Dendritic Cells

Chapter 8

Dendritic Cells: The Orchestrators of the Inflammatory Response in Autoimmune Diseases Jiram Torres-Ruiz1,2, Yehuda Shoenfeld2,3 1Department

of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Laboratory of the Mosaics of Autoimmunity, Saint-Petersburg University, Saint-Petersburg, Russian Federation 2Zabludowicz

INTRODUCTION Dendritic cells (DCs) are stellar-shaped leukocytes derived from the bone marrow that reside in the tissues and are responsible for capturing antigens from the local environment [1]. As professional antigen-presenting cells, in the steady state they favor central tolerance by the generation of regulatory T cells (Tregs) centrally in the thymus [2] and peripherally as they migrate in a small amount to the lymph nodes and present antigens to lymphocytes to favor a state of anergy in effector cells by expressing inhibitory molecules such as programmed death 1 (PD1) and cytotoxic T lymphocyte antigen 4 in T cells [2], as well as through the induction of Tregs through the secretion of transforming growth factor (TGF-β) and retinoic acid [2]. Although there are several DC subtypes distributed in almost all organs, skin, mucosa, and lymphoid tissue [3], globally, conventional dendritic cells (cDCs), those derived from monocytes and plasmacytoid dendritic cells (pDCs) have been linked to autoimmunity in several studies. pDCs are considered to be professional producers of IFN-α, but they also secrete TNF-α and IL-6 [4]. Type I IFNs are key cytokines in autoimmunity because they induce the maturation of cDC, promote antibodies secretion, and are able to promote the Th1 and CD8+ response [5]. DCs have a finger-like projection morphology and carry several pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) [2], C-type lectin receptors, and intracytoplasmic nucleotide-binding oligomerization domain (NOD)type receptors [6]. Multiple agents activate DCs, including microorganisms, dead cells (through alarmins such as heat shock proteins, high mobility group box 1 protein [HMGB-1], β-defensins, uric acid [UA]), cells of the innate and adaptive immune system, and pathogen-associated molecular patterns (PAMPs) [6]. Stimuli that induce DCs maturation include lipopolysaccharide (LPS), DNA, RNA, TNF-α, IL-1, IL-6, tissue factors, heat shock proteins, and CD154 from T lymphocytes [7]. In contrast, the low-affinity signal in T lymphocytes, IL-10, TGF-β, prostaglandins, and corticosteroids tend to modify the maturation of DCs and to divert the immune response toward Th2 [7]. When there is tissue damage or an infectious event, DCs migrate to the lymph nodes where they mature and increase the expression of peptides of the major histocompatibility complex (MHC), co-stimulatory molecules, chemokine receptors, and the production of key cytokines for the differentiation of effector T cells [1]. Thereafter, the cDC can polarize the response of helper T cells. The increased expression of TLR3 by CD141 + DCs and their ability to produce IFN-β, CXCL10, and IL-12p70 favor Th1. Nonlymphoid tissue residents cDCs induce Th1 and Th2 equally while Langerhans cells preferably induce a Th2 response [8]. On the other hand, CD1c + DCs induce a Th1 and Th17 response after stimulation of TLR7 combined with TLR4, TLR3, RIG-I, and MDA-5 [9]. The relationship between systemic autoimmunity and DCs has been demonstrated in several animal models including those deficient in IL-2, where the expansion of cDCs and pDCs entails an increased production of IL-12, IFN-γ leading to Th1 expansion and the death of BALB/C mice in 3–5 weeks secondary to autoimmune hemolytic anemia [10]. On the other hand, a higher expression of type I IFN-regulated genes (IFN signature) has been found in diverse autoimmune diseases and pDCs are the main source of IFN-α [11]. When peripheral blood monocytes are Mosaic of Autoimmunity. https://doi.org/10.1016/B978-0-12-814307-0.00008-6 Copyright © 2019 Elsevier Inc. All rights reserved.

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54  SECTION | II  Cellular and Molecular Mechanisms

cultured with Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) and IFN-α, they acquire the morphology of DCs with intense expression of TLR7 and increased secretion of IL-18 [11]. In addition, these cells produced higher amounts of IL-1β, IL-6, IL-10, and TNF-α, are capable of inducing a Th1 phenotype even in the absence of IL-12p70, and, by their increased expression of MHC-I, stimulate antigen-specific CD8+ T lymphocytes [11], which indicates that IFN-α is a key cytokine in the pathogenic autoimmune response and persistent inflammation in autoimmune diseases.

EVIDENCE OF THE PARTICIPATION OF DCS IN THE PATHOPHYSIOLOGY OF VARIOUS AUTOIMMUNE DISEASES In Table 8.1, we summarize the main studies involving abnormalities in DCs in a diversity of tissues and/or animal models of autoimmune diseases.

Dendritic Cells in Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is the prototype of systemic autoimmune disease and is characterized by loss of tolerance to intracellular antigens, especially chromatin antigens and ribonucleoproteins that promote damage by immune complexes deposition in virtually any organ. Virtually all leukocytes from patients with SLE are more predisposed to die and apoptotic blebs are a source of autoantigens [12]. In addition to this, it is known that patients with SLE have defects in phagocytosis, which promotes that the autoantigens persist in the environment making them accessible to the immune system [12]. In SLE patients, apoptotic blebs are accompanied by damage-associated molecular patterns (DAMPs) such as HMGB-1, which is a ligand for TLR2, TLR4, and the receptor for advanced glycation end products [12]. The activation of these PRRs promotes the expression of CD83, CD86, and MHC-II in myeloid dendritic cells (mDCs) in vitro [12]. In this way, activated DCs can stimulate CD4+ T lymphocytes to promote the production of cytokines and stimulate the secretion of autoantibodies. Another potential source of autoantigens in SLE is NETosis, which is a new mechanism of cell death where neutrophils extrude their decondensed chromatin as a network decorated with nuclear and cytoplasmic protein components named neutrophil extracellular traps (NETs) [13]. The NETs are a source of chromatin antigens including dsDNA, histones and nucleosomes, but patients with SLE have neutrophils with greater predisposition to carry out NETosis, and within the components of the NETs there have been found alarmins and antimicrobial peptides such as HMGB-1 and LL-37 [13]. The combination of LL-37 with anti-RNP has been shown to enhance the production IFN-α pDCs [13]. Type I IFNs play a key role in the pathogenesis of SLE [2]. The pDCs endocyte the immunoglobulin-DNA, RNA, and nucleoprotein complexes through the IgG FcγRIIa (CD32) low-affinity receptor, and the nucleic acids activate TLR7 and TLR9 in the endosomes promoting the synthesis of type I IFN, which increases the production of IL-6, TNF-α, and costimulatory molecules in DCs [12]. In addition, type I IFNs favor the CD4+ differentiation toward Th1 and augment the T cytotoxic response and the production of immunoglobulins by B lymphocytes [14]. The DCs in lupus not only present antigens and orchestrate autoimmunity but also present a source of IFN-α that perpetuates the pathogenic inflammatory response. The abnormal mechanisms of cell death in lupus are a key source of self-antigens that activate DCs to initiate the disease.

