Background/Purpose: Sjögren’s Syndrome (SS) bears the highest risk for lymphoma development among all autoimmune diseases. A growing body of evidence suggests activation of NFκB pathways as a critical step in the pathogenesis of both SS and B-cell non Hodgkin’s lymphomas (NHL), the major type of SS-related lymphomas. The mutation His159Tyr of the BAFF receptor has been found to confer increased risk in patients with NHL through activation of the NF-kB pathway. The aim of the current study was to evaluate the contribution of NFκB pathways activation in SS related lymphomagenesis and explore the potential role of the His159Tyr BAFF-R mutation.

Methods: Quantitative gene expression of both NFκΒ1 and NFκΒ2 transcripts was measured by real-time PCR in peripheral blood (PB) derived from 31 SS, 13 SS-lymphoma and 30 healthy controls (HC), in isolated B cells from 2 SS, 6 SS-lymphoma and 5 HC as well as in minor salivary gland tissues (MSG) tissues from 31 SS, 10 SS-lymphoma and 17 sicca controls (SC). The BAFF-R His159Tyr mutation was evaluated in 247 SS patients (177 non lymphoma and 70 SS-lymphoma patients), 145 systemic lupus erythematosus (SLE) patients, 101 rheumatoid arthritis (RA) patients and 180 healthy controls (HC), by PCR-RFLP and PCR-sequencing.

Results:

NFκΒ2 transcripts were significantly upregulated in the PB, MSG tissues and isolated B cells derived from SS patients complicated by lymphoma compared to HC in PB and B-cells, and to both SS-non lymphoma patients and SC in MSG tissues. At PB level, an opposite pattern was observed in regard to NFκΒ1 transcripts; they were found to be significantly reduced in SS patients complicated by lymphoma compared to the HC group. As a result, NFκΒ2/NFκΒ1 ratio was significantly increased in the peripheral blood from SS patients complicated by lymphoma compared to both SS and SC with an area under the receiver operating characteristic (ROC) curve of the NFκΒ2/ NFκΒ1 being 0.804, p=0.002, 95%CI (0.670-0.938). In regard to His159Tyr BAFF-R mutation, we observed an increased prevalence in SS patients compared to HC [17 out of 247 (6.9%) vs 3 out of 180 (1.7%), p=0.01)]. No such statistically significant difference was found among SS, SLE and RA groups, (6.9% vs 3.5% and 3% respectively, p-values>0.05 in all comparisons). Both SS subgroups exhibited significantly higher frequencies of the His159Tyr BAFF-R mutation compared to HC (SS-lymphoma: 8.6% and SS-non lymphoma: 6.2% vs 1.7% in HC). When we stratified the SS-lymphoma subgroup according to the lymphoma subtype and the age of SS onset, the His159Tyr BAFF-R mutation was detected in 71.4% of patients with mucosa associated lymphoid tissue (MALT) NHL and an age of SS onset between 31-40 years old, conferring an 147.5 fold increased risk compared to HC [(95% CI): (20.0-1087.5, p<0.0001)]. 

Conclusion: Taken together, our data suggest activation of alternative NFKB pathways as a central pathogenetic event in the malignant transformation in the setting of SS, with mutation of the BAFF-R receptor being a main contributor particularly in MALT patients with a SS onset at the fourth decade of life, though other concomitantly operating mechanisms cannot be excluded.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/activation-of-nfk%ce%b2-pathways-in-sjogrens-syndrome-related-lymphomagenesis-role-of-the-his159tyr-mutation-of-the-baff-r-receptor/