An Imbalance of Two Functionally and Phenotypically Different Subsets of Plasmacytoid Dendritic Cells Characterizes the Dysfunctional Immune Regulation in Multiple Sclerosis

Schwab, Nicholas; Zozulya, Alla L.; Kieseier, Bernd C.; Toyka, Klaus V.; Wiendl, Heinz

doi:10.4049/jimmunol.0903662

Cited by 57 publications

(53 citation statements)

References 39 publications

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“…On the other hand, pDCs type 2 (pDC2) are characterized by low CD123, and high CD86 and TLR2 expression, secrete IL-6 and TNF-α and direct naive T cells towards IL-17-secreting Th17 cells. Remarkably, the pDC1/pDC2 ratio in MS patients is shifted towards pDC2 as compared with healthy controls, 14 indicative of a more inflammatory phenotype. Finally, upon in vitro stimulation of pDCs of RRMS patients using IL-3 and CD40 ligand, impairment of the maturation process was observed as compared with healthy controls.…”

Section: Phenotype and Function Of Pdcs In Msmentioning

confidence: 93%

“…9,10 During relapse, the number of pDCs in the CSF further increases as compared with MS patients in remission. 10 Although seemingly contradictory data resulted from studies investigating the number of circulating DC subsets in MS patients, 7,[11][12][13][14] the abovementioned properties of DC subsets observed in the CNS suggest an important role for DCs in the disease pathogenesis of MS. Given the important role of DCs in the maintenance of the balance between T cell immunity and T cell tolerance, altered numbers or activation state of DCs could disturb this balance.…”

Section: Dendritic Cells In Msmentioning

confidence: 99%

“…7,11 It is possible that these discrepancies are dependent on the study population, as some studies did not exclusively include RRMS patients. Interestingly, Schwab et al 14 showed that pDCs contain at least two different subsets. Plasmacytoid DCs type 1 (pDC1) express high levels of CD123, low levels of CD86 and TLR2, are the main source of IFN-α and induce IL-10-producing T cells.…”

Section: Phenotype and Function Of Pdcs In Msmentioning

confidence: 99%

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Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies?

et al. 2013

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Many studies have demonstrated the role of the adaptive immune system in the pathogenesis of multiple sclerosis (MS). Recent data suggest that dendritic cells (DCs), which are innate immune cells, also contribute to the pathogenesis of MS. In patients with MS, DCs are abundantly present in brain lesions, and display an altered phenotype and/or function as compared with this in healthy controls. DCs are thus in the position to pathologically influence the effector function of (auto-reactive) T and B cells. Interestingly, current first-line immunomodulating therapies for MS have been shown to restore DC phenotype and function, albeit in a non-specific manner. To date, clinical trials using agents specifically targeting DC function are ongoing. Moreover, several studies worldwide are currently investigating possible strategies to develop tolerogenic DCs. This review focuses on the phenotypic and functional alterations of conventional DCs and plasmacytoid DCs in patients with MS. Furthermore, we discuss how existing immunomodulating therapies for MS patients affect DC function and address future perspectives in the development of immunotherapies specifically targeting DCs.

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Section: Phenotype and Function Of Pdcs In Msmentioning

confidence: 93%

Section: Dendritic Cells In Msmentioning

confidence: 99%

Section: Phenotype and Function Of Pdcs In Msmentioning

confidence: 99%

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Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies?

et al. 2013

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“…In addition to decreased numbers in the peripheral circulation, the pDCs from MS patients have an impaired maturation, characterized by the lower ex vivo expression of CD86 and 4-1BBL (33). MS patients have an altered ratio of pDC subsets, with lower numbers of IFN-a-producing pDC1s and higher numbers of mature IL-6-producing pDC2s, in comparison with HCs (34). pDC depletion during the active disease exacerbated EAE (35), which was characterized by increased numbers of Th1 and Th17 cells within the CNS.…”

Section: Ifn-b-1a Treatment Of Rrms Patients Induced Ifnar1 Signalingmentioning

confidence: 99%

The Role of Endogenous IFN-β in the Regulation of Th17 Responses in Patients with Relapsing-Remitting Multiple Sclerosis

