Characterisation of dendritic cell subsets in inflammatory arthritis
The first part of this thesis examined by comparative analysis the phenotype, tissue distribution and functional profile of the human DC subsets, myeloid (m) DC and plasmacytoid (DC), in RA and PsA. This study demonstrated that circulating pDC and mDC are reduced in the peripheral blood (PB) of RA and PsA patients, but are accumulated to the inflammatory synovial fluid (SF) and synovial membrane (SM), commensurate with altered migration. Furthermore, it was demonstrated that the majority of pDC and mDC within the synovial compartment displayed a predominantly immature phenotype as identified by the low to absent expression of specific co-stimulation and maturation markers including CD80, CD83, CD86 and dendritic cell lysosome-associated membrane protein (DC-LAMP). However, pDC and mDC purified from SF underwent ex vivo phenotypic maturation and released cytokines to TLR stimulation at comparable levels to their normal PB purified counterparts. Commensurate with that observation, cytokine profiling of SM localized pDC and mDC revealed expression of the pro-inflammatory cytokines IL-12p70, IL-23p19, IL-15, IL-18 and IFN-α/β. Together these data indicated no apparent intrinsic cellular defect, suggesting that extrinsic factors in the local synovial environment may be culpable for inhibition of DC maturation. In addition mDC in SM expressed predominantly IL-12p70 and IL-23p19, suggesting a central role in the regulation and expansion of T cells, in particular Th17, which have been ascribed a pathologic role in arthritis. In contrast, pDC expressed predominantly IL-15 and IL-18, cytokines that can enhance IL-12 induced IFN-γ release and inhibit T cell apoptosis, thus indicating a role in the amplification and prolongation of inflammatory arthritis. Of particular interest it was demonstrated that pDC also expressed IFN-α/β in abundance. As pDC constituted the dominant DC subset in the SM in both RA and PsA, this may have pathological implications as IFN-α has been critically linked to pathology in other autoimmune diseases, including systemic lupus erythematosus (SLE) and, of particular import to PsA, psoriasis. In conclusion, these studies indicate that mDC and pDC possess multi-faceted roles in inflammatory arthritis, involved in both the initiation and perpetuation of arthritis, but also the potential suppression thereof. The data provide a firm basis upon which to build rational tolerance induction regimes in due course as the appropriate biological targeting agents become available in the clinical environment.