Discussion
The critical role of the type I IFN pathway in the pathogenesis of pSS has been widely addressed [30, 31]. Acting as the premier producer of IFN-α, the role of pDC in the pathogenesis of pSS still remains inclusive. In the present study, we have deciphered the redundant role of pDC in the type I signature and disease development in pSS.
Consistent with previous studies, we have detected a peripheral reduction in pSS [20, 26]. We have demonstrated a negative feedback loop, in which, pDC promoted antibody production and in turn, high immunoglobulin could induce pDC apoptosis. It has been reported that IgG-complexed adenoviruses induce the apoptosis of human pDCs [32]. Hyperactivated B cells, characteristic autoantibodies (SSA, SSB), and hypergammaglobulinemia are hallmarks of pSS [33]. Previous studies have found that pDCs could efficiently promote the differentiation of B cells into plasmablasts and plasma cells through type I IFNs and IL-6 [34, 35]. Moreover, pDCs could enhance the autoreactivity of B cells via type I IFNs in a T cell-independent manner [36]. Although our data showed that, pSS-derived pDC did not display a stronger capacity for promoting plasma cell differentiation and antibody production, we gave a good explanation that the excess immunoglobulin (IgG and IgA) produced by hyperactivated B cells might result in the apoptosis and reduction of pDC in peripheral blood of pSS. In addition, Hydroxychloroquine (HCQ) effectively inhibits B cell activation [37] and a recent systematic review revealed that serum IgA in patients with pSS decreased significantly after using HCQ [38], which is consistent with our results that pDC frequency rebounded after HCQ therapy.
Nonetheless, pDC is noted for its unique ability in producing type I IFNs, our data suggest that it might not be the culprit of hyperactive type I IFN signaling in pSS. Recent studies in pSS have emphasized the critical role of dysregulated epithelial cells [29, 39], especially the active IFN signaling in salivary gland epithelial cells (SEGCs) [29]. SEGCs from pSS were found to be sensitive to the stimulation of TLR agonists and produced type I IFNs as a response to the stimulation [27, 28, 40]. Type I IFNs released by SEGCs could further promote the secretion of BAFF in an NF-κB dependent way [12, 27]. These results imply that gland epithelial cells are not purely innocent victims, but can also be the trigger of type I IFN signaling in pSS.
In SSc, pDCs directionally migrated to target organs and secreted IFN-α and CXCL4, thereby accelerated tissue fibrosis [15, 41]. In another autoimmune disease with fibrosis signature, IgG4-related disease, active pDCs and relevant IFN-α signaling were also observed in related pancreas, pDC also enhanced the production of IgG4 by B cells [42]. Dual role of pDCs on IFN-α production and promoting activation of pathogenic T cells in psoriasis has been revealed in psoriasis [43]. Study in RA mouse model suggested that pDC aggravated joint inflammation and bone erosion via TLR7 dependent type I IFNs [17]. Reduction of pDC in the peripheral blood as well as the concomitant infiltration and activation in related tissue were reported in SLE [44, 45]. A recent randomized controlled trial in SLE clarified that Litifilimab (anti-BDCA2 antibody, BDCA2 is an exclusive marker of pDC) is effective in disease remission [46], which indicated the feasibility of pDC purge strategy in SLE treatment. Whereas, newly published research revealed that SLE-derived pDC had senescence and inert phenotype, active keratinocytes should be responsible for the tupe I IFN signaling rather than pDC [26]. In general, pDCs contributed to the pathogenesis of autoimmune diseases through type I IFNs or interplay with other immune cells [47]. However, further studies are needed to elucidate the potential mechanism about pDC’s contribution to SLE and pSS.
Our available evidence does not support an overactive phenotype (resting and activating status) of pDCs from pSS patients, particularly in the production of IFN-α. However, a previous transcriptional study reported that pDCs from patients with pSS secreted more type I IFNs after TLR7 stimulation [21]. Antonios et al. ’s work that pDCs from patients with SLE or pSS did not show stronger secretion ability for inflammatory cytokines, especially IFNα [26], which is consistent with our findings. These divergent results may be caused by the difference of detection methods, further study will help to elucidate underlying mechanism.
In conclusion, we demonstrated the decreased percentage of pDC in pSS patients, which might result from the excess immunoglobulin (IgG and IgA) induced apoptosis. Moreover, we showed that pDC might not be the major contributor to the hyperactivation of type I interferon signaling in pSS patients. Our research provides a good addition to pSS pathogenesis and gives implications that targeting pDC might not be a good strategy for clinical pSS treatment.