Role of toll-like receptors in primary Sjögren’s syndrome with a special emphasis on B-cell maturation within exocrine tissues

Guerrier, Thomas; Devauchelle, Valérie; Pers, Jacques‐Olivier; Jamin, Christophe; Youinou, Pierre

doi:10.1016/j.jaut.2012.01.016

Cited by 39 publications

(12 citation statements)

References 75 publications

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“…3,11,12 This is confirmed by our finding that IL-6, IL-17A, and NO evolve together with the amount of cellular infiltration. Given that Toll-like receptor (TLR)-2, 47 TLR-4, 48 and TLR-9 49 have an effect on IL-6 production and B cell maturation, anti-TLRs, 50 competitors of the IL-6 receptor, 51 warrant further attention for the treatment of non-organ-specific autoimmune diseases. In addition, several studies conducted in inflammatory and experimental autoimmune models indicate a beneficial immunomodulatory effect of TLR2/4 inhibitors, such as VGX-1027.…”

Section: Discussionmentioning

confidence: 99%

A case for IL-6, IL-17A, and nitric oxide in the pathophysiology of Sjögren’s syndrome

Benchabane

Boudjelida

Toumi

et al. 2016

Int J Immunopathol Pharmacol

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Sjögren's syndrome (SS) is an autoimmune epithelitis characterized by mononuclear cell (MNC) infiltration of the lacrimal and salivary glands (SG), as well as the presence of serum autoantibodies. This condition is a growing public health concern in Algeria. Herein, we sought to determine if the levels of interleukin (IL)-6, IL-17A, and nitric oxide (NO), were correlated with the extent of MNC infiltration. The expression of inducible NO synthase (NOS2) and CD68 was measured in the SG of all patients, but not in those of the normal controls (NCs). We included 44 primary Sjögren's syndrome (pSS) patients and 15 NCs in this study; we found that the expression of NOS2 and CD68 was elevated in all of the SG of SS patients. Additionally, the serum and saliva levels of IL-6, IL-17A, and NO were higher in the pSS patients, compared with the NCs. Furthermore, the NOS2-induced excess NO was associated with the extent of the MNC infiltration, and thereby with tissue injury. It is also important to note that there were correlations between the levels of IL-6, IL-17A, and NO. Such findings indicate that through the effects of NO, IL-17A participates in the pathophysiology of the disease. With the purpose of improving both the diagnosis and prognosis, IL-6, IL-17A, and NO should be assayed in the serum and saliva of patients suspected of SS.

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Section: Discussionmentioning

confidence: 99%

A case for IL-6, IL-17A, and nitric oxide in the pathophysiology of Sjögren’s syndrome

Benchabane

Boudjelida

Toumi

et al. 2016

Int J Immunopathol Pharmacol

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“…In this respect, we have shown that TLR participate in the development of MZ B lymphocytes from immature BT2 cells (Guerrier et al , ). Also, interesting is our finding of mRNA for TLR9 in clusters of B cells infiltrating the SG of primary SS patients (Guerrier et al , ).…”

Section: B‐lymphocyte Subpopulationsmentioning

confidence: 90%

Are the B cells cast with the leading part in the Sjogren's syndrome scenario?

Pers

Youinou

2013

Oral Diseases

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The autoimmune exocrinopathy Sjögren's syndrome (SS) is characterized by mononuclear cell (MNC) infiltrates of exocrine glands and overactivity of B lymphocytes. Although T cells have long been perceived as the prime effectors, increasing evidence indicates that the key role is rather served by B cells. Among related abnormalities are rheumatoid factor (RF), anti-SSA/Ro, and anti-SSB/La antibodies (Ab). Also, supporting this view is our finding of an increase in the number of circulating naïve mature B (Bm) cells, with a reciprocal decrease in that of memory B cells. Furthermore, a ratio of Bm2-plus-Bm2' cells to early Bm5-plus-late Bm5 above 5 is diagnostic. This variation partly reflects the migration of active memory B cells into the exocrine glands of the patients, as well as into their skin. More recently, the B-cell-activating factor of the TNF family (BAFF) has been endorsed with a pivotal role in B-cell survival and hence implicated in the pathogenesis of autoimmunity. In practice, B cells have turned quite attractive as a target for biotherapy. For example, treatment with anti-CD20 Ab has afforded some benefits in this disease, while BAFF blockers are still on the way, but should expand our armamentarium for treating SS. With such B-cell-directed biotherapies in mind, we delineate herein the distinguishing traits of B lymphocytes in SS.

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“…TLR9 has been suggested to deliver sufficient signaling to keep B cells alive and confer auto-reactive B cells with a marginal zone-like phenotype. As clusters of transitional type II B cells in the salivary glands of SS patients express mRNAs for Notch-2, Blimp-1 and TLR9 but not Pax-5, Bcl-6 and activation-induced cytidine deaminase (AID) (Guerrier, et al, 2012). …”

Section: Sjögren’s Syndrome and Tlrsmentioning

confidence: 99%

Toll-like receptors as therapeutic targets for autoimmune connective tissue diseases

Wang

Zhang

et al. 2013

Pharmacology & Therapeutics

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Autoimmune connective tissue diseases (ACTDs) are a family of consistent systemic autoimmune inflammatory disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc) and Sjögren’s syndrome (SS). Toll-like receptors (TLRs) are located on various cellular membranes and sense exogenous and endogenous danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), playing a critical role in innate immune responses. During the past decade, the investigation of TLRs in inflammation autoimmune diseases has been fruitful. In this report, we review the significant biochemical, physiological and pathological studies of the key functions of TLRs in ACTDs. Several proteins in the TLR signaling pathways (e.g., IKK-2 and MyD88) have been identified as potential therapeutic targets for the treatment of ACTDs. Antibodies, oligodeoxyribonucleotides (ODNs) and small molecular inhibitors (SMIs) have been tested to modulate TLR signaling. Some drug-like SMIs of TLR signaling, such as RDP58, ST2825, ML120B and PHA-408, have demonstrated remarkable potential, with promising safety and efficacy profiles, which should warrant further clinical investigation. Nonetheless, one should bear in mind that all TLRs exert both protective and pathogenic functions; the function of TLR4 in inflammatory bowel disease represents such an example. Therefore, an important aspect of TLR modulator development involves the identification of a balance between the suppression of disease-inducing inflammation, while retaining the beneficiary host immune response.

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Role of toll-like receptors in primary Sjögren’s syndrome with a special emphasis on B-cell maturation within exocrine tissues

Cited by 39 publications

References 75 publications

A case for IL-6, IL-17A, and nitric oxide in the pathophysiology of Sjögren’s syndrome

A case for IL-6, IL-17A, and nitric oxide in the pathophysiology of Sjögren’s syndrome

Are the B cells cast with the leading part in the Sjogren's syndrome scenario?

Toll-like receptors as therapeutic targets for autoimmune connective tissue diseases

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