Interferon‐gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast‐like synoviocytes into immune effector cells

Abstract

Lyme arthritis (LA), a late disease manifestation of Borrelia burgdorferi infection, usually resolves with antibiotic therapy. However, some patients develop proliferative synovitis lasting months to several years after spirochetal killing, called postinfectious LA. In this study, we phenotyped haematopoietic and stromal cell populations in the synovial lesion ex vivo and used these findings to generate an in vitro model of LA using patient‐derived fibroblast‐like synoviocytes (FLS). Ex vivo analysis of synovial tissue revealed high abundance of IFNγ‐producing T cells and NK cells. Similar to marked IFNγ responses in tissue, postinfectious LA synovial fluid also had high levels of IFNγ. HLA‐DR‐positive FLS were present throughout the synovial lesion, particularly in areas of inflammation. FLS stimulated in vitro with B. burgdorferi, which were similar to conditions during infection, expressed 68 genes associated primarily with innate immune activation and neutrophil recruitment. In contrast, FLS stimulated with IFNγ, which were similar to conditions in the postinfectious phase, expressed >2,000 genes associated with pathogen sensing, inflammation, and MHC Class II antigen presentation, similar to the expression profile in postinfectious synovial tissue. Furthermore, costimulation of FLS with B. burgdorferi and IFNγ induced greater expression of IL‐6 and other innate immune response proteins and genes than with IFNγ stimulation alone. These results suggest that B. burgdorferi infection, in combination with IFNγ, initiates the differentiation of FLS into a highly inflammatory phenotype. We hypothesise that overexpression of IFNγ by lymphocytes within synovia perpetuates these responses in the postinfectious period, causing proliferative synovitis and stalling appropriate repair of damaged tissue.

Borrelia burgdorferipeptidoglycan is a persistent antigen in patients with Lyme arthritis

“…Although autoimmunity has been implicated in the pathogenesis of LA (9–13, 57), genetic and transcriptomic evidence suggests that variability in innate immune responses during and after B. burgdorferi infection is also an important disease determinant. Notably, transcripts encoding PG-cleaving protein lysozyme and PG-sensing protein NOD2 are elevated in synovial tissues of postinfectious LA patients months to several years after antibiotic therapy (58, 59). Therefore, immune responses to PG Bb and autoantigens may contribute to pathology, even after the infection itself has been cleared.…”

Granzyme A in Chikungunya and Other Arboviral Infections

“…Although NK cells have well-established anti-viral activity (65), mGzmA does not appear to mediate significant anti-viral activity against CHIKV (38). Nevertheless, NK cells have been implicated in inflammatory immunopathology in several settings (87)(88)(89), including CHIKV arthropathy (48) where mouse models suggest they may promote oedema (42). A pro-inflammatory role for NK-derived mGzmA has also been implicated in bacterial sepsis (90), with viral sepsis a rare but potentially fatal complication of acute CHIKV infection in humans (91).…”

Innate Immune Memory to Repeated Borrelia burgdorferi Exposure Correlates with Murine In Vivo Inflammatory Phenotypes

“…Human FLS have also been shown to express cytokines, chemokines, and proteases in response to B. burgdorferi (29)(30)(31). Moreover, the bacteria in combination with IFN-g present in arthritic joints have been shown to initiate the differentiation of human FLS into a highly inflammatory phenotype, notably through the upregulation of a large number of genes associated with Ag presentation (16).…”

“…Repeated IFN-b exposure has been shown to induce trained immunity in embryonic fibroblasts through histone methylation (47). In vitro, human FLS become highly inflammatory in response to IFNg, a critical cytokine for synovial lesion development in human and murine hosts (16,48). These events could train the cells upon re-exposure with the bacteria.…”

“…Synovial fibroblasts, also called fibroblast-like synoviocytes (FLS) are a major cell type present in the joint. They are involved in the inflammation observed in B. burgdorferi-infected mice as well as in human arthritis (14)(15)(16). FLS develop a persistent inflammatory phenotype through trained immunity following repeated exposures to inflammatory cytokines (17).…”