Dendritic Cells in Primary Sjögren’s Syndrome Primary Sjögren’s syndrome (pSS) is an autoimmune epithelitis characterized by keratoconjunctivitis sicca and a variable occurrence of systemic manifestations [15]. The participation of DCs in pSS-like autoimmunity is observed in Dcirdeficient animal models. Dcir is a C-type lectin immune receptor expressed mainly in DCs [16]. The deficiency of this receptor causes arthritis, enthesitis, sialadenitis, antinuclear antibodies, anti-Ro, anti-La antibodies, and rheumatoid factor in mice [16]. Because patients with pSS have type I IFN signature in approximately 50% of cases, it is possible that pDCs may be involved in the pathophysiology of the disease [15]. In addition, DCs have been shown to be an important source of IL-7, a key cytokine in the pathogenesis of pSS [17]. In the normal salivary gland, DCs are found between the epithelial cells in acini and ducts with extensions that extend basally and apically to the ducts lumen, as well as in the interstitial tissue [15]. Most studies that have evaluated DCs in patients with pSS have shown that they decrease in peripheral blood during the disease, which could

Dendritic Cells and Autoimmunity Chapter | 8  55

TABLE 8.1  Main Studies Demonstrating Quantitative and Qualitative Alterations in Dendritic Cells (DCs) of Patients With Autoimmune Diseases Disease

Model/Type of DC/Tissue

Principal Finding

References

Systemic lupus erythematosus

Myeloid dendritic cells (mDCs) ↓ Lin−HLA-DR+CD4+ DCs ↓ CD11c+ mDC frequency

↓ T cell stimulation capacity

[57–60]

Normal basal and lipopolysaccharide (LPS)– induced CD80, CD83, CD86 ↓ HLA-DR induction

No difference in TNF-α, IL-1β, IL-6, IL-12 on LPS and IFN-γ stimulation ↑ IL-6 in CD86 high expressing DCs

[61,62]

Normal mDC frequency CD80 and CD40 either ↑ or normal in mDCs ↑ CD86 ↑ BLyS ↓ CD83

↑ IL-8 secretion ↑ T cell proliferation and activation capacity

[63–66]

Plasmacytoid dendritic cells (pDCs)

↓ pDCs frequency

[58,59,61]

↑ pDCs in active versus active LN patients Presence of pDCs in LN kidney ↑ pDCs frequency Normal CD40, CD80, CD86 expression

↑ Allogeneic T cell proliferation, ↓ FoxP3 expression in co-cultured CD4+ T cells Persistent IL-10 mRNA expression and lack toll-like receptor (TLR9) induction on apoptotic cells stimulation

[63,67]

Normal pDC frequency ↓ ChemR23 expression in pDCs

↓ IFN-α production per pDC on CpG stimulation

[62,68]

Normal CD40 and CD80 expression

↑ Basal and CCL19-induced migration in pDCs

[66]

Human minor salivary gland biopsy

Upregulation of type I and II IFN genes Increased expression of TLR8 and TLR9 ↑ pDCs in salivary glands

[69]

pDC

No difference in peripheral blood vs. healthy controls Lower percentage and decreased numbers during active disease Present in salivary glands

[69–74]

Conventional dendritic cells (cDCs)

Lower percentage, no functional differences vs. healthy controls Present in salivary glands

Cladribine treatment

pDC increased during treatment Clinical improvement

IFN-β

cDC decreased during treatment pDC increased during treatment

pDCs

Located in white matter, leptomeninges, and cerebrospinal fluid (CSF), specially during exacerbations

[14]

↓ CD40 in primary-progressive vs. secondaryprogressive MS ↓ CD40 upregulation in relapsing-remitting MS

[76,77]

Primary Sjögren’s syndrome

Multiple sclerosis (MS)

[75]

↓ CD86 in relapsing-remitting MS ↓ CD123 in primary-progressive vs. secondaryprogressive MS ↓ IFN-α in relapsing-remitting MS

[77–80]

↑ IFN-α, IL-6, TNF-α in relapsing-remitting MS ↓ IFN-γ in relapsing-remitting MS Impaired Treg induction MS ↑ IL-17 MS

[81] Continued

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TABLE 8.1  Main Studies Demonstrating Quantitative and Qualitative Alterations in Dendritic Cells (DCs) of Patients With Autoimmune Diseases—cont’d Disease

Model/Type of DC/Tissue

Principal Finding

References

cDC

↑ CD40 on CSF and on relapsing-remitting vs. blood and secondary-progressive MS

[76,82,83]

↑ CD80 on CSF and in secondary-progressive vs. blood and relapsing-remitting MS ↓ CD80 In primary-progressive MS ↑ CD86, HLA-DR in CSF vs. peripheral blood ↓ CD86 in primary-progressive vs. relapsingremitting MS ↓ PDL-1 In secondary-progressive vs. relapsingremitting MS ↑ IL-12p70 in secondary-progressive MS

