Role of extracellular vesicles in autoimmune diseases

AUTREV-01782; No of Pages 10 Autoimmunity Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

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Article history: Received 2 November 2015 Accepted 5 November 2015 Available online xxxx

Immunology and Immunogenetic Department, Bordeaux Hospital, place Amélie Raba Léon, 33076 Bordeaux Cedex, France Rheumatology Department, Bordeaux Hospital, place Amélie Raba Léon, 33076 Bordeaux Cedex, France UMR-5164 CNRS, CIRID, University of Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France d UMR-5248-CBMN CNRS University of Bordeaux-IBP, allée Geoffroy Saint-Hilaire, 33600 Pessac, France e Internal Medicine and Clinical Immunology Department, Bordeaux Hospital, 1 rue Jean Burguet, 33075 Bordeaux Cedex, France b

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Extracellular vesicles (EVs) consist of exosomes released upon fusion of multivesicular bodies with the cell plasma membrane and microparticles shed directly from the cell membrane of many cell types. EVs can mediate cell–cell communication and are involved in many processes including inflammation, immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. Accumulating evidence reveals that EVs act in the establishment, maintenance and modulation of autoimmune processes among several others involved in cancer and cardiovascular complications. EVs could also present biomedical applications, as disease biomarkers and therapeutic targets or agents for drug delivery. © 2015 Published by Elsevier B.V.

Keywords: Autoimmune diseases Systemic lupus erythematosus Rheumatoid arthritis Extracellular vesicles Microparticles Exosomes

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Exosomes and MPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods of EV isolation and detection . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Pre-analytical phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Analytical phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EV involvement in pathophysiology of autoimmune diseases . . . . . . . . . . . . . . . . 4.1. EV mode of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Role of EVs in immune response . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. EVs: source of self-antigens . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. EVs: role of adjuvants and in innate immune response . . . . . . . . . . . 4.2.3. Secretion and transport capacities of EVs and role in inflammation / immunity 4.2.4. Immunosuppressive functions of EVs . . . . . . . . . . . . . . . . . . . 4.3. Role of EVs in coagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. EVs and vascular dysfunctions . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. EVs and vasomotion . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2. Role of EVs in angiogenesis . . . . . . . . . . . . . . . . . . . . . . . EVs and autoimmune diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Antiphospholipid syndrome (APS) . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Systemic sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Delphine Turpin a, Marie-Elise Truchetet b, Benjamin Faustin c, Jean-François Augusto c, Cécile Bordes a,c, Alain Brisson d, Patrick Blanco a,c,⁎, Pierre Duffau c,e

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⁎ Corresponding author at: Immunology and Immunogenetic Department, Bordeaux Hospital, place Amélie Raba Léon, 33076 Bordeaux Cedex, France. E-mail addresses: [email protected] (D. Turpin), [email protected] (M.-E. Truchetet), [email protected] (B. Faustin), [email protected] (J.-F. Augusto), [email protected] (C. Bordes), [email protected] (A. Brisson), [email protected] (P. Blanco), [email protected] (P. Duffau).

http://dx.doi.org/10.1016/j.autrev.2015.11.004 1568-9972/© 2015 Published by Elsevier B.V.

Please cite this article as: Turpin D, et al, Role of extracellular vesicles in autoimmune diseases, Autoimmun Rev (2015), http://dx.doi.org/10.1016/ j.autrev.2015.11.004

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5.5. ANCA-associated vasculitis . . . . . . . . . . . . . . . . . 5.6. Multiple sclerosis . . . . . . . . . . . . . . . . . . . . . 6. Use of EVs as therapeutic targets and/or agents in autoimmune diseases 7. Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Exosomes and MPs form the two main populations of EVs. The border between these two types of EVs is however tenuous as both

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Extracellular vesicles (EVs) are a heterogeneous family of extracellular structures bounded by a phospholipid bilayer and released by all cell types in various biological fluids. They contain and expose at their membrane surface protein and lipid components as well as nucleic acids originating from their original cell [1,2]. EVs are considered to consist of two main families: the exosomes and the microparticles (MPs) which are distinguished by their size, their mechanism of formation and their composition [3] as shown in Fig. 1. It is commonly recognized that EVs have various biological functions involved in different processes such as inflammation, immune signaling, coagulation, vascular reactivity, angiogenesis and tissue repair [1,4]. They mediate intercellular communication and can also act as platform for enzymatic processes. These characteristics give to EVs an increasingly documented role in physiological processes. EVs are also considered as potential biomarkers of activity or cell death and have been proposed as agents for drug delivery [5]. Their involvement in various pathological mechanisms represents a new area of research, particularly in pathogenesis of autoimmune diseases [4,6].

