when the antibodies
formed, either spontaneously or as a consequence of a
heteroimmune response, cross-react. That is, these
antibodies bind two different antigens. Immuno-
chemically some structural feature of each of the two
antigens is sufficiently similar to one another to
imitate or be a mimic. This antibody then plays the
ISSN 0891-6934 print/ISSN 1607-842X online q 2006 Taylor & Francis
Correspondence: J. A. James, Oklahoma Medical Research Foundation, 825 NE 13th Street Oklahoma, Oklahoma, OK 73104, USA.
Tel: 1 405 271 4987. Fax: 1 405 271 7063. E-mail: email@example.com
Autoimmunity, February 2006; 39(1): 63–70
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