[83]

↑ IL-23p19 in relapsing-remitting MS ↑ TNF-α in secondary-progressive vs. relapsingremitting MS ↑ IFN-γ/IL-4/IL-13 in relapsing-remitting vs. secondary-progressive MS Rheumatoid arthritis

Type 1 diabetes mellitus

Idiopathic inflammatory myopathies Inflammatory bowel disease

Synovial tissue

cDCs and pDC sin perivascular regions

[84]

Peripheral blood

Same percentage of pDCs in comparison to healthy controls

Synovial fluid

Higher proportion of CD11c + DC vs. CD123 + DC

pDCs

Expanded in peripheral blood

[5,85]

Lower frequency in peripheral blood

[86]

cDC and pDC

Lower absolute numbers in peripheral blood

[87]

Muscle biopsy of DM and PM patients

Higher fascin + DC, lower langerin + DC

[88]

Muscle biopsy of PM patients

mDC invading nonnecrotic myober regions

[89]

Skin biopsy of DM patients

Higher frequency of pDCs

[90]

Colon biopsy

Higher frequency of langerin + immature dendritic cells

[91]

Colon biopsy

Higher DC-SIGN + DCs expressing CD80 and producing IL-12 and IL-18 in comparison to healthy controls

[92]

indicate that they migrate to the tissues to cause damage and perpetuate the autoimmune response [15]. In fact, in severe salivary gland lesions of patients with pSS, there are fascin(+) DCs that form networks with B and T lymphocytes and germinal centers [15]. At the same time, epithelial cells of patients with pSS express CD40 and produce chemokines such as BCA-1 (CXCL13), TARC (CCL17), ELC (CCL19), SLC (CCL21), and MDC (CCL22) that attract DCs [15]. Apparently, salivary acinar cells attract and activate DCs in response to environmental stimuli or viral infections. Once in the glandular tissue, DCs favor the formation of germinal centers with the consequent sialadenitis.

Dendritic Cells and Autoimmunity Chapter | 8  57

Dendritic Cells in Systemic Sclerosis Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, autoantibodies, and diffuse deposition of collagen in skin and internal organs secondary to overactivation of fibroblasts [18]. Despite the difficulty of studying DCs in patients with SSc, it is known that fibroblasts appear to recruit DCs in the skin and in the inflamed lung, as demonstrated by the co-localization between fibroblasts and CD1a DCs in skin lesions [18]. In addition, the secretion of TGF-β1 IL-4, IL-5, and IL-13 by DCs could favor fibrogenesis in SSc patients [18].

Dendritic Cells in Multiple Sclerosis Multiple sclerosis (MS) is a demyelinating disease of the central nervous system [14]. Apparently, the triggering event involves the activation of peripheral cDCs and CD4+ T lymphocytes that penetrate the blood–brain barrier and cause neuronal damage [14]. Both MS and its animal model, the experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases mediated by the cooperating subpopulations Th1 and Th17 [19]. The DCs of patients with MS are able to induce the production of IFN-γ in mononuclear cells [20], favoring a Th1 phenotype, whereas in EAE the mature DCs secrete IL-6 and TGF-β1 with the consequent decrease in Tregs and increase in Th17 [21]. The DCs polarize the T lymphocytes to Th17 expressing IL-6 in the cytoplasmic membrane (IL-6 trans-presentation) [22]. This kind of IL-6 signal transduction is important because it forms clusters of activated T cells, and the elimination of IL-6 trans-presenting DCs induces the production of IFN-γ, decreases the secretion of IL-17, and suppresses the development of EAE [22]. In this regard, IFN-β is essential because in EAE, IFN-β-deficient mice have an increased Th17 [19]. In MS, DCs derived from TNF-α and iNOS secreting monocytes can activate CD8+ T cells and favor the secretion of IFN-γ and IL-17, which contributes to the recruitment of other leukocytes and neuronal damage [14]. Regarding other types of DCs, the kinetics of appearance of pDCs in EAE is fundamental. Depletion of pDCs before the disease onset gives protection reducing Th17 differentiation and augmenting the Th1 response and the expression of FoxP3 in splenocytes. If pDCs are absent 1 week after the disease onset, the symptoms are exacerbated [23]. In MS, DCs activate CD4+ in the periphery and orchestrate the pathogenic immune response to induce a Th1 and Th17 response once these cells migrate to neuronal tissue.

Dendritic Cells in Type 1 Diabetes Mellitus Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the infiltration of autoreactive T cells into the pancreas leading to destruction of beta cells and impediment of insulin production [24]. DCs are able to capture pancreatic antigens and present them to CD4+ and CD8+ T cells [24]. In animal models of T1DM, it has been shown that most DCs that infiltrate islets are CD11c+ and have a monocytic origin [25]. The release of DNA into the extracellular space after tissue damage (for example, after a viral infection) is able to activate TLR9 in pDCs, favoring the synthesis of IFN-α and the triggering of DM1, probably through the maturation of mDCs [26]. CD11c + CD11b + CD8α DCs activate T lymphocytes for the onset of insulitis [27]. In addition, DM1 is strongly associated with HLA-DR3/DQ2 and HLA-DR4/DQ8, and it has been shown that DCs from T1DM patients present three immunogenic peptides (preproinsulin, islet tyrosine phosphatase insulinoma associated Ag-2, and glutamic acid decarboxylase 65) through these risk HLA [28]. It is possible that in the face of tissue damage secondary to viral infections, there will be release of antigens that are captured by DCs and subsequently presented to CD4+ to promote insulitis and the development of T1DM in a genetically predisposed individual.