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structures share common characteristics. Moreover, this distribution according to their size is probably not very relevant in vivo [7]. In theory, EVs are produced by all cell types including immune cells and are found in all body fluids (blood, urine, saliva, cerebrospinal fluid, breastmilk, amniotic fluid, ascites, bile and semen). Exosomes have a size between 50 and 100 nm and derive from endocytic compartment [1–3,8]. They are generated by invagination of the endosomal membrane resulting in the formation of intraluminal vesicles in endosomal multivesicular body [9–11]. During the invagination process, cytosolic cell components are encapsulated inside vesicles and molecules present on endosomal membrane such as MHC molecules are expressed on the vesicle membrane. Then, the endosome fuses with plasma membrane releasing into extracellular medium the intraluminal vesicles called exosomes. Their production can be spontaneous [12] or induced by various stimuli [13,14] depending on cell types. The biochemical composition of exosomes is variable depending on their cell origin; nevertheless some constituents are found in a wide proportion of exosomes and can be considered as identification markers without being totally specific. Complementary proteomics and lipidomics approaches are useful to study the composition of exosomes as well as other EVs [15,16]. Generally, exosomes are surrounded by a phospholipid bilayer enriched with cholesterol, sphingomyelin and ceramide [17,18]. The presence of phosphatidylserine (PS) at the surface of exosomes differs depending on studies. Indeed, some studies showed that exosomes do not express PS on their surface [19,20] while PS has

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Fig. 1. Formation and composition of microparticles and exosomes.

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Pre-analytical steps from the collection of blood, or other body fluids, to EV isolation are critical. Indeed, many factors can induce the artefactual formation of EVs, particularly originating from platelets or red blood cells, which are highly sensitive to environmental parameters. These factors include the size of the sampling needle, the type of collection tube, the nature of anticoagulant, transport conditions and time between sampling and isolation [38]. The definition of standardized procedures is in progress, which will help minimizing the influence of pre-analytical variables [39]. Isolation of EVs must be performed within the first 2 h after collection, after minimal transportation. Exosomes are generally isolated by centrifugation at low speed followed by steps of size exclusion using filters or filtration chromatography before being pelleted with a high-speed centrifugation (100,000g) [40]. To increase purity, an ultracentrifugation on a density gradient can be achieved [7, 8]. MPs, according to ISTH 2010 and Lacroix et al. recommendations [38], are isolated by a double centrifugation of whole blood at 2500g during 15 min at room temperature.

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Due to their sub-micron size and their heterogeneity in size, cell origin and composition, the analysis of EVs is complex. Currently, there is no “gold-standard” method for the characterization of EVs. For more than two decades, flow cytometry has been the primary method used for the characterization of EVs, because it allows their phenotyping and quantification [1,2,41]. However, it is now well recognized that with the conventional flow cytometry method based on light scattering detection, only the largest EVs, close to 1 μm in size, are detected [35,

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4. EV involvement in pathophysiology of autoimmune diseases

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Depending on their origin and microenvironment, EVs can play many roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. This explains their participation in many processes such as inflammation, immune response, coagulation, vascular reactivity, angiogenesis and tissue repair [29]. After focusing on their potential modes of action, we will depict how EVs participate in pathophysiological processes involved in autoimmunity as shown in Fig. 2.

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EVs can interact with target cells or exert their functions by several mechanisms [4,7,23]. They can secrete soluble mediators which bind to their receptors and activate intracellular signaling pathways [60]. They can also act by direct membrane contact. The contact between both structures can have two consequences; it can lead to EV fusion with the target cell causing the transfer of its membrane components and contents to intracellular compartment [61,62] or cause endocytosis [22]. EVs, which are carried into endolysosomal compartments, have various roles in antigen presentation and activation of endosomal receptors (such as Toll-like receptors (TLR)). Finally, this interaction may result in activation of membrane receptors on the target cell resulting in activation of different signal transduction pathways [63,64].

