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.

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.

• Authors: Aristea Papageorgiou, Clio P Mavragani, Andrianos Nezos, Elias Zintzaras, Luca Quartuccio, Salvatore De Vita, Michael Koutsilieris, Athanasios G Tzioufas, Haralampos M Moutsopoulos, Michael Voulgarelis
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 67 Issue 10 Pg. 2732-41 (Oct 2015) ISSN: 2326-5205 [Electronic] United States
• PMID: 26097183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015, American College of Rheumatology.

Chemical References

• B-Cell Activation Factor Receptor
• NF-kappa B

Topics

• Adult
• Aged
• Arthritis, Rheumatoid (epidemiology, genetics)
• B-Cell Activation Factor Receptor (genetics)
• Case-Control Studies
• Female
• Genetic Predisposition to Disease (genetics)
• Heterozygote
• Humans
• Lupus Erythematosus, Systemic (epidemiology, genetics)
• Lymphoma, B-Cell, Marginal Zone (genetics)
• Lymphoproliferative Disorders (epidemiology, etiology, genetics)
• Male
• Middle Aged
• Mutation (genetics)
• NF-kappa B (physiology)
• Prevalence
• Signal Transduction (physiology)
• Sjogren's Syndrome (complications, epidemiology, genetics)