Dendritic Cells in Psoriasis Psoriasis is a chronic inflammatory skin disease characterized by erythematous squamous plaques that affect 2%–3% of the population [29]. In psoriasis, DCs are fundamental in the polarization of Th cells to a Th17 and Th1 phenotype by the production of IL-23 and IL-12 [30,31]. Thereafter, T cells produce IL-17, IFN-γ, TNF-α, and IL-22 that amplify inflammation and promote keratinocyte hyperplasia [31]. Apparently keratinocytes initiate the immune response after tissue damage. Psoriasis lesions can be triggered after a trauma (Koebner’s phenomenon), infections, or medication use, where the damage to keratinocytes releases the antimicrobial peptide LL-37 that forms complexes with RNA and DNA and activates the mDCs and pDCs through to TLR8 and TLR9, respectively, to induce inflammation and favor the secretion of type I IFN [29].

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Dendritic Cells in Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition of the gastrointestinal tract that mainly encompasses ulcerative colitis (UC) and Crohn’s disease (CD) [32]. One hundred trillion of bacteria, viruses, fungi, and protozoans habitat the human gastrointestinal mucosa [32]. The imbalance in the microbial system that leads to intestinal disorders (dysbiosis) is a key feature of the pathophysiology of IBD [32]. In the steady state and when intestinal homeostasis is present, the sampling of certain bacterial components such as polysaccharide A from Bacteroides fragilis by DCs leads to the induction of Tregs and the consequent secretion of IL-10 [32]. In IBD on the other hand, certain genetic and environmental factors lead to dysbiosis, which lead to uncontrolled inflammation, hyperactivation of Th1 and Th17 cells, and decreased differentiation of Tregs [32]. DCs seem to play an important role in the pathophysiology of IBD because animal models have shown that they are capable of priming T cells to develop a pathogenic autoimmune response, and because of their secretion of proinflammatory cytokines, they perpetuate the pathogenic autoimmunity [33]. A local inflammatory environment promotes the maturation of local DCs, which can pick up local antigens, migrate to lymphoid tissues, and expand the pathogenic autoimmune response [33]. In UC it has been shown that DCs release macrophage-inhibiting factor, a cytokine able to enhance their capability to activate T lymphocytes [34]. Nevertheless, DCs studies in patients with IBD have been contradictory, as some have shown a predominance of immature DCs while others have demonstrated raised CD40, CD80, CD83, and CD80 expression in DCs from patients with IBD compared to controls [35,36]; however, the role of DCs as orchestrators of the pathogenic autoimmune response in IBD is frank because they are distributed throughout the intestinal mucosa and polarize the immune response to a Th1 and Th17 phenotype when they are activated by the microbiota PAMPs in the context of dysbiosis.

Dendritic Cells in Rheumatoid Arthritis Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized mainly by the presence of chronic polyarthritis with the variable occurrence of extra-articular manifestations [37]. DCs in RA show an activated phenotype and produce chemokines such as IL-12 and IL-23 that promote differentiation toward Th1 and Th17 [38]. The presence of antigens with posttranslational modifications such as citrullination is important in the pathogenesis of RA because they may lead to an enhanced immune response. In this regard, DCs in the synovium may uptake these antigens [7] and present them more efficiently than DCs of control subjects [39] The pDCs contribute to inflammation through the production of IFN-α, IFN-β, IL-18, IL-23, and BAFF [38]. Finally, DCs derived from monocytes in RA are able to produce TNF, IL-6, and IL-1β, which in turn bias the T cell response toward Th17 [7]. Probably, pDCs of patients with RA favor the B cells survival and the maturation of DCs, which uptake immunogenic citrullinated antigens and present them to T lymphocytes, leading to synovitis and joint destruction.

Dendritic Cells in Idiopathic Inflammatory Myopathies Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases characterized by proximal muscle weakness, increased Creatine kinase (CK), myopathic findings in electromyography, and inflammatory infiltrate in muscle biopsy [40]. Included in the spectrum of IIM are dermatomyositis (DM), polymyositis (PM), necrotizing myopathy, and antisynthetase syndrome (AS) [40]. The first evidence of the participation of DCs in IIM is the presence of immature DCs infiltrating the muscle in these diseases [41]. On the other hand, anti–histidyl synthetase (HisRS) antibodies are the most frequent type of antisynthetase antibodies and previous works have demonstrated that the NH2-terminal domain of HisRS is chemotactic for immature DCs [42]. In muscle biopsies of DM and juvenile DM patients, DCs are located mainly in the perivascular space, whereas in PM they penetrate deep into the muscle [43]. The recruitment of DCs can be facilitated in muscle by the secretion of CXCR4 CCL19 CCL21 by mononuclear cells [43]. DCs in IIM also produce IL-18, which favors the proliferation and differentiation of naïve T cells [44], and pCDs are involved in the type IFN signature found in patients with DM because it is known that they are present in the perimysial, fascial, and endomysial inflammatory infiltrate [45].

Dendritic Cells in the Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants Due to the abundance in the expression of PRRs, DCs are fundamental in the autoimmune reactions induced by adjuvants. The prototypes of these reactions are macrophagic myofasciitis and adverse reactions after vaccines. In macrophagic

Dendritic Cells and Autoimmunity Chapter | 8  59

myofasciitis, aluminum hydroxide (Al (OH)3) persists for years after the administration of a vaccine [46]. The adjuvant is found at injection sites and in the body of patients with the disease, which is characterized by myalgias, arthralgias, chronic fatigue, and an inflammatory infiltrate of PAS(+) macrophages that express MHC-I and that show aluminum in their cytoplasm by electron microscopy [46]. At the same time, there are CD8+ T cells and damaged muscle fibers in the muscle biopsy [46]. Aluminum hydroxide (Al (OH)3) favors tissue damage with the consequent release of UA and activation of the NALP3 inflammasome on DCs, with the consequent chemotaxis of neutrophils, eosinophils, and mononuclear cells to the injection site [46]. After that, there is activation of the immune system and the bias of the immune response toward a Th2 phenotype [46,47]. When UA is released into the extracellular space, it is recognized as DAMP, promoting the capture of antigens by inflammatory monocytes at the site of injury [46]. Posteriorly, those monocytes migrate to the lymph nodes where they mature to DCs and activate CD4+ T cells [46]. Aluminum also directly activates the NALP3 inflammasome on DCs with the consequent release of IL-1β [46,47]. Aluminum enhances the normal function of DCs, but in a subject genetically predisposed (for example, a carrier of HLADRB1*01), it can promote the development of chronic inflammation with systemic manifestations as in macrophage myofasciitis.