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42–44]. Recent studies have introduced an alternative approach of flow cytometry, in which detection is based on fluorescence intensity, which allows detecting most EVs except the smallest ones [43,45–47]. The development of flow cytometers with improved performances is expected to advance the field and enable the detection of smaller particles [48]. Since the early discovery of platelet MPs [49], electron microscopy has made major contributions to the EV field, providing direct images of EVs with basic information on their size and phenotype expression [2, 50,51]. Recent studies by cryo-electron microscopy, a technique that preserves best the native structure of complex objects, have provided unprecedented views of EVs in blood plasma and other body fluids [35,52,53]. A complete description of EVs in pure plasma was obtained, which confirmed that the main EV population consists of spherical EVs ranging in diameter from 50 to 500 nm, and showed that plasma contains also tubular EVs and membrane fragments several micrometers in size [35]. In addition, this study demonstrated that only about half of EVs exposed PS. Cryo-electron microscopy is unique for revealing the existence and diversity of individual objects in native biological fluids, at nm resolution, as illustrated by the discovery of μm-sized immune complexes tightly associated with EVs in synovial liquids of arthritis patients [52]. However, electron microscopy remains a slow and expensive analytical method which requires expert users, thus cannot be envisioned for clinical use. Other conventional techniques used to determine EV phenotype are western blot and ELISA, which use antibodies to detect the presence of intravesicular or membrane protein markers [54]. RT-qPCR is used to detect the presence of RNA molecules into EVs [55]. Several novel technologies have recently become popular for the high-throughput analysis of EVs, principally nanoparticle tracking analysis (NTA) [56,57] and tunable resistive pulse sensing (TRPS) [58, 59]. Both techniques are able to detect small particles, down to 50 nm, and have proven useful principally for the characterization of purified exosome preparations. On the other hand, they are hardly applicable in the case of heterogeneous samples like pure plasma, and do not allow distinguishing EVs from potential contaminant such as lipoproteins [56]. The on-going development of flow cytometers with increased performances, brighter fluorescent dyes and novel technologies is expected to improve the characterization and knowledge of EVs.

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been found by others [2,7,21–23]. The type of cells secreting exosomes could lead to these differing results. Nevertheless, PS expression remains lower than in MPs [24,25]. Among the surface molecules anchored in exosomal membrane, adhesion molecules, tetraspanin proteins (CD9, CD63, CD81 and CD82), proteins involved in membrane trafficking (Rab protein) and MHC molecules have been identified. Exosomes contain also chaperone proteins (HSP), cytoskeleton proteins (actin, tubulin), annexins, proteins involved into the formation of multivesicular bodies and protein sorting (alix, clathrin, TSG101), RNAs (mRNA, microARN) and metabolic enzymes (GAPDH, pyruvate kinase, α-enolase) [8,15,21]. MPs range in size between 100 nm and 1 μm. They are produced by activated or apoptotic cells through a budding process at the plasma membrane following a loss of asymmetric distribution of phospholipids and a reorganization of the cytoskeleton [5,26,27]. As for exosomes, intravesicular and membrane composition of MPs reflect the nature and the activation state of the parent cell. Due to their formation mechanism, MPs are usually described as exposing PS [4,28,29]. PS is involved in the formation of enzyme complexes of the blood coagulation [30] and participles to the clearance of senescent cells by the reticuloendothelial system [31,32]. However, it was shown that not all MPs express PS [33–35] suggesting that some MPs can be formed by other mechanisms yet unsolved. Although PS is often considered as one of the most characteristic marker of MPs [4,21,36], it lacks specificity. MPs are also characterized by the presence of specific cell markers stemming from the original cell, e.g. CD41 (glycoprotein GpIIb/IIIa) for platelets or CD235a (glycophorin) for red blood cells [37]. MPs may also express adhesion molecules (integrins), MHC molecules and tissue factor. Their lumen contains DNA, RNA (ribosomal, messenger and micro), cytoskeletal proteins, nuclear proteins when issued from apoptotic cells as well as various enzymes and cytokines [16,25]. The classification of EVs in exosomes and MPs is rather dogmatic because of the difficulties of EV characterization, as discussed below.

