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This is the inaugural article in a new series of reviews that will be focused on basic molecular mechanisms and technologies as they apply to discovery in the rheumatic diseases. As indicated by the heading Disease Mechanisms in Rheumatology—Tools and Pathways, the series is designed to increase readers' understanding of important and emerging biologic pathways of central relevance to the pathogenesis of the rheumatic diseases, and of various new multiparameter assay technologies by which these pathways can be further investigated. The goal is to introduce technologies and basic science concepts in ways that are accessible to the broad readership, including both investigators and practitioners.

Introduction

  1. Top of page
  2. Introduction
  3. The interferons
  4. Characteristics of pDCs
  5. Activation of pDCs
  6. Endogenous IFN inducers
  7. Functions of pDCs in the immune response
  8. Plasmacytoid DCs in autoimmune rheumatic diseases
  9. Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases
  10. Conclusions
  11. AUTHOR CONTRIBUTIONS
  12. REFERENCES

Plasmacytoid dendritic cells (pDCs) are a rare type of cells that specialize in the production of type I interferon (IFN) in response to viral infections (1). The IFN that is produced induces viral resistance in target cells and promotes an antiviral immune response. Plasmacytoid DCs are therefore central actors in the IFN system, which includes the inducers of IFN production, the IFN-producing cells themselves, the different IFNs, and their target cells. The observation that serum levels of IFNα are increased and type I IFN–regulated genes (an IFN signature) are overexpressed in systemic lupus erythematosus (SLE) as well as several other autoimmune diseases has stimulated investigation of the mechanisms behind the activation of the type I IFN system in these diseases (2, 3). Accordingly, the role of activated pDCs in ongoing production of type I IFN and in the development and perpetuation of an autoimmune process is the subject of intensive study. These investigations have also been prompted by the observation that treatment with type I IFN occasionally induces a rheumatic disease, suggesting a causal relationship between type I IFN production and development of autoimmunity (4).

Studies during the late 1990s and the last decade have reveled that, in many autoimmune rheumatic diseases, pDCs are stimulated by endogenous, i.e., self-derived, type I IFN inducers (2). Recent reports have also provided insights into the possible role of such activated pDCs in the maintenance and loss of tolerance, which is relevant for the understanding of autoimmune processes. It has been demonstrated that pDCs can present antigen, stimulate activation and differentiation of T cells, and promote B cell development and antibody production. In the present review, we will summarize basic characteristics of the type I IFN system and, in particular, the biology of pDCs and their possible role in the development of autoimmune rheumatic diseases. We will also discuss therapeutic strategies targeting the type I IFN system that have been developed and launched in recent years.

The interferons

  1. Top of page
  2. Introduction
  3. The interferons
  4. Characteristics of pDCs
  5. Activation of pDCs
  6. Endogenous IFN inducers
  7. Functions of pDCs in the immune response
  8. Plasmacytoid DCs in autoimmune rheumatic diseases
  9. Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases
  10. Conclusions
  11. AUTHOR CONTRIBUTIONS
  12. REFERENCES

Three main types of cytokines, designated types I, II, and III IFN, exert antiviral activity. The type I IFNs are encoded by 17 genes: 13 highly homologous genes encoding the IFNα subtypes and 4 less homologous single genes encoding IFNβ, IFNω, IFNκ, and IFNε (5). The type II IFN, also termed IFNγ, is encoded by 1 gene (6). In contrast, type III IFNs are encoded by 3 homologous genes encoding IFNλ1 (interleukin-29 [IL-29]), IFNλ2 (IL-28A), and IFNλ3 (IL-28B) (7) (Table 1 and Figure 1).

Table 1. Type I, II, and III interferons (IFNs)
IFN typeGenesProteins% sequence homology
  • *

    Average homology with IFNα.

