Lupus (2010) 19, 783–792 http://lup.sagepub.com REVIEW Clinical and Molecular Evidence for Association of SLE with parvovirus B19 M Pavlovic 1 , A Kats 2 , M Cavallo 2 and Y Shoenfeld 3 1 Department of Computer and Electrical Engineering and Computer Science, Florida Atlantic University, FL, USA; 2 Department of Biological Sciences, Florida Atlantic University, FL, USA; and 3 Department of Medicine ’B’ and Center for Autoimmune Diseases, Sheba MedicalCenter (Affiliated to Tel-Aviv University), Tel-Hashomer 52621, Israel In addition to genetic and environmental factors, viruses have been suspected as causes and/or contributors to human autoimmune diseases, although direct evidence for the association is generally lacking. Parvovirus B19, the cause of Fifth disease in childhood, and possible trigger in the spectrum of autoimmune diseases in adults, has emerged as one of the central viral candidates within the last few years. In this article we propose a possible model for parvovirus B19 association with systemic lupus erythematosus (SLE). The basis for our model is the secretion of hydrolyzing anti-ssDNA autoantibodies in 30–70% of cases with SLE, which in turn can either hydrolyze viral B19 ssDNA in blood and other fluids, or intranuclear, replicated viral ssDNA after re-activation and translocation of the virus into the nucleus of the host permissive cells. Both mechanisms contribute to perpetuation and maintenance of a ‘vicious cycle’ with concomitant flares in SLE, and involve inevitable TLR9 sensitization and genetic switch for anti-ssDNA autoantibody production from activated B cells in indivi- duals prone to triggering. This model strongly suggests a major potential impact upon early prevention (vaccination) and targeted therapy of this subclass within the SLE spectrum of diseases. Incorporated in this new concept is an innovative idea for developing the tool for more precise (individualized) diagnosis, prevention, and therapy. Lupus (2010) 19, 783–792. Key words: autoimmune diseases; cytokine microarray profiling; hydrolytic anti-DNA autoantibodies; parvovirus B19; systemic lupus erythematosus (SLE) Introduction Background The cause of lupus is unknown but a number of disease agents have been implicated. 1,2 Epstein– Barr virus, parvovirus B19, bacterial species and drugs have been connected to the disease. 3–8 The presence of viruses was sought in a colony of dogs bred from parents with systemic lupus erythe- matosus (SLE). 4 Cell-free filtrates prepared from the spleens of these animals were injected into new- born dogs, mice, and rats. The canine recipients developed antinuclear antibody (ANA) and posi- tive lupus erythematosus (LE) cell tests, proving that the illness is transmissible 4 and, with respect to injection with cell-free filtrate, probably of viral origin. Lupus patients exhibit an interferon alpha (IFN-a) signature, suggesting an underlying infec- tion of yet unknown origin. 9,10 Therefore, the key question is what agent or agents drive the inflam- mation and elicit the inflammatory cascade in SLE? The parvovirus is at the focus of many derma- tologic and rheumatologic disease-related studies previously attributed to unknown factors. 11–21 Initially, B19 was identified as the causative agent of erythema infectiosum (erythrovirus), a common childhood rash found in outbreaks among school- children during the winter and spring months, later called Fifth disease or slapped cheek disease. 22–25 Since then, B19 has been shown to be the causative agent of many diseases, some of them classified as autoimmune in origin, including arthropathy, tran- sient aplastic crisis, persistent anemia, and hydrops fetalis (Table 1). Yet, its best known infection remains erythema infectiosum or Fifth disease, 22 Correspondence to: Dr Mirjana Pavlovic MD, PhD, Research Professor, Department of Computer and Electrical Engineering and Computer Science, Florida Atlantic University, 777 Glades Rd, Boca Raton, FL, 33431, USA Email: mpavlovi@fau.edu or pmirjana@aol.com Received 27 October 2009; accepted 15 February 2010 ! The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203310365715