Background/Purpose:

Multiple B cell aberrances have been linked to primary Sjögren’s syndrome (pSS), including autoantibody production and a skewed B cell differentiation. Further, approximately 50% of all patients with pSS display hypergammaglobulinemia.

Chloroquine-derived antimalarial drugs, commonly used in treatment of pSS, are thought to mediate their therapeutic effect by inhibiting the endosome, and thereby affecting TLR7 and 9 signaling. However, so far little is known about why chloroquines have a beneficial effect.

Methods:

Freshly prepared PBMCs from untreated and chloroquine-treated pSS patients and healthy controls were sorted by flow cytometry. Naïve IgD+ B cells were cultured eight days with class-switch inducing agents; anti-CD40, BAFF, Imiquimod (TLR7) and CpG (TLR9), all supplemented with IL-10. Culture supernatants were analyzed for IgM and IgG concentrations and cells were phenotyped by flow cytometry. Microarray-based mRNA expression analysis was performed on PBMC from untreated pSS patients and controls.

Results:

Upon induction of class-switch, B cells will secrete IgM and subsequently IgG and some will develop further into plasma cells expressing CD138.

When stimulating with TLR7 and 9 agonists significantly higher titers of IgM and IgG were observed in supernatants of cells from pSS patients compared to controls. Further, a significantly increased proportion of CD138+ plasmablasts were observed in the cultures established from pSS patients compared to controls. No significant differences were observed when stimulating with other class-switch inducing agents (CD40, BAFF). To further support our findings an mRNA expression analysis of unmanipulated PBMCs from pSS patients (n=14) and controls (n=18) was performed. Key genes in the endosomal TLR pathways, including TLR7 and 9, TNFAIP3 and IRF5, were significantly up regulated in pSS patients. However, the signaling pathways of CD40 and BAFF were unaffected.

Class-switch was also induced in B cells from patients treated with antimalarial drugs. Interestingly, lower levels of IgG and IgM were seen in chloroquine treated patients, compared to untreated pSS patients. In concordance, fewer plasmablasts were detected in the choloroquine-treated patients.

Conclusion:

More than 50% of patients with primary Sjögren’s syndrome display hypergammaglobulinemia. We show here that B cell class switch and IgG production is increased in pSS patients after endosomal TLR triggering, and that this can be inhibited in vivo by treatment with antimalarials. Our data confirm the importance of TLR7 and 9 pathways in driving the disease and clinical phenotype of pSS.

---

« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/hyperammaglobulinemia-in-primary-sjogrens-syndrome-is-induced-by-triggering-of-tlr7-and-9/