IIFNA1, 2, 4, 5, 6, 7, 8, 10, 13, 14, 16, 17, 21IFNα1, 2, 4, 5, 6, 7, 8, 10, 13, 14, 16, 17, 21 (n = 13)>75 between IFNα subtypes
IIFNB1IFNβ30*
IIFNE1IFNε30*
IIFNKIFNκ30*
IIFNW1IFNω75*
IIIFNGIFNγNot significant*
IIIIL29, IL28A, IL28BIFNλ1,2,3 (IL-29, IL-28A, IL-28B)>80 between IFNλ subtypes; low with IFNα
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Figure 1. Signaling pathways used by the types I, II, and III interferon (IFN) receptors. The receptor chains and receptor-associated janus kinases JAK-1, JAK-2, and Tyk-2 are indicated, as are the involved STAT factors. The latter are activated by phosphorylation. Types I and III IFN typically activate STAT-1 and STAT-2, which form a trimolecular complex with IFN regulatory factor 9 (IRF-9), termed IFN-stimulated transcription factor 3. The latter interacts with IFN-stimulated response element (ISRE) in promoters of IFN-stimulated genes (ISGs). STAT-1 also forms dimers that interact with IFNγ-activated sites (GAS) in ISGs. The signaling pathways and target genes of types I and III IFN are similar and partially overlap those of type II IFN, the latter causing STAT-1 dimer formation, which is less pronounced with types I and III IFN. The IFNs also activate STATs 3–6 and, in addition, non-STAT pathways, including MAPK and phosphatidylinositol 3′-kinase/Akt–mammalian target of rapamycin pathways (not shown). IL-28R = interleukin-28 receptor; IFNAR = IFNα/β/ω receptor; IFNGR = IFNγ receptor.

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All type I IFNs act on the same dimeric cell surface receptor, IFNα/β/ω receptor (IFNAR), which is expressed by most cell types (8, 9). Upon ligation, IFNAR is associated with the cytosolic janus kinases JAK-1 and Tyk-2 (Figure 1). Typically, receptor ligation causes phosphorylation of the STAT factors STAT-1 and STAT-2 that form either trimolecular complexes with IFN regulatory factor 9 (IRF-9), termed IFN-stimulated transcription factor 3, or STAT-1 homodimers. The former binds to IFN-stimulated response elements and the latter to IFNγ-activated sites, both of which are present in many gene promoters.

IFNγ interacts with its receptor, IFNγR, which has a 4-chain structure with 2 IFNγRI and 2 IFNγRII chains that associate with JAK-1 and JAK-2, which phosphorylate STAT-1 (Figure 1). JAK-2 forms dimers that interact with IFNγ-activated sites.

The type III IFNs, IFNλ1, IFNλ2, and IFNλ3, act on the dimeric IL-28 receptor (IL-28R [IL-28RI and IL-10RII]), which, like IFNAR, uses JAK-1 and Tyk-2 and follows signaling pathways similar to those observed with IFNAR (7). However, the distribution of IL-28R is limited, being expressed preferentially on epithelial cells, including keratinocytes and hepatocytes. It is also expressed on T, B, and natural killer (NK) cells and on pDCs (10). IFNλ itself is produced by activated pDCs in addition to epithelial cells (11).

Besides STAT-1 and STAT-2, types I–III IFNs activate STATs 3–6 and also JAK/STAT-independent pathways such as the MAPK and phosphatidylinositol 3′-kinase/Akt–mammalian target of rapamycin pathways (9). The actions of IFN are therefore complex, affecting a large number of IFN-stimulated genes. One estimate is that 1,333 genes are up-regulated by type I IFN, 1,044 by type II IFN, and 723 by both (12). Type III IFN stimulates 114 genes, all also stimulated by type I IFN and more than half also stimulated by type II IFN. Thus, there is considerable overlap between the IFN-stimulated genes activated by the different IFNs.

Characteristics of pDCs

  1. Top of page
  2. Introduction
  3. The interferons
  4. Characteristics of pDCs
  5. Activation of pDCs
  6. Endogenous IFN inducers
  7. Functions of pDCs in the immune response
  8. Plasmacytoid DCs in autoimmune rheumatic diseases
  9. Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases
  10. Conclusions
  11. AUTHOR CONTRIBUTIONS
  12. REFERENCES

Early studies by several investigators including our group (13, 14) identified a population of infrequent IFNα-producing cells among human peripheral blood mononuclear cells (PBMCs) (∼1/500 PBMCs). They produce 10–100 times more IFNα than other cell types (up to 109 IFNα molecules per cell in 24 hours) when exposed to virus or bacteria. The IFN-producing cells had the phenotype of immature DCs (14, 15) and were termed natural IFN-producing cells. They were subsequently shown to be identical to type 2 dendritic cell precursors, previously termed plasmacytoid monocytes or plasmacytoid T cells (16, 17) but now termed pDCs.

