Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Antibiotic-refractory Lyme arthritis (LA) is characterized by marked proliferative synovitis that persists for months-to-years after oral and IV antibiotic therapy for Borrelia burgdorferi. Although the infection serves as the initial trigger for LA, the processes that that shape the post-antibiotic phase of refractory LA are incompletely understood. Herein we assessed the role of fibroblast-like synoviocytes (FLS), the predominant cell type in synovial lesion, in modulating the responses to infection with highly virulent B. burgdorferi RST1 strain and the prototypical Th1 effector cytokine, IFNγ; the key microbial and immune factors in antibiotic-refractory LA.
Methods: FLS were derived from synovia of antibiotic-refractory LA patients undergoing arthroscopic synovectomies. Low passage FLS were stimulated with B. burgdorferi, IFNγ, or a combination for 16h. After stimulation, genome-wide transcriptome profiles were assessed using RNASeq and protein levels of inflammatory mediators were measured using Luminex.
FLS sense and respond to B. burgdorferi by upregulating the expression of 68 genes associated primarily with pathogen sensing and innate immune responses, such as TLR2, NOD2, IL-1β, and IL-6. In contrast, stimulation with IFNγ leads to marked upregulation >2000 genes involved in pathways associated with immune dysregulation, cancer, and autoimmunity. These responses were amplified in FLS costimulated with B. burgdorferi and IFNγ which acted in synergistic fashion to induce a unique signature of differentially expressed genes that most closely resembled the transcriptome profiles in patients’ synovial tissue, including high upregulation of antigen-presenting molecules (HLA-DR, CIITA, CD40, and PD-L1; P<1×10-12). Moreover, cytokine and chemokine protein profiles secreted by FLS in response to costimulation, mimicked those in synovial fluid and tissue from patients with antibiotic-refractory LA, linking FLS to excessive inflammation in the joint.
FLS play an important role in arthritis pathogenesis by initially shaping the immune responses to B. burgdorferi infection, and later by perpetuating dysregulated inflammatory responses in patients with antibiotic-refractory LA by responding to inflammatory milieu in the joint. The highly-activated state of FLS, including antigen-presentation, suggests an immune effector function of these cells even in the post-infectious period. These findings help explain how the initial host-pathogen interactions such as infection with an RST1 strain in patients with a TLR1-1805GG SNP, which lead to excessive IFNγ responses, may contribute to synovial hypertrophy and dysregulated immunity in the post-antibiotic period when few if any intact spirochetes remain.
To cite this abstract in AMA style:Strle K, Lochhead R, Sadreyev R, Steere AC, Aversa J. Fibroblast-like Synoviocytes As Immune Effectors in the Pathogenesis of Synovial Lesion in Antibiotic-Refractory Lyme Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/fibroblast-like-synoviocytes-as-immune-effectors-in-the-pathogenesis-of-synovial-lesion-in-antibiotic-refractory-lyme-arthritis/. Accessed August 14, 2020.
« Back to 2018 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/fibroblast-like-synoviocytes-as-immune-effectors-in-the-pathogenesis-of-synovial-lesion-in-antibiotic-refractory-lyme-arthritis/