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.

Predicting the risk for lymphoma development in Sjogren syndrome

“…It is of interest that these adverse predictors are present early, as soon as the diagnosis of SS is made, implying that a distinct genetic background might determine low and high risk SS subtypes. In support of this hypothesis, genetic alterations related to B cell activation, such as variants of B-cell activating factor, a survival factor for B lymphocytes, [14] tumor necrosis factor alpha-induced protein 3, a gatekeeper of NFKB activation, [15] and the His159Tyr of the B-cell activating factor receptor previously shown to enhance alternate NFKB signaling [46,47] and immunoglobulin production, [46] are implicated in the pathogenesis of SS MALT lymphoma. [47] Other molecules associated with B lymphocytes proliferation and organization in lymphoid tissues, such as Fms-like tyrosine kinase 3 ligand [48] and chemokine C-X-C motif ligand 13, [49] have also been proposed as serum biomarkers of lymphoma in the setting of SS.…”

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis

“…Although the underlying mechanisms leading to lymphomagenesis remain unclear, we postulate that the reduced levels of the antiproliferative IFNα in a context of IFNγ-related chronic inflammation could be a major driver of malignant transformation in the setting of SS. On the other hand, it has been been suggested that activation of NFkB signaling pathways -recently shown to be activated in SS- [10], leads to decreased IFNα levels through proteasomal degradation of Interleukin-1 receptor-associated kinase 1 (IRAK1) impairing phosphorylation of the interferon regulatory factor 7 (IRF7), an essential transcription factor for IFNα production [57]. …”

“…Clinical, serological and histopathological features such as purpura, salivary gland enlargement, C4 hypocomplementemia, germinal center formation and the presence of interleukin-18 (IL-18) producing macrophages in minor salivary gland (MSG) tissues have been previously associated with lymphoma development in the setting of SS [3-5]. Additionally, mutations of the p53 gene, the presence of the t(14:18) translocations, genetic variants of the B cell activating factor (BAFF) and its receptor, as well as the tumor necrosis factor alpha-induced protein 3 (TNFAIP3) gene have been considered to confer increased risk for lymphoma development [6-10]. …”

Predicting lymphoma development in patients with Sjögren’s syndrome

“…Genetic abnormalities, oncogenetic events, the involvement of NF-kB pathway, of cytokines, growth factors and chemokines [8,44,47,[71][72][73][74][75][76][77][78][79][80][81][82][83][84][85] and the ongoing expansion in tissue lesions of the same B-cell clone [33], are also linked to the increased risk of lymphoma development or to multistep lymphomagenesis in pSS (reviewed in [86] and in [26]). They include B cell activating factor (BAFF) and Tumor necrosis factor alpha induced protein 3 (TNFAIP3) variants, BAFF receptor His159Tyr mutation, chromosomal translocations and oncogene deregulation, increased serum levels of Fms-related tyrosine kinase 3 ligand (Flt3-L), of C-X-C motif ligand 13 (CXCL13), and high Interferon (IFN) γ/IFNα ratio in minor SG biopsy.…”