9 research outputs found
TLR7 Signaling Drives the Development of Sjögren’s Syndrome
International audienceSjögren’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
A BAFF Receptor His159Tyr Mutation in Sjogren's Syndrome-Related Lymphoproliferation
Objective. To study the prevalence, clinical associations, and
functional implications of the His159Tyr mutation of the BAFF receptor
(BAFF-R) in patients with Sjogren’s syndrome (SS).
Methods. The BAFF-R His159Tyr mutation was evaluated using polymerase
chain reaction (PCR)-based assays in 247 patients with SS (of whom 70
had SS complicated by lymphoma [SS-lymphoma]), 145 with systemic lupus
erythematosus (SLE), and 101 with rheumatoid arthritis (RA), as well as
180 healthy controls. Real-time PCR and Western blotting were performed
for the quantification of both NF-kappa B1 and NF-kappa B2 messenger RNA
(mRNA) transcript and protein levels in isolated B cells from patients
with SS-lymphoma carrying the mutation
(SS-lymphoma-BAFF-R-His159Tyr-derived B cells) compared to B cells from
patients with SS-lymphoma who were not carriers of the mutation and
healthy controls.
Results. Both the SS-lymphoma and SS-nonlymphoma patient subgroups
exhibited significantly higher frequencies of the His159Tyr BAFF-R
mutation compared to healthy controls (8.6% of SS-lymphoma patients and
6.2% of SS-nonlymphoma patients versus 1.7% of healthy controls;
P=0.02 and P=0.04, respectively). The corresponding frequencies of the
His159Tyr BAFF-R mutation in SLE and RA patients were 3.5% and 3%,
respectively. Of interest, 71.4% of the SS patients with
mucosa-associated lymphoid tissue (MALT) lymphoma who were between the
ages of 31 and 40 years at disease onset were mutation carriers. The
generalized odds ratio for the development of SS-related MALT lymphoma
in the younger age at onset (age <40 years) group in the presence of the
BAFF-R mutation was 6.1 (95% confidence interval 2.0-18.7) (P < 0.01).
Expression of NF-kappa B at both the mRNA and protein level was
up-regulated in SS-lymphoma-BAFF-R-His159Tyr-derived B cells.
Conclusion. This study identifies an increased prevalence of the BAFF-R
His159Tyr mutation in patients with SS, particularly in those with SS
complicated by MALT lymphoma whose disease onset occurred at a younger
age. BAFF-R-His159Tyr-mediated activation of the alternate NF-kappa B
pathway might contribute to the pathogenesis of SS-related
lymphoproliferative disease