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Fig. 2. Role of microparticles in autoimmune response.

4.2. Role of EVs in immune response

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4.2.1. EVs: source of self-antigens EVs express both self-antigens and peptide–MHC complexes. EVs could therefore represent a source of self-antigens [6] and might activate autoreactive T-cells in the context of MHC. Thus, EVs arise a lot of interest as actor in autoimmune response.

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4.2.1.1. EVs participate in the formation of immune complexes. Based on their autoantigen content, EVs are likely to participate in the formation of immune complexes. As an example the synovial fluid of rheumatoid arthritis (RA) patients contains proinflammatory immune complexes formed by the association of platelet-derived MPs and autoantibodies against citrullinated peptides, the biological signature of RA [52]. In systemic lupus erythematous (SLE), it has been shown that in vitro generated MPs from apoptotic cells were carrying molecules of nuclear origin, representing a potential source of autoantigens. Indeed, some anti-DNA and anti-nucleosome monoclonal antibodies from lupus mice could bind to these MPs as well as some antibodies contained in plasma of SLE patients. Characterization of MPs found in plasma of SLE patients showed that circulating MPs carried immunoglobulin G (IgG), immunoglobulin M (IgM) and C1q [65,66]. In addition, IgG-associated MPs were quantitatively more important in patients compared to healthy subjects and their amount was correlated to serum anti-DNA antibodies titres and complement activation. Nevertheless, it was not clearly demonstrated whether IgG associated with MPs had an autoantibody activity. The nature of the association between IgG and MPs also was not determined. Immunoglobulins can bind to MPs in an unspecific way through Fc or complement receptors. Further studies are required in order to

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demonstrate that MPs are involved in the formation of immune com- 262 plexes during SLE. 263 4.2.1.2. EVs: role in autoantigen presentation. The participation of EVs in antigen presentation has mainly been studied for exosomes. Exosomes secreted by antigen presenting cells (APC) express class I and class II MHC molecules as well as co-stimulation molecules and then theorically possess the elements required for antigen presentation and activation of autoreactive T lymphocytes [67]. In vitro, the immunostimulatory capacity of APC-derived exosomes varies according to studies. Some studies have shown that exosomes can directly stimulate T cells, while others have shown that exosomes require APC. These conflicting results may be related to experimental conditions. Exosomes act directly on antigen specific T lymphocytes stemming from cell lines, cell clones or primed activated T cells [64,68–71] but not on purified naive T cells [11], apart from one study showing that APC-derived exosomes could directly stimulate purified naive T lymphocytes [72]. Moreover, the number of MHC and co-stimulatory molecules present on exosome surface is critical for the formation of an effective immunologic synapse. It has been shown that exosomes would be even more effective if they are released by mature dendritic cells rather than immature dendritic cells [64,71,72]. Their concentration as well as the affinity for the antigen could also influence their immunostimulatory properties. Exosomes might act indirectly through the interaction with APC [22, 73–77]. This mechanism appears more relevant, particularly for naive T cell activation [73,78]. EVs could bind to APC via adhesion molecules exposing to the outside the autoantigen/MHC complex, which is then accessible for T cell receptor (TCR) [77]. Costimulatory molecules expressed by APC provide necessary second signal for activation of T lymphocytes.

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4.2.3. Secretion and transport capacities of EVs and role in inflammation / immunity EVs can carry and secrete multiple molecules involved in the maintenance of inflammatory and immunological phenomena. They can secrete or express on their surface proinflammatory cytokines such as interleukin-1 (IL1) [60,90] and TNF [91]. For example, in RA, platelet-derived EVs release large amounts of IL-1β involved in proinflammatory responses of synovial fibroblasts, thus enhancing joint inflammation by the release of IL6 and 8 [92,93]. More particularly, fibroblasts secrete exosomes expressing TNFα at their surface, which bind to autoreactive T lymphocytes and make them resistant to activation induced cell death (AICD) [94]. So, EVs might promote the survival of autoreactive T lymphocytes. EVs are also involved in lipid metabolism. Platelet-derived EVs may transfer arachidonic acid to adjacent platelets or to endothelial cells initiating the production of thromboxane A2 and cyclooxygenase, both mediators of inflammation [95]. Macrophage- and dendritic cellderived exosomes can transfer leukotriene synthases causing secretion of proinflammatory leukotrienes by target cells [96]. EVs can also act through their enzymatic content. For example, in RA, cartilage erosion is related in part to the secretion by synovial fibroblasts of proteinase and glycosidase enzymes degrading the cartilage matrix. Their secretion by fibroblasts is enhanced by EVs [97], which can also contain these enzymes [98]. The metalloproteinases also participate in the disruption of the blood–brain barrier in multiple sclerosis, a key process in the pathophysiology of the disease [99].

