The Balance between Plasmacytoid DC versus Conventional DC Determines Pulmonary Immunity to Virus Infections

Achieving remission in rheumatoid arthritis (RA) remains elusive despite current biological therapeutics. Consequently, interest has increased in strategies to re-establish immune tolerance to provide long-term disease suppression. Although dendritic cells (DC) are prime candidates in initiating autoreactive T cell responses, and their presence within the synovial environment suggests a role in generation and maintenance of autoreactive, synovial T cell responses, their functional importance remains unclear. We investigated the contribution made by plasmacytoid DCs (pDCs) in the spontaneous breach of tolerance to arthritis-related self proteins, including rheumatoid factor, citrullinated peptide, and type II collagen observed in a novel arthritis model. Selective pDC depletion in vivo enhanced the severity of articular pathology and enhanced T and B cell autoimmune responses against type II collagen. pDC may offer a net anti-inflammatory function in the context of articular breach of tolerance. Such data will be vital in informing DC modulatory/therapeutic approaches.

Section: Discussioncontrasting

confidence: 85%

Plasmacytoid Dendritic Cells Regulate Breach of Self-Tolerance in Autoimmune Arthritis

Jongbloed

Benson

Nickdel

et al. 2009

“…Taken together, these effects allowed pDCs to establish a reduced inflammatory pattern, but at the same time to favor tumor progression/establishment. A similar phenomenon has already been described in other models of lung disease, including asthma (9), virus infection (35), and cigarette smoke exposure (36). Overall, this dichotomy in potential CpG effects on pDC function may explain why CpG therapy has been successful, in part, in melanoma, but unsuccessful in a phase III clinical trial for lung cancer (6).…”

Section: Discussionsupporting

confidence: 63%

Plasmacytoid Dendritic Cells Alter the Antitumor Activity of CpG-Oligodeoxynucleotides in a Mouse Model of Lung Carcinoma

Sorrentino

Morello

Luciano

et al. 2010

“…This is one of several mechanisms by which RV infection might precipitate acute asthma exacerbations. Animal models support this hypothesis, with multiple reports that pDC function to inhibit immunopathology associated with both allergic airway inflammation and viral lung infections (41)(42)(43)(44). Further studies are clearly required using asthmatic and atopic cohorts; these investigations must, however, take into consideration the studies of Grayson et al (45) and Subrata et al (5), who describe type-I IFN induction of higher expression of the high-affinity IgE receptor (FcεRI) on DC and monocytes.…”

Section: Discussionmentioning

confidence: 99%

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

Pritchard

Carroll

Burel

et al. 2012

Human rhinoviruses (RV) cause only minor illness in healthy individuals, but can have deleterious consequences in people with asthma. This study sought to examine normal homeostatic mechanisms regulating adaptive immunity to RV in healthy humans, focusing on effects of IFN-αβ and plasmacytoid dendritic cells (pDC) on Th2 immune responses. PBMC were isolated from 27 healthy individuals and cultured with RV16 for up to 5 d. In some experiments, IFN-αβ was neutralized using a decoy receptor that blocks IFN signaling, whereas specific dendritic cell subsets were depleted from cultures with immune-magnetic beads. RV16 induced robust expression of IFN-α, IFN-β, multiple IFN-stimulated genes, and T cell-polarizing factors within the first 24 h. At 5 d, the production of memory T cell-derived IFN-γ, IL-10, and IL-13, but not IL-17A, was significantly elevated. Neutralizing the effects of type-I IFN with the decoy receptor B18R led to a significant increase in IL-13 synthesis, but had no effect on IFN-γ synthesis. Depletion of pDC from RV-stimulated cultures markedly inhibited IFN-α secretion, and led to a significant increase in expression and production of the Th2 cytokines IL-5 (p = 0.02), IL-9 (p < 0.01), and IL-13 (p < 0.01), but had no effect on IFN-γ synthesis. Depletion of CD1c+ dendritic cells did not alter cytokine synthesis. In healthy humans, pDC and the IFN-αβ they secrete selectively constrain Th2 cytokine synthesis following RV exposure in vitro. This important regulatory mechanism may be lost in asthma; deficient IFN-αβ synthesis and/or pDC dysfunction have the potential to contribute to asthma exacerbations during RV infections.