scholarly journals Defective Efferocytosis in a Murine Model of Sjögren’s Syndrome Is Mediated by Dysfunctional Mer Tyrosine Kinase Receptor

2021 ◽  
Vol 22 (18) ◽  
pp. 9711
Author(s):  
Richard Witas ◽  
Astrid Rasmussen ◽  
Robert H. Scofield ◽  
Lida Radfar ◽  
Donald U. Stone ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Protective Role ◽  
Sjogren's Syndrome ◽  
Tyrosine Kinase Receptor ◽  
Apoptotic Cells ◽  
Sjögren‘S Syndrome

Sjögren’s syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands in which the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here, we investigated the role of Mer signaling in SjS. Mer knockout (MerKO) mice were examined for SjS disease criteria. SjS-susceptible (SjSS) C57BL/6.NOD-Aec1Aec2 mice were assessed for defective Mer signaling outcomes, soluble Mer (sMer) levels, A disintegrin and metalloprotease 17 (ADAM17) activity, and Rac1 activation. In addition, SjS patient plasma samples were evaluated for sMer levels via ELISA, and sMer levels were correlated to disease manifestations. MerKO mice developed submandibular gland (SMG) lymphocytic infiltrates, SMG apoptotic cells, anti-nuclear autoantibodies (ANA), and reduced saliva flow. Mer signaling outcomes were observed to be diminished in SjSS mice, as evidenced by reduced Rac1 activation in SjSS mice macrophages in response to apoptotic cells and impaired efferocytosis. Increased sMer was also detected in SjSS mouse sera, coinciding with higher ADAM17 activity, the enzyme responsible for cleavage and inactivation of Mer. sMer levels were elevated in patient plasma and positively correlated with focus scores, ocular staining scores, rheumatoid factors, and anti-Ro60 levels. Our data indicate that Mer plays a protective role in SjS, similar to other autoimmune diseases. Furthermore, we suggest a series of events where enhanced ADAM17 activity increases Mer inactivation and depresses Mer signaling, thus removing protection against the loss of self-tolerance and the onset of autoimmune disease in SjSS mice.

scholarly journals Sjogren’s Syndrome and TAM Receptors: A Possible Contribution to Disease Onset

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Richard Witas ◽  
Ammon B. Peck ◽  
Julian L. Ambrus ◽  
Cuong Q. Nguyen
Keyword(s):  
Autoimmune Disease ◽  
Sjögren’S Syndrome ◽  
Lupus Erythematosus ◽  
Sjögren's Syndrome ◽  
Disease Onset ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Type I ◽  
Apoptotic Cells ◽  
Sjögren‘S Syndrome

Sjogren’s syndrome (SS) is a chronic, progressive autoimmune disease featuring both organ-specific and systemic manifestations, the most frequent being dry mouth and dry eyes resulting from lymphocytic infiltration into the salivary and lacrimal glands. Like the related autoimmune disease systemic lupus erythematosus (SLE), SS patients and mouse models display accumulation of apoptotic cells and a Type I interferon (IFN) signature. Receptor tyrosine kinases (RTKs) of the Tyro3, Axl, and Mer (TAM) family are present on the surface of macrophages and dendritic cells and participate in phagocytosis of apoptotic cells (efferocytosis) and inhibition of Type I IFN signaling. This review examines the relationship between TAM receptor dysfunction and SS and explores the potential contributions of TAM defects on macrophages to SS development.

scholarly journals TLR7 Signaling Drives the Development of Sjögren’s Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Yawen Wang ◽  
Annie Roussel-Queval ◽  
Lionel Chasson ◽  
Noël Hanna Kazazian ◽  
Laetitia Marcadet ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Autoimmune Disease ◽  
Salivary Glands ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Autoantibody Production ◽  
Deficient Mice ◽  
Sjögren‘S Syndrome

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.

scholarly journals Advances in Mast Cell Activation by IL-1 and IL-33 in Sjögren’s Syndrome: Promising Inhibitory Effect of IL-37

2020 ◽  
Vol 21 (12) ◽  
pp. 4297 ◽  
Author(s):  
Pio Conti ◽  
Luisa Stellin ◽  
Alesssandro Caraffa ◽  
Carla E. Gallenga ◽  
Rhiannon Ross ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Current Knowledge ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Biologically Active ◽  
Mast Cell Activation ◽  
Mediators Of Inflammation ◽  
Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune inflammatory disease that affects primarily older women and is characterized by irreversible damage of the exocrine glands, including tear (xerophthalmia) and salivary glands (xerostomia). Secretory glands lose their functionality due to the infiltration of immune cells, which produce cytokines and cause inflammation. Primary SS is characterized by dry syndrome with or without systemic commitment in the absence of other pathologies. Secondary SS is accompanied by other autoimmune diseases with high activation of B lymphocytes and the production of autoantibodies, including the rheumatoid factor. Other cells, such as CD4+ T cells and mast cells (MCs), participate in SS inflammation. MCs are ubiquitous, but are primarily located close to blood vessels and nerves and can be activated early in autoimmune diseases to express a wide variety of cytokines and chemokines. In the SS acute phase, MCs react by generating chemical mediators of inflammation, tumor necrosis factor (TNF), and other pro-inflammatory cytokines such as interleukin (IL)-1 and IL-33. IL-33 is the specific ligand for ST2 capable of inducing some adaptive immunity TH2 cytokines but also has pro-inflammatory properties. IL-33 causes impressive pathological changes and inflammatory cell infiltration. IL-1 family members can have paracrine and autocrine effects by exacerbating autoimmune inflammation. IL-37 is an IL-1 family cytokine that binds IL-18Rα receptor and/or Toll-like Receptor (TLR)4, exerting an anti-inflammatory action. IL-37 is a natural inhibitor of innate and acquired immunity, and the level is abnormal in patients with autoimmune disorders. After TLR ligand activation, IL-37 mRNA is generated in the cytoplasm, with the production of pro-IL-37 and later mature IL-37 caspase-1 mediated; both precursor and mature IL-37 are biologically active. Here, we discuss, for the first time, the current knowledge of IL-37 in autoimmune disease SS and propose a new therapeutic role.

scholarly journals Targeting the Splicing of mRNA in Autoimmune Diseases: BAFF Inhibition in Sjögren's Syndrome as a Proof of Concept

2014 ◽  
Vol 22 (4) ◽  
pp. 821-827 ◽  
Author(s):  
N. Roescher ◽  
J.L. Vosters ◽  
G. Alsaleh ◽  
P. Dreyfus ◽  
S. Jacques ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Proof Of Concept ◽  
Sjögren‘S Syndrome
Sign in / Sign up

Export Citation Format

Share Document