The pDCs in human blood are round cells with a secretory morphology with abundant endoplasmic reticulum. They express class II major histocompatibility complex (MHC) molecules but are immature as DCs in the sense that they express few or no costimulatory molecules (CD40, CD80, CD86, inducible costimulator ligand [ICOSL], or programmed death ligand 1 [PDL-1]) (1, 18). They express these molecules upon functional maturation at activation by IL-3/granulocyte–macrophage colony-stimulating factor (GM-CSF), CD40L, or typical IFN inducers such as virus, and then become efficient antigen-presenting cells, but poor IFN producers. Thus, immature pDCs are efficient IFN-producing cells, and mature pDCs are antigen-presenting.

Immature pDCs express markers including C-type lectin blood dendritic cell antigen 2 (BDCA-2)/CD303, BDCA-4/CD304 (neuropilin 1), IL-3 receptor α-chain (CD123), and immunoglobulin-like transcript 7 (14, 19). However, the expression of these markers is not entirely pDC-specific and/or is altered by the environment of pDCs.

Immature pDCs also express the chemokine receptors CXCR4 (which is activated by the chemokine CXCL12) and CXCR3 (which is activated by the IFN-inducible chemokines CXCL9/10/11 and acts in concert with CXCR4) (14). In this way, pDCs use type I IFN to recruit further pDCs to inflamed tissue. The activated pDCs express CCR5 and CCR7, and the chemerin receptor (ChemR23). These receptors are responsible for migration of pDCs to lymph nodes and spleen (20, 21). Plasmacytoid DCs activated by IL-3/GM-CSF express CCR6 and CCR10, which direct migration of the cells to mucosa and skin (22). Thus, pDCs can be recruited to inflamed tissue via chemokine receptors.

Activation of pDCs

  1. Top of page
  2. Introduction
  3. The interferons
  4. Characteristics of pDCs
  5. Activation of pDCs
  6. Endogenous IFN inducers
  7. Functions of pDCs in the immune response
  8. Plasmacytoid DCs in autoimmune rheumatic diseases
  9. Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases
  10. Conclusions
  11. AUTHOR CONTRIBUTIONS
  12. REFERENCES

Plasmacytoid DCs are normally activated when they encounter viral or bacterial nucleic acids (18, 23) (Figure 2). A strong activation signal is initiated in pDCs when single-stranded RNA or double-stranded DNA is internalized and sensed by Toll-like receptor 7 (TLR-7) or TLR-9, respectively. This interaction takes place in early endosomes and requires that the nucleic acids are endocytosed and the TLRs are recruited to this compartment from endoplasmic reticulum. Upon triggering of TLR-7 or TLR-9, a signaling complex consisting of the key adaptor molecule myeloid differentiation factor 88, Bruton's tyrosine kinase, tumor necrosis factor (TNF) receptor–associated factor 6, and IL-1R–associated kinase 4 is formed. The downstream signals are mediated either via NF-κB, leading to production of proinflammatory cytokines and enhanced antigen presentation, or via involvement of IRFs, leading to activation of type I and III IFN genes (18, 23). The phosphorylation and nuclear translocation of IRF-7 especially promotes strong type I IFN production in response to TLR-7/9 ligand engagement in pDCs (24). IRF-3 is involved in activation of IFNβ production via engagement of TLR-3 or cytosolic nucleic acid sensors (18), although it is not clear if the latter mechanism is activated in pDCs. The IRFs also stimulate the expression of the costimulatory molecules CD80, CD86, and CD40 in pDCs.

