S-12 Bacterial triggers and autoimmune rheumatic diseases H.J. Girschick 1 , L. Guilherme 2 , R.D. Inman 3 , K. Latsch 1 , M. Rihl 4 , Y. Sherer 5 , Y. Shoenfeld 5 , H. Zeidler 6 , S. Arienti 7 , A. Doria 7 1 Pediatric Rheumatology, Immunology, Infectious Diseases, Children’s Hospital, ’s Hospital, ’ University of Wuerzburg, Germany; 2 Heart Institute (InCor), School of Medicine, University of São Paulo; Institute for Immunology Investigation, Millenium Institute, São Paulo, Brazil; 3 Department of Medicine and Immunology, University of Toronto, Toronto, Canada; 4 Division of Clinical Immunology and Rheumatology, Hannover Medical School (MHH), Hannover, Germany; 5 Department of Medicine ‘B’ and Center ’ and Center ’ of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel-Aviv University, Israel; 6 Rheumatologikum Hannover, Hannover, 6 Rheumatologikum Hannover, Hannover, 6 Germany; 7 Division of Rheumatology, University of 7 Division of Rheumatology, University of 7 Padova, Italy. Hermann J. Girschick; Luiza Guilherme; Robert D. Inman; Kirsten Latsch; Markus Rihl; Yaniv Sherer; Yehuda Shoenfeld; Henning Zeidler; Silvia Arienti; Andrea Doria. Please address correspondence to: Prof. Andrea Doria, Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy. E-mail: adoria@unipd.it Received and accepted on January 18, 2008. © Copyright Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2008. 2008. Key words: Reactive arthritis, spondyloarthritis, ankylosing spondylitis, rheumatic fever, rheumatic heart disease, Lyme disease, antiphospholipid antibodies, antiphospholipid syndrome, infectious diseases. Competing interests: none declared. ABSTRACT Autoimmune rheumatic diseases are generally considered as a multifactorial aetiology, mainly genetic susceptibility combined with environmental triggers of which bacteria are considered one of the most prominent. Among the rheu- matic diseases where bacterial agents are more clearly involved as triggers are: reactive arthritis (ReA), rheumatic fever (RF) and Lyme disease. The role of bacterial infections in inducing oth- er seronegative spondyloarthritis and antiphospholipid antibody syndrome has been hypothesized but is still not proven. The classic form of ReA is as- sociated with the presence of HLA-B27 and is triggered by the urethritis or enteritis causing pathogens Chlamy- dia trachomatis and the enterobacteria Salmonella, Shigella, and Yersinia, respectively. But several other patho- gens such as Brucella, Leptospira, Mycobacteria, Neisseria, Staphylococ- cus and Streptococcus have also been reported to cause ReA. RF is due to an autoimmune reaction triggered by an untreated throat infection by Strepto- coccus pyogenes in susceptible indi- viduals. Carditis is the most serious manifestation of RF and HLA-DR7 is predominantly observed in the develop- ment of valvular lesions. Lyme disease is a tick-transmitted disease caused by the spirochete Borrelia burgdorferi. Knowledge is limited about how this spirochete interacts with human tissues and cells. Some data report that Borre- lia burgdorferi can manipulate resident cells towards a pro- but also anti-in- flammatory reaction and persist over a long period of time inside the human body or even inside human cells. Introduction Until the second half of the 20th cen- tury, infectious diseases, especially of bacterial etiology, were the first cause of mortality in the world population. The discovery of antimicrobial drugs changed this state, but a lower lethality has not led to a lower morbidity, in fact some bacterial infections have been shown to cause a number of rheumatic and non-rheumatic diseases which were previously considered of unknown ori- gin. A possible mechanism to explain how a pathogen may induce these dis- eases could be molecular mimicry (1) in which host immune responses are inadvertently directed against endog- enous host tissues by virtue of anti- genic cross-reactivity between host and microbial determinants (2, 3). An- other possible explanation is that the persistence of bacterial agents could give a long-lasting over-stimulation of the immune system characterized by a robust production of cytokines and consequently tissue damage. Also, during normal immune response, the presence of particular polymorphisms of immune related genes (i.e., human leukocyte antigens, cytokines) could produce an abnormal reaction towards autologous tissues (4). In this review, we discuss some rheumatic diseases in which bacteria are considered the most prominent triggers. Reactive arthritis The current definition of reactive ar- thritis (ReA) was introduced in 1969 by Ahvonen (5) referring to a joint inflammation which is triggered by a preceding bacterial infection of an ex- trarticular site, most commonly urethri- tis, enteritis, and respiratory infections. As opposed to septic arthritis, ReA is sterile and thus the causative microbial agent can not be cultured from the syn- ovial compartment of the joint. There are several predisposing factors in ReA of which the best studied one is HLA- B27; in fact, 30-80% of ReA patients carry this antigen and they are more likely to experience a chronic course or an axial manifestation. Some stud- ies suggest correlations with sequence variants of the interleukin-10 gene. The