Background/Purpose:

Antibiotic-refractory Lyme arthritis is defined as persistent synovitis for months to years after antibiotic therapy for Borrelia burgdorferi, the causative agent of Lyme disease. Rather than persistent infection, this condition is thought to result from inappropriate activation of inflammatory immune responses which are elicited by the spirochetes and further augmented by host genetics. Fibroblast-like synoviocytes (FLS) are the predominant cell type in hypertrophied synovial tissue, but their responses to B. burgdorferi are not well-defined. Here we assessed the inflammatory responses of FLS to a highly virulent B. burgdorferiRST1 strain and evaluated these responses according to a host TLR1-1805GG polymorphism, a risk factor for antibiotic-refractory Lyme arthritis.

Methods:

FLS were obtained from synovia of antibiotic-refractory Lyme arthritis patients who underwent synovectomies due to incomplete responses to treatment with antibiotics and then DMARDs. Protein levels of 8 matrix metalloproteinases and 21 cytokines and chemokines in B. burgdorferi-stimulated FLS were assessed using Luminex. mRNA expression in synovial biopsies and FLS was assessed using QuantiGene and whole-genome RNASeq analyses.

Results:

FLS sense and respond to B. burgdorferi by producing high levels of matrix metalloproteinases (MMP1, MMP2, MMP3, MMP9, and MMP13) which degrade cartilage and bone. In addition, B. burgdorferi-stimulated FLS produce large amounts of inflammatory mediators associated with both innate (IL-6, IL-8, IL-10, TNF, CCL2), and adaptive Th1-like responses (CXCL9, CXCL10). These responses corroborate in vivo findings in the joint fluid of patients with antibiotic-refractory Lyme arthritis, linking FLS to excessive joint inflammation. Moreover, FLS responded directly to stimulation with IFNγ, the prototypical Th1 effector cytokine, leading to high levels of CXCL9 and CXCL10, which are potent chemoattractants for CD4⁺Th1 cells, the predominant T-effector cell type in joints of patients with refractory arthritis. These responses were amplified in FLS from patients with a TLR1-1805GG polymorphism, which leads to diminished TLR1 expression on the cell surface. Cells with 1805GG had altered SOCS3 mRNA expression suggesting that the greater inflammatory responses in the 1805GG group may be due to a loss of a regulatory pathway. In addition, RNASeq analysis revealed that a deficiency in TLR1 in patients with 1805GG also leads to increased expression of other pathogen-recognition receptors, including TLRs and NODs, which could further contribute to excessive inflammation in patients with 1805GG.

Conclusion:

FLS are an important cell type in the pathogenesis of antibiotic-refractory Lyme arthritis because of their ability to shape and perpetuate innate and adaptive immune responses. These responses are altered in patients with TLR1-1805GG polymorphism, a risk factor for antibiotic-refractory Lyme arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fibroblast-like-synoviocytes-shape-and-perpetuate-the-inflammatory-immune-responses-associated-with-antibiotic-refractory-lyme-arthritis/