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Figure 2. Activation of type I interferon (IFN) and inflammatory cytokine production in plasmacytoid dendritic cells. RNA is recognized by cytosolic RNA sensors, e.g., laboratory of physiology and genetics 2 (LPG-2), melanoma differentiation–associated protein 5 (MDA-5), and retinoic acid–inducible gene 1 (RIG-1). DNA is recognized by, e.g., DNA-dependent activators of IFN-regulatory factors (DAIs) and by RIG-1–like receptors after conversion to RNA by RNA polymerase III (RNA pol III). The RNA sensors signal via, e.g., mitochondrial antiviral signaling protein (MAVS), tumor necrosis factor receptor–associated factor 3 (TRAF3), and the protein kinases TANK-binding kinase 1 (TBK-1) and inhibitor of NF-κB kinase subunit ε (IKBKE), which together activate NF-κB and the IFN regulatory factors (IRFs). DAI and RIG-1 require stimulator of IFN genes (STING) for downstream activation. Viral RNA/DNA and endogenous self nucleic acid–containing immune complexes reaching endosomes can trigger Toll-like receptor 7 (TLR-7) and TLR-9. A signaling cascade, which includes myeloid differentiation factor 88 (MyD88), TRAF6, Bruton's tyrosine kinase (BTK), interleukin-1 receptor–associated kinase 1 (IRAK-1), and IRAK-4, is then activated. This activates IRF-5 and IRF-7, which trigger production of type I IFN and inflammatory cytokines. The activation of IFN genes is highly dependent on signaling via IFNα/β/ω receptor (IFNAR) due to promoters containing IFN-stimulated response elements (ISREs). ER = endoplasmic reticulum; FcγRIIa = Fcγ receptor IIa.

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It still remains to be explored how important TLR-independent cytoplasmic nucleic acid sensors, e.g., RNA helicase retinoic acid–inducible gene 1–like receptors and DNA receptors, (23, 25), are in the activation of pDC. Recently, an endoplasmic reticulum–associated molecule termed stimulator of IFN genes (STING) was described to be a critical regulator of IFN production in response to cytoplasmic DNA (26). Additionally, STING signals via dual downstream pathways, using either IRF-3 dimers or NF-κB, to induce production of type I IFN and proinflammatory cytokines, respectively (26).

The uniquely high production of IFNs by pDCs is probably due to the expression of TLR-7 and TLR-9 and high constitutive expression of transcription factors IRF-3, IRF-5, and IRF-7. Also important is the ability of types I and II IFN to amplify their own production in a process termed priming (14, 27), probably mediated by enhanced expression and activation of the IRF-5 and IRF-7 (28). In addition, IL-3 and GM-CSF can increase the production of type I IFN (18).

Endogenous IFN inducers

  1. Top of page
  2. Introduction
  3. The interferons
  4. Characteristics of pDCs
  5. Activation of pDCs
  6. Endogenous IFN inducers
  7. Functions of pDCs in the immune response
  8. Plasmacytoid DCs in autoimmune rheumatic diseases
  9. Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases
  10. Conclusions
  11. AUTHOR CONTRIBUTIONS
  12. REFERENCES

The earlier paradigm that pDCs recognize only microbial nucleic acids, but not self-derived RNA or DNA, was proven to be incorrect by several groups, including ours (29, 30). The initial observation of continuous type I IFN production and an IFNα-inducing factor in the sera of many SLE patients suggested that an IFNα trigger could consist of immune complexes (ICs) containing endogenous, i.e., self-derived, DNA or RNA and autoantibodies recognizing nucleic acids or nucleoproteins (31, 32). Subsequent studies revealed that material from dying cells containing DNA and RNA in the presence of autoantibodies to nucleoproteins form ICs that induce type I IFN production in pDCs (33, 34). Such DNA/RNA-containing ICs activate pDCs via a pathway in which IgG interacts with Fcγ receptor IIa expressed on pDCs, resulting in accumulation of ICs into the early endosomes and activation of the TLR-7– and TLR-9–mediated signals (35, 36). The activation of pDCs can be enhanced when the DNA binding protein high mobility group box chromosomal protein 1 (HMGB-1) is secreted from necrotic cells and forms ICs (18).

An alternative pathway in which self-derived nucleic acids can activate type I IFN production by pDCs was described (37, 38). It was found that the endogenous antimicrobial peptide LL37 binds and protects DNA or RNA against degradation, and allows access of such complexes to early endosomes and triggering of TLR-7/9. LL37 is produced especially by inflamed keratinocytes and neutrophils and can therefore be an important component in the activation of IFN production in diseases such as psoriasis and SLE.

A mechanism for the alternative generation of endogenous nucleic acids, involving neutrophils dying by NETosis and release of NETs (neutrophil extracellular traps), was recently described (39, 40). Such traps have multiple components, including HMGB-1, LL37, histones, and DNA, and are relatively resistant to degradation by DNase I. They induce IFNα production in pDCs, although forming complexes with autoantibodies effectively potentiates their IFNα-inducing capacity and such traps can therefore be a cause of overactivation of pDCs both in psoriasis and in systemic autoimmune diseases.

