title: A BAFF receptor His159Tyr mutation in Sjögren's syndrome-related lymphoproliferation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Aristea
authors.initials: A
authors.lastname: Papageorgiou
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Clio P
authors.initials: CP
authors.lastname: Mavragani
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Andrianos
authors.initials: A
authors.lastname: Nezos
authors.affiliation: University of Thessaly School of Medicine, Larissa, Greece, and The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, and Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Elias
authors.initials: E
authors.lastname: Zintzaras
authors.affiliation: University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Quartuccio
authors.affiliation: University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: De Vita
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Michael
authors.initials: M
authors.lastname: Koutsilieris
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Athanasios G
authors.initials: AG
authors.lastname: Tzioufas
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Haralampos M
authors.initials: HM
authors.lastname: Moutsopoulos
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Michael
authors.initials: M
authors.lastname: Voulgarelis
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics; D053265:B-Cell Activation Factor Receptor / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology / Q000235:genetics; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000502:physiology; D015995:Prevalence; D015398:Signal Transduction / Q000502:physiology; D012859:Sjogren's Syndrome / Q000150:complications* / Q000453:epidemiology / Q000235:genetics*
chemical_list: D053265:B-Cell Activation Factor Receptor; D016328:NF-kappa B