Faculty Collaboration Database

Interferon-gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast-like synoviocytes into immune effector cells. Cell Microbiol 2019 Feb;21(2):e12992

Date

12/15/2018

Pubmed ID

30550623

Pubmed Central ID

PMC6336510

DOI

10.1111/cmi.12992

Scopus ID

2-s2.0-85059527799 (requires institutional sign-in at Scopus site)   25 Citations

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.

Author List

Lochhead RB, Ordoñez D, Arvikar SL, Aversa JM, Oh LS, Heyworth B, Sadreyev R, Steere AC, Strle K

Author

Robert Lochhead PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Borrelia burgdorferi
Cell Differentiation
Fibroblasts
Humans
Interferon-gamma
Lyme Disease
Synovial Membrane
Synoviocytes
Synovitis
T-Lymphocytes