Functions of pDCs in the immune response

  1. Top of page
  2. Introduction
  3. The interferons
  4. Characteristics of pDCs
  5. Activation of pDCs
  6. Endogenous IFN inducers
  7. Functions of pDCs in the immune response
  8. Plasmacytoid DCs in autoimmune rheumatic diseases
  9. Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases
  10. Conclusions
  11. AUTHOR CONTRIBUTIONS
  12. REFERENCES

The pDCs can influence the functions of many other immune cells in innate and adaptive immunity, via direct interaction with them or via type I and type III IFN and other cytokines that are produced (see below). These immunomodulatory actions of pDCs are relevant in resistance to infections, but also in autoimmunity.

Direct antiviral effects of IFN.

Types I and III IFN activate >10 genes whose products interfere with viral replication (41, 42). The importance of type I IFN in defense against virus is evidenced by the finding that nearly all viruses have acquired one or more means to interfere with the production and action of type I IFN (41). Experimental studies in mice indicate that the type I IFN system is important in the defense against some, but not all, viruses (43). However, both IFNλ1–3 and IFNγ can here contribute to the antiviral defense (7, 11).

Role of pDCs in the antigen-presenting function of the immune system.

Activated pDCs efficiently present endogenous and exogenous antigen on class I and II MHC, and display strong cross-presentation (44). Depending on their activation and expression of, e.g., costimulatory molecules (CD80, CD86, ICOSL, PDL-1), pDCs can stimulate proliferation and differentiation of T and B cells. They can also, via production of type I IFN, especially together with GM-CSF, stimulate the development of myeloid DCs from monocytes (45). Such myeloid IFN-DCs are potent antigen-presenting cells and can cross-present and migrate to lymph nodes and promote Th1 and B cell immune responses. The IFNs also increase expression of class I and II MHC on DCs and many other cell types. Accordingly, activated pDCs may dramatically increase the total antigen-presenting function of the immune system in rheumatic diseases such as SLE.

Role of pDCs as regulators of T cell development.

Antigen-specific CD8+ naive and memory cytotoxic T cells are strongly stimulated by cross-presenting pDCs activated by TLR agonists (46). It was shown that pDCs activated by only IL-3 or CD40L promoted Th2 cell development, while further TLR activation of pDCs by virus changed the response to a Th1 profile (47). TLR-7–activated pDCs also support development of Th17 cells that, besides IL-17, also produce IL-22 and TNFα (48). Development of a subset of memory CD4+ cells that produced only IL-22 and displayed skin homing properties has also been reported (49). Thus, when activated via TLR-7/9, pDCs can give rise to autoimmune Th17 and Th22 cells, which cause inflammation and production of antimicrobial peptides such as LL37 that are relevant in autoimmune disease, and can also give rise to Th1 cells that provide, e.g., help to B cells.

Many functions of pDCs may be related to the effects of type I IFN on T cells (50). Thus, type I IFN can expand CD8+ T cells via inhibition of apoptosis, increased IL-2 production, increased cross-presentation, increased class I MHC expression, and IFN-induced production of IL-15. Additionally, type I IFN increases the cytolytic activity of CD8+ T cells. Type I IFN can stimulate Th1 development via, e.g., STAT-4 activation and T-bet induction, but appears to require assistance in this process from other cytokines, such as IL-12 and IL-18. Th1 cells are also protected against apoptosis upon activation by antigen, and this results in increased development of central memory-like Th1 cells. In contrast, type I IFN suppresses the development of Treg cells and of Th2 and Th17 cells. It can be concluded that pDCs and type I IFN indeed have a wide influence on development of T cell immunity, with a profile that promotes, e.g., efficient antiviral immunity, but also autoimmunity and inflammatory activity.

Role of pDCs in tolerance.

Recent findings suggest that immature pDCs are important in the maintenance of self tolerance in at least two ways: via central tolerance in the thymus (51) and via Treg cells (52). In central tolerance, immature pDCs in mice take up and transport native antigen from the periphery to the thymus and cause clonal deletion of antigen-specific CD4+ thymic lymphocytes (51). This migration of pDCs depends on their expression of CCR9. Interestingly, activation of pDCs by a TLR agonist terminates this pathway via down-regulation of CCR9. Thus, self-derived IFN inducers present in autoimmune diseases such as SLE may also counteract induction of central tolerance by their ability to activate TLR-7/9 in pDCs.