TOLEROGENIC DENDRITIC CELLS Immature DCs and pDCs are considered to be naturally tolerogenic because of their low expression of MHC and co-stimulatory molecules. For example, immature DCs are able to induce tolerance in an EAE model when they are administered intravenously by increasing the production of IL-10 and Tregs [48]. However, tolerogenic dendritic cells (tolDCs) derived from peripheral blood have been generated in multiple in vitro models by cytokines such as IL-10, TGF-β, or with immunosuppressive drugs such as cyclosporine, rapamycin, mycophenolate mofetil, vitamin D3, dexamethasone, or other agents such as N-acetyl-cysteine, glucosamine, HLA-G, cAMP, or PGE2 [49]. TolDCs can be conventional or plasmacytoid and maintain peripheral tolerance through anergy and apoptosis of autoreactive T cells and through the induction of Tregs [50]. TolDCs can also exert their action by the expression of indoleamine 2,3-dioxygenase or programmed death ligand 1 (PDL-1) [49]. Its objective is to reestablish antigen-specific tolerance without promoting general immunosuppression [50]. The tolDCs do not change their phenotype in vitro, that is, even after being stimulated they do not favor the activation of self-reactive cells [50]. TolDCs have been tested mainly in animal models of MS and RA. For example, the use of tolDCs transfected with lentiviruses that inhibit the production of CD40 and IL-23 decreases the phenotype of EAE by inhibiting differentiation toward Th17 and increasing the production of IL-10 [51]. It is possible that the manipulation of transcription factors in DCs is able to modulate the immune response, for example; the increase in the expression of SOCS3 in DCs polarizes the immune response toward Th2 and decreases the symptomatology of EAE [52]. Other molecules such as LPS decrease the phenotype of EAE by creating tolDCs that reduce ROR-γt and IFN-γ in T cells prestimulated with myelin oligodendrocyte glycoprotein (MOG) [53]. The use of DCs expressing TRAIL (a member of the superfamily of TNF receptors) or PDL-1 together with MOG favors the formation of Tregs and the apoptosis of effector T cells in a murine model of EAE [54,55]. In animal models of collagen-induced arthritis, the IL-10 and TGF-β induced tolDCs have been shown to decrease the severity of the disease by increasing Tregs [38,56]. Despite the technical difficulties involved in the development and administration of tolDCs in humans, their efficacy in animal models offer hope for a personalized treatment of autoimmune diseases without the need for global immunosuppression.

CONCLUSIONS In a genetically predisposed individual, infections and tissue damage induced favor the activation of DCs. When there are alterations in central or peripheral tolerance, the antigenic presentation and production of cytokines by DCs promotes the polarization of helper cells toward Th1 and Th17, which in turn promote tissue damage through a pathogenic autoimmune response. In Fig. 8.1, we propose a general model to explain the participation of DCs as triggers and perpetuating agents in autoimmune diseases.

FIGURE 8.1  In patients with autoimmune diseases, epithelial and connective tissue cells secrete various chemokines that attract dendritic cells (DCs). In response to environmental stimuli including tissue damage, NETosis, infections, or the use of adjuvants such as alum, there is activation of the transmembrane and cytoplasmic pattern recognition receptors (PRRs) in DCs leading to the secretion of proinflammatory cytokines. As a result, there is a polarization of the Th response toward Th1 and Th17, which are known to be involved in the pathophysiology of many autoimmune diseases. DCs are also professional antigen-presenting cells, especially of those antigens containing posttranslational modifications and as professional type I producers, pDC induce the maturation of myeloid dendritic cells and the secretion of autoantibodies by B cells, expanding the inflammatory response. Finally, the secretion of TFG-β and IL-13 may relate dendritic cells with fibrosis in patients with systemic sclerosis.

