High Chlamydia Burden Promotes Tumor Necrosis Factor–Dependent Reactive Arthritis in SKG Mice

Abstract

Objective Chlamydia trachomatis is a sexually transmitted obligate intracellular pathogen that causes inflammatory reactive arthritis, spondylitis, psoriasiform dermatitis, and conjunctivitis in some individuals after genital infection. The immunologic basis for this inflammatory response in susceptible hosts is poorly understood. As ZAP‐70W163C–mutant BALB/c (SKG) mice are susceptible to spondylo‐arthritis after systemic exposure to microbial β‐glucan, we undertook the present study to compare responses to infection with Chlamydia muridarum in SKG mice and BALB/c mice. Methods After genital or respiratory infection with C muridarum, conjunctivitis and arthritis were assessed clinically, and eye, skin, and joint specimens were analyzed histologically. Chlamydial major outer membrane protein antigen–specific responses were assessed in splenocytes. Treg cells were depleted from FoxP3‐DTR BALB/c or SKG mice, and chlamydial DNA was quantified by polymerase chain reaction. Results Five weeks after vaginal infection with live C muridarum, arthritis, spondylitis, and psoriasiform dermatitis developed in female SKG mice, but not in BALB/c mice. Inflammatory bowel disease did not occur in mice of either strain. The severity of inflammatory disease was correlated with C muridarum inoculum size and vaginal burden postinoculation. Treatment with combination antibiotics starting 1 day postinoculation prevented disease. Chlamydial antigen was present in macrophages and spread from the infection site to lymphoid organs and peripheral tissue. In response to chlamydial antigen, production of interferon‐γ and interleukin‐17 was impaired in T cells from SKG mice but tumor necrosis factor (TNF) responses were exaggerated, compared to findings in T cells from BALB/c mice. Unlike previous observations in arthritis triggered by β‐glucan, no autoantibodies developed. Accelerated disease triggered by depletion of Treg cells was TNF dependent. Conclusion In the susceptible SKG strain, Chlamydia‐induced reactive arthritis develops as a result of deficient intracellular pathogen control, with antigen‐specific TNF production upon dissemination of antigen, and TNF‐dependent inflammatory disease.

In VivoandEx VivoImaging Reveals a Long-Lasting Chlamydial Infection in the Mouse Gastrointestinal Tract following Genital Tract Inoculation

“…Although genital tract infection with Chlamydia may result in joint pathologies in both humans (43,44) and mice (45), the association of chlamydial infection with GI tract pathologies is unclear (24)(25)(26). In fact, no inflammatory pathology was detected despite the long-lasting presence of the C. muridarum organisms in the GI tract (16).…”

Epidemiology ofClostridium difficileInfection–Associated Reactive Arthritis in Children

“…The co-occurrence of arthritis with C difficile infection may relate to other genetic, immunologic, and microbiologic factors, as reported with other infectious triggers. 26-28 Interestingly, some children with C difficile -associated arthralgias were neutropenic with their illness, which may have prevented frank arthritis from manifesting. In contrast, those with CDIAReA resembling septic arthritis had robust neutrophilic immune responses in the blood and synovial fluid.…”

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

“…Alternatively, arthritis may be induced in SKG mice by infection with Chlamydia muridarum. This leads to the development of a ReA, spondylitis, and skin lesions . In the model of genital Chlamydia‐induced disease, it is theorized that macrophages at the site of infection take up Chlamydia and transport bacteria to the distant sites such as the joints, and subsequently release IL‐23 .…”