In addition, immature pDCs can maintain self tolerance via their ability to stimulate development of CD4+CD25+FoxP3+ natural Treg (nTreg) cells (52, 53). Such cells appear to mediate cell contact–dependent antigen-specific suppression of autoreactive T cells (52). In contrast, pDCs activated by, e.g., TLR agonists induce differentiation of Treg cells to cells that produce IL-10 and express the costimulatory molecule ICOS. Such cells, which correspond to Tr1 cells, can, via IL-10, suppress antigen presentation by DCs and inflammation (54). Interestingly, exposure of human nTreg cells to type I IFN and complement factor C3b promotes transition of nTreg cells to Tr1 cells, explaining the nTreg deficiency observed in SLE (54). Such suppression of Treg cells by type I IFN may be relevant in autoimmune diseases with overproduction of type I IFN (55). However, pDCs can also induce other Treg cell types, including lymphocyte activation gene 3–positive CD8+FoxP3+CTLA-4+ cells (56). From these observations it is clear that the tolerogenic role of pDCs in autoimmune rheumatic diseases warrants further investigation.

Effect of pDCs on B cells.

When activated by TLR agonists, pDCs produce type I IFN and IL-6, which activate B cell proliferation, costimulatory antigen expression, plasma cell differentiation, and IgM and IgG secretion (57). Furthermore, monocytes differentiated to DCs by exposure to type I IFN–containing SLE serum stimulated naive and memory B cells to differentiate into IgG and IgA plasmablasts; this was dependent on production of BAFF/IL-10 and APRIL, respectively (58), BAFF and APRIL being induced by type I IFN. In addition, CD70 on activated pDCs can stimulate B cells via CD27 (59). The pDCs can consequently promote both T cell–dependent and –independent B cell immunity, often via type I IFN.

Plasmacytoid DCs as regulators of cell migration.

When activated by TLR-7/9 agonists, including viruses and interferogenic ICs, pDCs produce ∼12 different chemokines, with a further 2–4 chemokines expressed before activation (36, 60). These chemokines have been shown to be produced in 3 successive waves after activation. At 2–4 hours, chemokines that attract neutrophils, cytotoxic T cells, and NK cells (including CXCL1, CXCL2, and CXCL4) appear. Within 8–12 hours, chemokines that attract monocytes and effector memory T cells (including CCL4, CCL5, CXCL9, CXCL10, and CXCL11) are produced. Finally, at 12–48 hours, when pDCs are expected to reach peripheral lymphoid nodes, chemokines that attract naive and central memory T cells, Th2 cells, DCs, and naive B lymphocytes (including CCL19, CCL22, and CXCL13) are produced. Plasmacytoid DCs are therefore well equipped for the regulation of cell migration during innate and adaptive immune responses in infections and autoimmunity.

Cytotoxic actions of NK cells and pDCs.

One of the earliest discovered immunomodulatory functions of type I IFN is its ability to increase the cytotoxicity of NK cells (14). Interestingly, pDCs, the principal IFN-producing cells, themselves also exert major cytotoxic functions under appropriate conditions. Accordingly, pDCs activated by TLR-7/9 agonists or by type I IFN express TRAIL and secrete granzyme B and are cytotoxic for certain tumor cells and CD4+ T cells (61, 62). Furthermore, increased TRAIL expression on pDCs and keratinocytes is a feature in cutaneous LE and SLE (63) and may contribute to the elevated apoptosis that is important in the etiology and pathogenesis of the disease and generates self-derived IFN inducers (see below).