Dendritic Cells and Autoimmunity Chapter | 8  61

REFERENCES [1] Wu L, Dakic A. Development of dendritic cell system. Cell Mol Immunol 2004;1(2):112–8. [2] Kim JM, Park SH, Kim HY. Kwok SKA plasmacytoid dendritic cells-type I interferon Axis is critically implicated in the pathogenesis of systemic lupus erythematosus. Int J Mol Sci 2015;16(6):14158–70. [3] Chen K, Wang JM, Yuan R, et al. Tissue-resident dendritic cells and diseases involving dendritic cell malfunction. Int Immunopharmacol 2016;34:1–15. [4] Xie ZX, Zhang HL, Wu XJ, Zhu J, Ma DH, Jin T. Role of the immunogenic and tolerogenic subsets of dendritic cells in multiple sclerosis. Mediators Inflamm 2015;2015:513295. [5] Xia CQ, Peng R, Chernatynskaya AV, et al. Increased IFN-alpha-producing plasmacytoid dendritic cells (pDCs) in human Th1-mediated type 1 diabetes: pDCs augment Th1 responses through IFN-alpha production. J Immunol 2014;193(3):1024–34. [6] Blanco P, Palucka AK, Pascual V, Banchereau J. Dendritic cells and cytokines in human inflammatory and autoimmune diseases. Cytokine Growth Factor Rev 2008;19(1):41–52. [7] Lutzky V, Hannawi S, Thomas R. Cells of the synovium in rheumatoid arthritis. Dendritic cells. Arthritis Res Ther 2007;9(4):219. [8] Boltjes A, Van Wijk F. Human dendritic cell functional specialization in steady-state and inflammation. Front Immunol 2014;5:131. [9] Leal Rojas IM, Mok WH, Pearson FE, Minoda Y, Kenna TJ, Barnard RT, Radford KJ. Human blood CD1c+ dendritic cells promote Th1 and Th17 effector function in memory CD4+ T cells. Front Immunol 2017;8:971. [10] Isakson SH, Katzman SD, Hoyer KK. Spontaneous autoimmunity in the absence of IL-2 is driven by uncontrolled dendritic cells. J Immunol 2012;189(4):1585–93. [11] Mohty M, Vialle-Castellano A, Nunes JA, Isnardon D, Olive D, Gaugler B. IFN- Skews monocyte differentiation into toll-like receptor 7-expressing dendritic cells with potent functional activities. J Immunol 2003;171(7):3385–93. [12] Chan VS, Nie YJ, Shen N, Yan S, Mok MY, Lau CS. Distinct roles of myeloid and plasmacytoid dendritic cells in systemic lupus erythematosus. Autoimmun Rev 2012;11(12):890–7. [13] Garcia-Romo GS, Caielli S, Vega B, et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 2011;3(73):73ra20. [14] Galicia G, Gommerman JL. Plasmacytoid dendritic cells and autoimmune inflammation. Biol Chem 2014;395(3):335–46. [15] Hillen MR, Ververs FA, Kruize AA, Van Roon JA. Dendritic cells, T-cells and epithelial cells: a crucial interplay in immunopathology of primary Sjögren’s syndrome. Expert Rev Clin Immunol 2014;10(4):521–31. [16] Fujikado N, Saijo S, Yonezawa T, et al. Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells. Nat Med 2008;14(2):176–80. [17] Van Roon JA, Kruize AA, Radstake TR. Editorial: interleukin-7 and its receptor: the axis of evil to target in Sjogren’s syndrome? Arthritis Rheum 2013;65(8):1980–4. [18] Lu TT. Dendritic cells: novel players in fibrosis and scleroderma. Curr Rheumatol Rep 2012;14(1):30–8. [19] Pennell LM, Fish EN. Interferon-beta regulates dendritic cell activation and migration in experimental autoimmune encephalomyelitis. Immunology 2017;152(3):439–50. [20] Huang YM, Stoyanova N, Jin YP, Teleshova N, Hussien Y, Xiao BG, Fredrikson S, Link H. Altered phenotype and function of blood dendritic cells in multiple sclerosis are modulated by IFN-beta and IL-10. Clin Exp Immunol 2001;124(2):306–14. [21] Lu P, Cao Y, Wang M, et al. Mature dendritic cells cause Th17/Treg imbalance by secreting TGF-beta1 and IL-6 in the pathogenesis of experimental autoimmune encephalomyelitis. Cent Eur J Immunol 2016;41(2):143–52. [22] Heink S, Yogev N, Garbers C, et al. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat Immunol 2017;18(1):74–85. [23] Isaksson M, Ardesjo B, Ronnblom L, et al. Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE. Eur J Immunol 2009;39(10):2925–35. [24] Da Silva RC, Cunha Tavares Nde A, Moura R, et al. DC-SIGN polymorphisms are associated to type 1 diabetes mellitus. Immunobiology 2014;219(11):859–65. [25] Klementowicz JE, Mahne AE, Spence A, et al. Cutting edge: origins, recruitment, and regulation of CD11c+ cells in inflamed islets of autoimmune diabetes mice. J Immunol 2017;199(1):27–32. [26] Guerder S, Joncker N, Mahiddine K, Serre L. Dendritic cells in tolerance and autoimmune diabetes. Curr Opin Immunol 2013;25(6):670–5. [27] Abram DM, Fernandes LGR, Ramos Filho ACS, Simioni PU. The modulation of enzyme indoleamine 2,3-dioxygenase from dendritic cells for the treatment of type 1 diabetes mellitus. Drug Des Dev Ther 2017;11:2171–8. [28] Van Lummel M, Van Veelen PA, De Ru AH, et al. Dendritic cells guide islet autoimmunity through a restricted and uniquely processed peptidome presented by high-risk HLA-DR. J Immunol 2016;196(8):3253–63. [29] Lowes MA, Suarez-Farinas M, Krueger JG. Immunology of psoriasis. Annu Rev Immunol 2014;32:227–55. [30] Harden JL, Krueger JG, Bowcock AM. The immunogenetics of Psoriasis: a comprehensive review. J Autoimmun 2015;64:66–73. [31] Kim J, Krueger JG. The immunopathogenesis of psoriasis. Dermatol Clin 2015;33(1):13–23. [32] Zhang M, Sun K, Wu Y, Yang Y, Tso P, Wu Z. Interactions between intestinal microbiota and host immune response in inflammatory bowel disease. Front Immunol 2017;8:942. [33] Leon F, Smythies LE, Smith PD, Kelsall BL. Involvement of dendritic cells in the pathogenesis of inflammatory bowel disease. Adv Exp Med Biol 2006;579:117–32.

