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Infection in Mice Borrelia garinii Contributes to the Pathogenesis of Persistent Disordered Lymphoid Purine Metabolism

ExtracellularATPandadenosineareimportantregulatorsofimmuneresponses;however,contributionofpurinergicsignalingtohost defense during persistent microbial infections remains obscure. Lyme borreliosis is a common arthropod-borne infection caused by Borrelia burgdorferi sensu lato. In this study, we investigated whether lymphoid purinergic signaling contributes to the mechanisms by which borreliae species evade the immune system and trigger joint inﬂammation. Intracutaneous inoculation of Borrelia garinii to C3H/He mice induced symptomatic infection manifested in elevated levels of borrelia-speciﬁc IgG Abs, persistent spirochete dissemination into the tissues and joint swelling, as well as ∼ 2- to 2.5-fold enlargement of draining lymph nodes with hyperplasia of B cell follicle area and L-selectin shedding from activated T lymphocytes. Purine catabolism was also activated in lymph nodes but not spleen and blood of infected C3H/He mice within the ﬁrst 4 postinfection weeks, particularly manifested in transient upregulations of adenosine triphosphatase/ectonucleoside triphosphate diphosphohydrolase and ecto-5 9 -nucleotidase/CD73 on CD4 + CD8 + T lymphocytes and adenosine deaminase activity on B220 + B lymphocytes. Compared with borrelia-susceptible C3H/He strain, lymphocytes from C57BL/6 mice displayed markedly enhanced adenosine-generating capability due to approximately three times higher ratio of ecto-5 9 -nucleotidase to adenosine deaminase. Borrelia -infected C57BL/6 mice efﬁciently eradicated the inoculated spirochetes at more chronic stage without any signs of arthritis. Strikingly, deletion of key adenosine-generating enzyme, ecto-5 9 -nucleotidase/CD73, was accompanied by signiﬁcantly enhanced joint swelling in borrelia-infected CD73-deﬁcient C57BL/6 mice. Collectively, these data suggest that insufﬁcient basal adenosine level and/or pathogen-induced disordered lymphoid purine homeostasis may serve as important prerequisite for promotion of inﬂammatory responses and further host’s commitment to persis-tence of bacterial infection and arthritis development. The Journal of Immunology , 2010, 184: 5112–5120. reduced the leukocyte accumulation and TNF- a concentration and simulta-neously increased adenosine concentration in the air-pouch exu-dates of wild-type but not A 2A and A 3 receptor knockout (38) or CD73-deﬁcient (39) mice. Data on signiﬁcantly elevated ADA activity in the synovial ﬂuid but not in serum of rheumatoid arthritis patients (40) also lend credence to the role of adenosine in pathogenesis of joint inﬂammation. We believe that our study gains another novel insight into these concepts by demonstrating the important role of adenosine signaling as a link between the infection and immunity.