Plasmacytoid DCs in autoimmune rheumatic diseases

  1. Top of page
  2. Introduction
  3. The interferons
  4. Characteristics of pDCs
  5. Activation of pDCs
  6. Endogenous IFN inducers
  7. Functions of pDCs in the immune response
  8. Plasmacytoid DCs in autoimmune rheumatic diseases
  9. Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases
  10. Conclusions
  11. AUTHOR CONTRIBUTIONS
  12. REFERENCES

A number of studies have shown that circulating pDCs are reduced in patients with various rheumatic diseases. This has been demonstrated in SLE (64) and primary Sjögren's syndrome (SS) (65), but also in rheumatoid arthritis (RA) and psoriatic arthritis (66). The reason for the decreased number of pDCs in the blood seems to be migration of these cells to tissues. Thus, infiltrating pDCs can be seen in biopsy specimens from skin (67), kidneys (68), and lymph nodes (29) of patients with SLE, minor salivary gland biopsy specimens from patients with primary SS (69), muscle biopsy specimens from patients with myositis (70), and synovial fluid from patients with RA (66). In psoriasis, activated pDCs infiltrate the skin early in the development of skin lesions (71). The reason for the migration of pDCs to inflamed tissue is unclear, but IL-18 and chemerin have been suggested as two possible chemoattractants (68, 72). Plasmacytoid DCs infiltrating inflamed tissue are activated and produce type I IFN, resulting in increased expression of type I IFN–regulated genes.

This type I IFN signature is a typical finding in a subset of patients with most systemic autoimmune rheumatic diseases (3), and a prominent IFN signature in SLE correlates with more active disease. Recently, patients with cutaneous LE, lichen rubor, and dermatomyositis were shown to have strong epidermal expression of IFNλ (i.e., type III IFN) and significant levels of IFNλ in serum (63). Because of the great similarity between types I and III IFNs, the role of such IFNλ in the pathogenesis of autoimmune diseases merit further investigation.

The main reason behind the activation of pDCs in autoimmune rheumatic diseases seems to be the stimulation of pDCs by interferogenic ICs, as described above and in Figure 3. Because formation of such ICs should regularly occur in all individuals during viral infections, without the subsequent development of an autoimmune condition, one may ask why the IFNα production is not down-regulated in patients with systemic autoimmune diseases. At least two different mechanisms may contribute to the ongoing IFNα synthesis in these diseases. First, the genetic background in many patients with autoimmune rheumatic diseases will promote enhanced production of IFNα or an increased response to the ligation of IFNAR. Thus, studies have shown that IRF5 gene variants associated with autoimmune disease are linked to increased expression of IRF-5 in blood cells of patients with SLE (73) and that there is an association between a lupus IRF5 risk haplotype and serum IFNα activity (74). Similarly, a single-nucleotide polymorphism in TLR-7 is associated with both SLE and a more pronounced IFN signature (75), and a STAT4 gene variant is associated with enhanced sensitivity to IFNα (76), increased risk of lupus, and a more severe disease phenotype (77).

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Figure 3. Role of plasmacytoid dendritic cells (pDCs) and type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus. Microorganisms activate immature pDCs to produce IFN and to mature into efficient antigen-presenting cells. RNA- or DNA-containing proteins released by dying cells are potent autoantigens. Autoimmune B cells will bind nucleic acid–containing autoantigens via their B cell receptors (BCRs) and become further activated via Toll-like receptor 7 (TLR-7) and TLR-9, and finally differentiate into plasma cells. The autoantibodies form immune complexes (ICs) with DNA/RNA-containing autoantigens, and activate TLR-7 or TLR-9. The continuous production of IFN and other components of the inflammatory process contributes to the increased generation of potential type I IFN inducers via increased cell death and autoantigen expression. In the disease model, B cells, via production of autoantibodies, form a supply of interferogenic ICs that continuously activate pDCs, which then support further autoantibody formation. Development of autoimmune Th1, Th17, and Tc cells is increased by interferogenic ICs, while Treg cell formation might be impaired. Thus, pDCs/IFN and autoimmune B cells sustain the autoimmunity by a process that has features of a vicious circle, the activity of which is also regulated by, e.g., natural killer (NK) cells and monocytes. IFNAR = IFNα/β/ω receptor; FcγR = Fcγ receptor; moDC = monocyte-derived dendritic cell.

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A second reason for the increased activation of pDCs in autoimmune diseases could be a lack of negative feedback signals to pDCs. B cells and NK cells strongly promote the function of pDCs after IC stimulation, which includes the production not only of IFNα, but also of many other proinflammatory cytokines and chemokines (78, 79). The NK cells are inhibited by monocytes, but this inhibitory function is deficient in SLE patients due to reduced production of reactive oxygen species (27), which may contribute to unabated pDC activation. Lack of sufficient amounts of C1q to suppress the activation of pDCs by ICs, as mentioned above, is another possible reason for the pDC activation in SLE (80, 81), which is characterized by low production or increased consumption of C1q or, in some cases, the presence of neutralizing C1q autoantibodies. We originally proposed an etiopathogenic model to explain how activation of pDCs by interferogenic ICs, via especially the production of immunomodulatory type I IFNs, could cause development and maintenance of the autoimmune process in SLE (30). This model has been successively updated over the years (82), based on additional findings by us and many other investigators (summarized in Figure 3).

Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases

  1. Top of page
  2. Introduction
  3. The interferons
  4. Characteristics of pDCs
  5. Activation of pDCs
  6. Endogenous IFN inducers
  7. Functions of pDCs in the immune response
  8. Plasmacytoid DCs in autoimmune rheumatic diseases
  9. Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases
  10. Conclusions
  11. AUTHOR CONTRIBUTIONS
  12. REFERENCES

Given the pivotal role of pDCs in autoimmune disease processes, it is not surprising that several therapies that target these cells or the type I IFNs themselves have been developed. The standard treatment of SLE and related diseases is hydroxychloroquine, which binds to nucleic acids and masks TLR-binding epitopes (83). The mammalian target of rapamycin pathway regulates type I IFN production after TLR-9 activation, and rapamycin, which has been used as a treatment in SLE, suppresses IFNα/β (84). Currently, 3 anti-IFNα monoclonal antibodies (sifalimumab, rontalizumab, and AGS-009) are in clinical trials for SLE and early data suggest beneficial effects, with anti-IFNα–treated patients experiencing fewer flares and requiring less immunosuppressive treatment in conjunction with inhibition of the IFN signature (85, 86). In contrast, anti-IFNα demonstrated no clinical benefit in the treatment of patients with plaque psoriasis and could not inhibit the IFN signature in affected skin, suggesting that the IFN signature in psoriasis is triggered by other type I IFNs or type III IFN (87).

Another approach to down-regulating the IFN signature is to vaccinate against IFNα. Recently it was shown that an IFNα kinoid vaccine was able to induce a dose-related anti-IFNα response in SLE patients, which was associated with significant down-regulation of the IFNα signature (88).

The possibility of specifically targeting pDCs in SLE was suggested as early as >10 years ago (89), but so far no clinical trial of such a treatment has been conducted in humans. However, several treatments for SLE that are already in use, e.g., steroids, affect the function of pDCs (90). New therapies, such as the proteasome inhibitor bortezomib, which targets plasma cells, also inhibit the survival and function of pDCs (91). Further studies are needed in order to prove that specific targeting of pDCs in autoimmune diseases will inhibit the disease process. Another therapeutic possibility is to prevent the activation of pDCs, either by reducing the amount of interferogenic ICs by nucleases or by blocking the activation of TLRs with inhibitory oligodeoxynucleotides (92, 93).

Conclusions

  1. Top of page
  2. Introduction
  3. The interferons
  4. Characteristics of pDCs
  5. Activation of pDCs
  6. Endogenous IFN inducers
  7. Functions of pDCs in the immune response
  8. Plasmacytoid DCs in autoimmune rheumatic diseases
  9. Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases
  10. Conclusions
  11. AUTHOR CONTRIBUTIONS
  12. REFERENCES

The pDC is a unique cell type that specializes in producing large amounts of type I IFN in response to viral infections. The IFN that is produced not only induces virus resistance, but also stimulates the innate and adaptive immune systems. During the last decade, it has become clear that pDCs are activated in many rheumatic diseases and continuously produce type I IFN, which acts as an immune adjuvant and contributes to the autoimmune process. These observations have spurred the development of many new therapies aimed at inhibiting or modulating the overactivated pDCs. Results of early clinical trials in patients with SLE have shown that neutralization of type I IFN is feasible and of potential clinical benefit.

REFERENCES

  1. Top of page
  2. Introduction
  3. The interferons
  4. Characteristics of pDCs
  5. Activation of pDCs
  6. Endogenous IFN inducers
  7. Functions of pDCs in the immune response
  8. Plasmacytoid DCs in autoimmune rheumatic diseases
  9. Therapeutic targeting of pDCs and the type I IFN system in rheumatic diseases
  10. Conclusions
  11. AUTHOR CONTRIBUTIONS
  12. REFERENCES