62  SECTION | II  Cellular and Molecular Mechanisms

[34] Murakami H, Akbar SM, Matsui H, Horiike N, Onji M. Macrophage migration inhibitory factor activates antigen-presenting dendritic cells and induces inflammatory cytokines in ulcerative colitis. Clin Exp Immunol 2002;128(3):504–10. [35] Stagg AJ, Hart AL, Knight SC, Kamm MA. The dendritic cell: its role in intestinal inflammation and relationship with gut bacteria. Gut 2003;52(10):1522–9. [36] Vuckovic S, Florin TH, Khalil D, et al. CD40 and CD86 upregulation with divergent CMRF44 expression on blood dendritic cells in inflammatory bowel diseases. Am J Gastroenterol 2001;96(10):2946–56. [37] Angelotti F, Parma A, Cafaro G, Capecchi R, Alunno A, Puxeddu I. One year in review 2017: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 2017;35(3):368–78. [38] Schinnerling K, Soto L, Garcia-Gonzalez P, Catalan D, Aguillon JC. Skewing dendritic cell differentiation towards a tolerogenic state for recovery of tolerance in rheumatoid arthritis. Autoimmun Rev 2015;14(6):517–27. [39] Waalen K, Førre O, Teigland J, Natvig JB. Human rheumatoid synovial and normal blood dendritic cells as antigen presenting cell–comparison with autologous monocytes. Clin Exp Immunol 1987;70(1):1–9. [40] Milone M. Diagnosis and management of immune-mediated myopathies. Mayo Clin Proc 2017;92(5):826–37. [41] Chevrel G, Page G, Miossec P. Novel aspects on the contribution of T cells and dendritic cells in the pathogenesis of myositis. Autoimmunity 2006;39(3):171–6. [42] Howard OM, Zack, Dong HF, Yang De, et al. Histidyl–tRNA synthetase and asparaginyl–tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T Lymphocytes and immature dendritic cells. J Exp Med 2002;196(6):781–91. [43]  De Padilla CM, Reed AM. Dendritic cells and the immunopathogenesis of idiopathic inflammatory myopathies. Curr Opin Rheumatol 2008;20(6):669–74. [44] Tucci M, Quatraro C, Dammacco F, Silvestris F. Increased IL-18 production by dendritic cells in active inflammatory myopathies. Ann N Y Acad Sci 2007;1107:184–92. [45] Li L, Dai T, Lv J, et al. Role of Toll-like receptors and retinoic acid inducible gene I in endogenous production of type I interferon in dermatomyositis. J Neuroimmunol 2015;285:161–8. [46] Israeli E, Agmon-Levin N, Blank M, Shoenfeld Y. Macrophagic myofaciitis a vaccine (alum) autoimmune-related disease. Clin Rev Allergy Immunol 2011;41(2):163–8. [47] Kool M, Petrilli V, De Smedt T, et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol 2008;181(6):3755–9. [48] Zhou F, Ciric B, Zhang GX, Rostami A. Immune tolerance induced by intravenous transfer of immature dendritic cells via up-regulating numbers of suppressive IL-10(+) IFN-gamma(+)-producing CD4(+) T cells. Immunol Res 2013;56(1):1–8. [49] Mok M. Tolerogenic dendritic cells: role and therapeutic implications in systemic lupus erythematosus. Int J Rheum Dis 2015;18(2):250–9. [50] Gross CC, Jonuleit H, Wiendl H. Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis. Eur J Immunol 2012;42(3):569–72. [51] Kalantari T, Karimi MH, Ciric B, Yan Y, Rostami A, Kamali-Sarvestani E. Tolerogenic dendritic cells produced by lentiviral-mediated CD40- and interleukin-23p19-specific shRNA can ameliorate experimental autoimmune encephalomyelitis by suppressing T helper type 17 cells. Clin Exp Immunol 2014;176(2):180–9. [52] Li Y, Chu N, Rostami A, Zhang GX. Dendritic cells transduced with SOCS-3 exhibit a tolerogenic/DC2 phenotype that Directs type 2 Th cell differentiation in vitro and in vivo. J Immunol 2006;177(3):1679–88. [53] Zhou F, Ciric B, Zhang GX, Rostami A. Immunotherapy using lipopolysaccharide-stimulated bone marrow-derived dendritic cells to treat experimental autoimmune encephalomyelitis. Clin Exp Immunol 2014;178(3):447–58. [54] Hirata S, Matsuyoshi H, Fukuma D, et al. Involvement of regulatory T cells in the experimental autoimmune encephalomyelitis-preventive effect of dendritic cells expressing myelin oligodendrocyte glycoprotein plus TRAIL. J Immunol 2007;178(2):918–25. [55] Hirata S, Senju S, Matsuyoshi H, Fukuma D, Uemura Y, Nishimura Y. Prevention of experimental autoimmune encephalomyelitis by transfer of embryonic stem cell-derived dendritic cells expressing myelin oligodendrocyte glycoprotein peptide along with TRAIL or programmed Death-1 ligand. J Immunol 2005;174(4):1888–97. [56] Ning B, Wei J, Zhang A, et al. Antigen-specific tolerogenic dendritic cells ameliorate the severity of murine collagen-induced arthritis. PLoS One 2015;10(6):e0131152. [57] Scheinecker C, Zwolfer B, Koller M, Manner G, Smolen JS. Alterations of dendritic cells in systemic lupus erythematosus: phenotypic and functional deficiencies. Arthritis Rheum 2001;44(4):856–65. [58] Migita K, Miyashita T, Maeda Y, et al. Reduced blood BDCA-2+ (lymphoid) and CD11c+ (myeloid) dendritic cells in systemic lupus erythematosus. Clin Exp Immunol 2005;142(1):84–91. [59] Fiore N, Castellano G, Blasi A, et al. Immature myeloid and plasmacytoid dendritic cells infiltrate renal tubulointerstitium in patients with lupus nephritis. Mol Immunol 2008;45(1):259–65. [60] Koller M, Zwolfer B, Steiner G, Smolen JS, Scheinecker C. Phenotypic and functional deficiencies of monocyte-derived dendritic cells in systemic lupus erythematosus (SLE) patients. Int Immunol 2004;16(11):1595–604. [61] Tucci M, Quatraro C, Lombardi L, Pellegrino C, Dammacco F, Silvestris F. Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18. Arthritis Rheum 2008;58(1):251–62. [62] Henriques A, Ines L, Carvalheiro T, et al. Functional characterization of peripheral blood dendritic cells and monocytes in systemic lupus erythematosus. Rheumatol Int 2012;32(4):863–9.

