Περίληψη:
Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease that affects predominately salivary and lacrimal glands. SS can occur alone or in combination with another autoimmune disease like systemic lupus erythematosus (SLE). Here we report that TLR7 signaling drives the development of SS since TLR8-deficient (TLR8ko) mice that develop lupus due to increased TLR7 signaling by dendritic cells, also develop an age-dependent secondary pathology similar to associated SS. The SS phenotype in TLR8ko mice is manifested by sialadenitis, increased anti-SSA and anti-SSB autoantibody production, immune complex deposition and increased cytokine production in salivary glands, as well as lung inflammation. Moreover, ectopic lymphoid structures characterized by B/T aggregates, formation of high endothelial venules and the presence of dendritic cells are formed in the salivary glands of TLR8ko mice. Interestingly, all these phenotypes are abrogated in double TLR7/8-deficient mice, suggesting that the SS phenotype in TLR8-deficient mice is TLR7-dependent. In addition, evaluation of TLR7 and inflammatory markers in the salivary glands of primary SS patients revealed significantly increased TLR7 expression levels compared to healthy individuals, that were positively correlated to TNF, LT-α, CXCL13 and CXCR5 expression. These findings establish an important role of TLR7 signaling for local and systemic SS disease manifestations, and inhibition of such will likely have therapeutic value. © Copyright © 2021 Wang, Roussel-Queval, Chasson, Hanna Kazazian, Marcadet, Nezos, Sieweke, Mavragani and Alexopoulou.
Συγγραφείς:
Wang, Y.
Roussel-Queval, A.
Chasson, L.
Hanna Kazazian, N.
Marcadet, L.
Nezos, A.
Sieweke, M.H.
Mavragani, C.
Alexopoulou, L.
Λέξεις-κλειδιά:
autoantibody; chemokine receptor CXCR5; CXCL13 chemokine; cytokine; messenger RNA; polyclonal antibody; RNA antibody; toll like receptor 7; toll like receptor 8; tumor necrosis factor; chemokine; cytokine; toll like receptor 7, adult; animal cell; animal experiment; animal model; animal tissue; Article; B lymphocyte; clinical article; controlled study; cytokine production; endothelium; female; histology; histopathology; human; human tissue; immune complex deposition; immunofluorescence; immunohistochemistry; innate immunity; knockout mouse; male; microscopy; minor saliva gland; mouse; nonhuman; phenotype; pneumonia; protein expression; protein function; real time polymerase chain reaction; RNA isolation; salivary gland biopsy; serology; signal transduction; Sjoegren syndrome; systemic lupus erythematosus; T lymphocyte; tertiary lymphoid structure; X chromosome; aged; animal; C57BL mouse; genetics; immunology; middle aged; physiology; pneumonia; signal transduction; Sjoegren syndrome, Adult; Aged; Animals; Chemokines; Cytokines; Female; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Pneumonia; Signal Transduction; Sjogren's Syndrome; Toll-Like Receptor 7
