Untitled

Abstract

Dendritic cells (DCs) comprise heterogeneous subsets of professional antigen-presenting cells, linking innate and adaptive immunity. Analysis of DC subsets has been hampered by a lack of specific DC markers and reliable quantitation assays. We characterised the immunophenotype and functional characteristics of psoriatic arthritis (PsA)-derived and rheumatoid arthritis (RA)-derived myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) to evaluate their potential role in arthritis. Circulating peripheral blood (PB) pDC numbers were significantly reduced in PsA patients (P = 0.0098) and RA patients (P = 0.0194), and mDCs were significantly reduced in RA patients (P = 0.0086) compared with healthy controls. The number of circulating mDCs in RA PB was significantly inversely correlated to C-reactive protein (P = 0.021). The phenotype of both DC subsets in PsA PB and RA PB was immature as compared with healthy controls. Moreover, CD62L expression was significantly decreased on both mDCs (PsA, P = 0.0122; RA, P = 0.0371) and pDCs (PsA, P = 0.0373; RA, P = 0.0367) in PB. Both mDCs and pDCs were present in PsA synovial fluid (SF) and RA SF, with the mDC:pDC ratio significantly exceeding that in matched PB (PsA SF, P = 0.0453; RA SF, P = 0.0082). pDCs isolated from RA SF and PsA SF displayed an immature phenotype comparable with PB pDCs. RA and PsA SF mDCs, however, displayed a more mature phenotype (increased expression of CD80, CD83 and CD86) compared with PB mDCs. Functional analysis revealed that both SF DC subsets matured following toll-like receptor stimulation. pDCs from PB and SF produced interferon alpha and tumour necrosis factor alpha on TLR9 stimulation, but only SF pDCs produced IL-10. Similarly, mDCs from PB and SF produced similar tumour necrosis factor alpha levels to TLR2 agonism, whereas SF mDCs produced more IL-10 than PB controls. Circulating DC subset numbers are reduced in RA PB and PsA PB with reduced CD62L expression. Maturation is incomplete in the inflamed synovial compartment. Immature DCs in SF may contribute to the perpetuation of inflammation via sampling of the inflamed synovial environment, and in situ presentation of arthritogenic antigen.

Human dendritic cell subsets and function in health and disease

“…Although previously described as ''CD1c ? DC'' in rheumatoid arthritis synovial fluid [147][148][149], transcriptome analyses showed these cells to be most closely related to in vitroderived MoDC and of monocyte origin, and therefore the likely human equivalents of the mouse ''inflammatory'' DC [64]. These data provide evidence to suggest that inflammatory DC may be the main drivers of many autoimmune pathologies and may also contribute to tumor pathogenesis.…”

“…Myeloid DC infiltrate the inflamed tissues of many human autoimmune diseases including the epidermis and dermis of psoriatic lesions, synovial fluids of rheumatoid arthritis patients, and inflamed intestinal tissue in Crohn's disease patients [64,[146][147][148][149][150][151]. They can also be found in the ascitic fluid of patients with breast and ovarian cancers [64].…”

Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis

“…6–9 In RA, pDCs are decreased in circulation, presumably migrating preferentially into inflamed tissues. 10 This finding has also been observed in other diseases in which type I IFN has been implicated in pathogenesis, such as lupus 11–13 and idiopathic inflammatory myositis. 14 Furthermore, previous studies have suggested that baseline type I IFN levels may predict treatment response in RA.…”

Role of Dendritic Cells in the Pathogenesis of Whipple's Disease

“…The decrease of M-DC might be induced by migration of mature DC to the gut, the major site of T. whipplei infection, as described for Crohn's disease (34). However, apoptosis following chronic activation by high levels of circulating inflammatory mediators (23) or by a T. whipplei infection, as shown for macrophages (35), also might be responsible for reduced numbers of circulating DC, since elevated apoptosis markers have been described for serum of untreated CWD patients (36). During chronic disorders, circulat- (20), and, especially during inflammatory bowel disease, this might be triggered by microbial translocation through a leaky intestinal barrier.…”

“…In addition, 6-sulfo LacNAc DCs (slanDCs) were described as a source of IL-12 (17). Impaired T cell-stimulatory capacity has been demonstrated for DC infected with Mycobacterium tuberculosis (18), and alterations in the distribution and functionality of DC subsets have been described for various infections and chronic inflammatory diseases (19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”