Tao

Zhang

Chopra

et al. 2014

The Journal of Immunology

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IFN-β has been used as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). Because only a few studies have addressed the role of endogenous IFN-β in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In vitro studies have demonstrated that IFN-β inhibits IL-17A, IL-17F, IL-21, IL-22, and IFN-γ secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion 1 and suppressor of cytokine secretion 3. We found that patients with RRMS have increased serum and cerebrospinal fluid Th17 (IL-17A and IL-17F) cytokine levels in comparison with the control subjects, suggesting that deficient endogenous IFN-β secretion or signaling can contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFN-β from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison with healthy controls. In addition, in vitro studies have revealed deficient endogenous and exogenous IFN-β signaling in the CD4+ cells derived from patients with MS. Interestingly, upon inhibition of the endogenous IFN-β signaling by silencing IFN regulatory factor (IRF) 7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22, and IL-9, suggesting that endogenous IFN-β suppresses the secretion of these pathogenic cytokines. In vivo recombinant IFN-β–1a treatment induced IFNAR1 and its downstream signaling molecules’ gene expression, suggesting that treatment reconstitutes a deficient endogenous IFN-β regulation of the CD4+ T cells’ pathogenic cytokine production in patients with MS.

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“…Furthermore, alterations in phenotype and/or function of different DC subsets have been observed in MS [7,12]. pDCs for example show an imbalance in the ratio between tolerogenic and immunogenic subtypes generating a propensity to generate proinflammatory Th17 cell responses in MS [16]. The "dysfunctional state" of certain DC subsets in MS could be linked to the observation of dysfunctional Treg-cell responses in MS [5].…”

Section: Immunological Tolerance Induction Its Maintenance By Dcs Anmentioning

confidence: 99%

Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis

2012

Self Cite

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Autoimmune diseases including multiple sclerosis (MS) are the result of an imbalanced immune tolerance network. Dendritic cells (DCs) are key players in both initiating immunity (immunogenic DCs) and regulating immune responses (tolerogenic DCs= IntroductionMultiple sclerosis (MS) is the prototype of a central nervous system (CNS) directed, antigen-driven, predominantly T-cell medi- Immunological tolerance induction, its maintenance by DCs and what goes wrong in MSThe major subtypes of human DCs are conventional myeloid (CD11c + ) DCs (mDCs) and type I interferon-secreting plasmacytoid (CD11c dim CD123 + ) DCs (pDCs). Depending on the antigen presented and the activation status of the DCs, both subsets can either exhibit immunogenic or tolerogenic features [9,10]. Immature DCs are located in the peripheral tissues where they constantly encounter/sample antigens. While TLR ligands and pro-inflammatory cytokines induce maturation into immunogenic DCs that migrate to secondary lymphoid organs where they prime naïve T cells, anti-inflammatory cytokines including IL-10 and TGF-β induce DCs with a more tolerogenic phenotype (tolDCs) [10]. The term tolDCs summarizes a heterogeneous group of different DC subsets (mDCs and pDCs) located in various tissues where they use different mechanisms to induce and maintain both central and peripheral tolerance. In the thymus, DCs eliminate autoreactive T cells by clonal deletion of high-affinity thymocytes or diversion into Treg cells [11]. Despite these central tolerance mechanisms, some low avidity autoreactive T cells escape into the periphery, where peripheral tolerance mechanisms are required to prevent spontaneous autoimmunity. Multiple peripheral tolerance mechanisms have been identified for myelin-specific T cells, most importantly Treg cells and tolerogenic DCs [5,12]. TolDCs keep autoreactive T cells under control by inducing anergy, apoptosis, phenotypic skewing, and/or Treg cells [13][14][15].In MS, both immunogenic and tolerogenic features of different DC subsets are disrupted [7,12]. Elevated numbers of mature mDCs have been found in the peripheral blood of MS patients, and the occurrence of both mDCs and pDCs in the CSF of MS patients suggests their active participation in disease pathogenesis [12]. Furthermore, alterations in phenotype and/or function of different DC subsets have been observed in MS [7,12]. pDCs for example show an imbalance in the ratio between tolerogenic and immunogenic subtypes generating a propensity to generate proinflammatory Th17 cell responses in MS [16]. The "dysfunctional state" of certain DC subsets in MS could be linked to the observation of dysfunctional Treg-cell responses in MS [5]. Therefore, therapies targeting DCs for MS aim to either diminish their immunogenic potential or enhance their tolerogenic features [7]. Chances and pitfalls of the therapeutic use of tolDCsSo far, most of our knowledge in using tolDCs to treat autoimmunity is derived from extensive work in animal models including experimental autoimmune encephalitis (EA...

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An Imbalance of Two Functionally and Phenotypically Different Subsets of Plasmacytoid Dendritic Cells Characterizes the Dysfunctional Immune Regulation in Multiple Sclerosis

Abstract: Material

Cited by 57 publications

References 39 publications

Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies?

Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies?

The Role of Endogenous IFN-β in the Regulation of Th17 Responses in Patients with Relapsing-Remitting Multiple Sclerosis

Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis

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