Background/Purpose:  The sterile inflammatory arthritis associated with spondylitis, uveitis and rash, known as reactive arthritis, commences weeks after certain gastrointestinal or genitourinary infections, including Salmonella and Chlamydia in genetically-susceptible patients. Several potential mechanisms are proposed, including auto-immunity by molecular mimicry and persistent inflammation in response to intra-cellular live Chlamydia. ZAP-70^W163C mutant BALB/c mice (known as SKG), which exhibit reduced T cell receptor signaling, an autoreactive CD4+ T cell repertoire, relative lymphopenia and increased regulatory T cells are susceptible to spondyloarthritis after bacterial beta-glucan. Chlamydia muridarum (Cmu) is an obligate intracellular pathogen normally controlled by macrophages.  We studied whether Cmu genital infection triggered reactive arthritis in SKG mice to explore the relationship between host immunity, bacterial clearance and joint inflammation.

Methods: SKG and BALB/c mice were genitally infected with mouse-adapted Cmu (5×10²-10⁶ IFUs). Conjunctivis, lid swelling/thickening and arthritis were assessed weekly for 12 weeks post infection (wpi). Eye, skin and joint sections were scored after sacrifice.  Bacterial load was quantified in genital swabs. Cmu Major Outer Membrane Protein (MOMP) antigen-specific cytokine production was assessed in splenocytes 1 wpi; cytokines were measured in serum, skin and joint explants at 12 wpi. Regulatory T cells (Treg) were depleted from FoxP3-DTR BALB/c or SKG mice. Cmu genomic ompA DNA was quantified by PCR in spleens, iliac lymph nodes and joints. Non parametric tests assessed statistical significance.

Results: SKG but not BALB/c mice developed typical histological features of chronic reactive arthritis, with  and remained autoantibody-negative, from 5 weeks after genital infection. Cmu load in genital tract was significantly increased in SKG relative to BALB/c mice in the first week after infection, associated with impaired Cmu MOMP-antigen-specific T cell interferon (IFN)-gamma and increased TNF response. Arthritis severity was correlated with prior Cmu load and live Cmu infection was required for reactive arthritis, as no disease occurred after bacterial inactivation with UV or antibiotics. While depletion of regulatory T (Treg) cells from Cmu-infected Foxp3.DTR SKG mice prompted rapid bacterial clearance, it also hastened onset of severe arthritis, conjunctivitis and dermatitis, accompanied by increased MOMP-specific IFN-gamma production. Cmu DNA was detected in myeloid cells derived from spleen and lymph nodes draining the genital tract of both strains, confirming their capacity to transport Chlamydial inclusions from the site of infection to other organs.  The proportion of myeloid cells was 2-fold higher in SKG relative to BALB/c mice and this, together with the increased bacterial load, increases the likelihood of systemic delivery of Cmu DNA to peripheral sites.  

Conclusion: Cmu induced reactive arthritis results from an exuberant inflammatory response to a deficient early control of infection and incomplete inflammatory suppression by Treg in the setting of host genetic T cell receptor-ZAP70 signalling deficiency.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impaired-bacterial-clearance-and-an-exuberant-inflammatory-response-promote-chlamydia-induced-reactive-arthritis-in-skg-mice/