Dendritic Cells and Autoimmunity Chapter | 8  63

[63] Jin O, Kavikondala S, Sun L, et al. Systemic lupus erythematosus patients have increased number of circulating plasmacytoid dendritic cells, but decreased myeloid dendritic cells with deficient CD83 expression. Lupus 2008;17(7):654–62. [64] Decker P, Kotter I, Klein R, Berner B, Rammensee HG. Monocyte-derived dendritic cells over-express CD86 in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2006;45(9):1087–95. [65] Ding D, Mehta H, Mccune WJ, Kaplan MJ. Aberrant phenotype and function of myeloid dendritic cells in systemic lupus erythematosus. J Immunol 2006;177(9):5878–89. [66] Gerl V, Lischka A, Panne D, et al. Blood dendritic cells in systemic lupus erythematosus exhibit altered activation state and chemokine receptor function. Ann Rheum Dis 2010;69(7):1370–7. [67] Jin O, Kavikondala S, Mok MY, et al. Abnormalities in circulating plasmacytoid dendritic cells in patients with systemic lupus erythematosus. Arthritis Res Ther 2010;12(4):R137. [68] Kwok SK, Lee JY, Park SH, et al. Dysfunctional interferon-alpha production by peripheral plasmacytoid dendritic cells upon Toll-like receptor-9 stimulation in patients with systemic lupus erythematosus. Arthritis Res Ther 2008;10(2):R29. [69] Gottenberg JE, Cagnard N, Lucchesi C, et al. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren’s syndrome. Proc Natl Acad Sci U S A 2006;103(8):2770–5. [70] Ozaki Y, Ito T, Son Y, et al. Decrease of blood dendritic cells and increase of tissue-infiltrating dendritic cells are involved in the induction of Sjogren’s syndrome but not in the maintenance. Clin Exp Immunol 2010;159(3):315–26. [71] Wildenberg ME, Van Helden-Meeuwsen CG, Van De Merwe JP, Drexhage HA, Versnel MA. Systemic increase in type I interferon activity in Sjogren’s syndrome: a putative role for plasmacytoid dendritic cells. Eur J Immunol 2008;38(7):2024–33. [72] Ozaki Y, Amakawa R, Ito T, et al. Alteration of peripheral blood dendritic cells in patients with primary Sjogren’s syndrome. Arthritis Rheum 2001;44(2):419–31. [73] Vogelsang P, Brun JG, Oijordsbakken G, Skarstein K, Jonsson R, Appel S. Levels of plasmacytoid dendritic cells and type-2 myeloid dendritic cells are reduced in peripheral blood of patients with primary Sjogren’s syndrome. Ann Rheum Dis 2010;69(6):1235–8. [74] Thewissen K, Nuyts AH, Deckx N, et al. Circulating dendritic cells of multiple sclerosis patients are proinflammatory and their frequency is correlated with MS-associated genetic risk factors. Mult Scler 2014;20(5):548–57. [75] Mitosek-Szewczyk K, Tabarkiewicz J, Wilczynska B, et al. Impact of cladribine therapy on changes in circulating dendritic cell subsets, T cells and B cells in patients with multiple sclerosis. J Neurol Sci 2013;332(1–2):35–40. [76] Lopez C, Comabella M, Al-Zayat H, Tintore M, Montalban X. Altered maturation of circulating dendritic cells in primary progressive MS patients. J Neuroimmunol 2006;175(1–2):183–91. [77] Stasiolek M, Bayas A, Kruse N, et al. Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis. Brain 2006;129(Pt 5):1293–305. [78] Bayas A, Stasiolek M, Kruse N, Toyka KV, Selmaj K, Gold R. Altered innate immune response of plasmacytoid dendritic cells in multiple sclerosis. Clin Exp Immunol 2009;157(3):332–42. [79] Hirotani M, Niino M, Fukazawa T, et al. Decreased interferon-alpha production in response to CpG DNA dysregulates cytokine responses in patients with multiple sclerosis. Clin Immunol 2012;143(2):145–51. [80] Balashov KE, Aung LL, Vaknin-Dembinsky A, Dhib-Jalbut S, Weiner HL. Interferon-beta inhibits toll-like receptor 9 processing in multiple sclerosis. Ann Neurol 2010;68(6):899–906. [81] Schwab N, Zozulya AL, Kieseier BC, Toyka KV, Wiendl H. An imbalance of two functionally and phenotypically different subsets of plasmacytoid dendritic cells characterizes the dysfunctional immune regulation in multiple sclerosis. J Immunol 2010;184(9):5368–74. [82] Pashenkov M, Huang YM, Kostulas V, Haglund M, Soderstrom M, Link H. Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain 2001;124(Pt 3):480–92. [83] Karni A, Abraham M, Monsonego A, et al. Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response. J Immunol 2006;177(6):4196–202. [84] Cavanagh L, Boyce A, Smith L, Padmanabha J, Filgueira L, Pietschmann P, Thomas R. Rheumatoid arthritis synovium contains plasmacytoid dendritic cells. Arthritis Res Ther 2005;7(2):R230–40. [85] Allen JS, Pang K, Skowera A, et al. Plasmacytoid dendritic cells are proportionally expanded at diagnosis of type 1 diabetes and enhance islet autoantigen presentation to T-cells through immune complex capture. Diabetes 2009;58(1):138–45. [86] Chen X, Makala LH, Jin Y, et al. Type 1 diabetes patients have significantly lower frequency of plasmacytoid dendritic cells in the peripheral blood. Clin Immunol 2008;129(3):413–8. [87] Vuckovic S, Withers G, Harris M, et al. Decreased blood dendritic cell counts in type 1 diabetic children. Clin Immunol 2007;123(3):281–8. [88] Gendek-Kubiak H, Gendek EG. Fascin-expressing dendritic cells dominate in polymyositis and dermatomyositis. J Rheumatol 2013;40(2):186–91. [89] Greenberg SA, Pinkus GS, Amato AA, Pinkus JL. Myeloid dendritic cells in inclusion-body myositis and polymyositis. Muscle Nerve 2007;35(1):17–23. [90] Wenzel J, Schmidt R, Proelss J, Zahn S, Bieber T, Tuting T. Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis. Clin Exp Dermatol 2006;31(4):576–82. [91] Kaser A, Ludwiczek O, Holzmann S, et al. Increased expression of CCL20 in human inflammatory bowel disease. J Clin Immunol 2004;24(1):74–85. [92] Te Velde AA, Van Kooyk Y, Braat H, et al. Increased expression of DC-SIGN+IL-12+IL-18+ and CD83+IL-12-IL-18- dendritic cell populations in the colonic mucosa of patients with Crohn’s disease. Eur J Immunol 2003;33(1):143–51.