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CD28 Deficiency Exacerbates Joint Inflammation upon Borrelia burgdorferi Infection, Resulting in the Development of Chronic Lyme Arthritis¹

Bettina P. Iliopoulou^*, Joseph Alroy and Brigitte T. Huber^2,*

^* Department of Pathology, and Department of Pathology-Veterinary Medicine and Tufts-New England Medical Center, Tufts University School of Medicine, Boston, MA 02111

Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi (Bb), is a multisystem illness, affecting many organs, such as the heart, the nervous system, and the joints. Months after Bb infection, 60% of patients experience intermittent arthritic attacks, a condition that in some individuals progresses to chronic joint inflammation. Although mice develop acute arthritis in response to Bb infection, the joint inflammation clears after 2 wk, despite continuous infection, only very rarely presenting with chronic Lyme arthritis. Thus, the lack of an animal system has so far prevented the elucidation of this persistent inflammatory process that occurs in humans. In this study, we report that the majority of Bb-infected CD28^–/– mice develop chronic Lyme arthritis. Consistent with observations in chronic Lyme arthritis patients, the infected mutant, but not wild-type mice present recurring monoarticular arthritis over an extended time period, as well as anti-outer surface protein A of Bb serum titers. Furthermore, we demonstrate that anti-outer surface protein A Abs develop in these mice only after establishment of chronic Lyme arthritis. Thus, the Bb-infected CD28^–/– mice provide a murine model for studying chronic Lyme arthritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AR45386, Global and Regional Asperger Syndrome Project Center National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grant DK34924, and the Eshe Fund.

² Address correspondence and reprint requests to Dr. Brigitte T. Huber, Department of Pathology, Tufts University School of Medicine, Jaharis 512, 150 Harrison Avenue, Boston, MA 02111. E-mail address: brigitte.huber{at}tufts.edu

³ Abbreviations used in this paper: Bb, Borrelia burgdorferi; OspA, outer surface protein A; Treg, regulatory T cells; wt, wild type; TRLA, treatment-resistant Lyme arthritis; AUC, area under the curve.