Arthritis & rheumatology (Hoboken, N.J.) · 2015
A BAFF receptor His159Tyr mutation in Sjögren's syndrome-related lymphoproliferation.
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Papageorgiou Aristea, Mavragani Clio P, Nezos Andrianos, Zintzaras Elias, Quartuccio Luca, De Vita Salvatore, Koutsilieris Michael, Tzioufas Athanasios G, Moutsopoulos Haralampos M, Voulgarelis Michael
Аннотация
OBJECTIVE: To study the prevalence, clinical associations, and functional implications of the His159Tyr mutation of the BAFF receptor (BAFF-R) in patients with Sjögren'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-κB1 and NF-κB2 messenger RNA (mRNA) transcript and protein levels in isolated B cells from patients with SS-lymphoma carrying the mutation (SS-lymphoma-BAFF-RHis159Tyr -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-κB at both the mRNA and protein level was up-regulated in SS-lymphoma-BAFF-RHis159Tyr -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-RHis159Tyr -mediated activation of the alternate NF-κB pathway might contribute to the pathogenesis of SS-related lymphoproliferative disease.
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-κB1 and NF-κB2 messenger RNA (mRNA) transcript and protein levels in isolated B cells from patients with SS-lymphoma carrying the mutation (SS-lymphoma-BAFF-RHis159Tyr -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-κB at both the mRNA and protein level was up-regulated in SS-lymphoma-BAFF-RHis159Tyr -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-RHis159Tyr -mediated activation of the alternate NF-κB pathway might contribute to the pathogenesis of SS-related lymphoproliferative disease.
Предметные рубрики MeSH
AdultAgedArthritis, RheumatoidB-Cell Activation Factor ReceptorCase-Control StudiesFemaleGenetic Predisposition to DiseaseHeterozygoteHumansLupus Erythematosus, SystemicLymphoma, B-Cell, Marginal ZoneLymphoproliferative DisordersMaleMiddle AgedMutationNF-kappa BPrevalenceSignal TransductionSjogren's Syndrome