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4.4.1. EVs and vasomotion Vascular endothelium actively contributes to many essential physiological functions including regulation of vasomotion. An endothelial dysfunction can result in the occurrence of atherothrombotic complications which are a major complication of autoimmune diseases [105]. Due to their composition, EVs participate in some endothelial dysfunction. EVs participate in the regulation of vasomotion by causing a decrease of vascular relaxation. Indeed, endothelial MPs may act by reducing the production of nitric oxide [106]. Nitric oxide is an endogenous molecule released in part by endothelial cells and macrophages which has a vasodilatator role recognized as indispensable to endothelium preservation. EVs may also act as a source of thromboxane A2 which has a vasoconstrictor role and promotes platelet aggregation [107]. Finally, it has been described that endothelial MPs may act by increasing the oxidative stress factor [108].

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4.4.2. Role of EVs in angiogenesis Angiogenesis or growth of new blood capillaries from pre-existing vessels plays a critical role in the pathogenesis of several autoimmune diseases. For example, in RA, angiogenesis occurs in synovia. This vascular proliferation enables the development and growth of the synovial membrane secondarily promoting cartilage and bone destruction as well as articular remodeling. SLE patients may develop vasculitis of small vessels. In these circumstances, angiogenesis could provide a compensatory response to ischemia but also represent an inflammatory stimulus because endothelial cells of new vessels express adhesion

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Thrombosis as well as accelerated atherosclerosis are key features of many autoimmune diseases [101] . Some autoimmune diseases are more specifically associated with thrombotic events such as antiphospholipid syndrome (APS). Because of their phospholipid composition and the potential presence of factors involved in coagulation at their surface, EVs play an essential role in pro-coagulant phenomena. Indeed, EVs can express PS which serves as a binding site for coagulation factors II, Va and Xa [37,102]. In the presence of calcium, the serine protease factor Xa associates to factor Va at a membrane surface rich in PS, forming the pro-thrombinase complex which catalyzes the conversion of prothrombin to thrombin or factor II which in turn allows the transformation of fibrinogen into fibrin. Platelet-derived MPs also participate in thrombotic events by exposing at their surface a major initiator of the extrinsic coagulation pathway, the tissue factor [103,104]. Tissue factor binds to circulating activated factor VII, which activates the coagulation factor X leading to thrombin generation and ultimately to the formation of a clot. This procoagulant tissue factor activity is greatly enhanced by PS. Finally, some EVs express multimers of von Willebrand factor which promote and stabilize platelet aggregation therefore promote thrombotic events [33]. EVs represent a platform for the assembly of enzymatic complexes involved in coagulation thus contributing to thrombotic risk in inflammatory autoimmune diseases.

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4.2.4. Immunosuppressive functions of EVs In addition to their role as promoter of immune responses, EVs also have the ability to suppress / control it [4]. This role has mainly been described in tumor and allergic contexts as well as during pregnancy [11,21]. It was shown in the early phase of the inflammatory response that neutrophil-derived MPs could inhibit the release of proinflammatory factors by macrophages (interleukin 8, 10 and TNFα) and trigger the release of the anti-inflammatory cytokine TGFβ1. EVs can also enhance the function of Tregs, suppress NK and CD8 + cytotoxic functions, inhibit monocyte differentiation and maturation into DCs [100], and mediate T cell killing when secreted by primed CD4+ and placenta cells.

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4.2.2. EVs: role of adjuvants and in innate immune response One hypothesis to explain the onset of autoimmune diseases is the development of an abnormal immune response triggered by the occurrence of an infectious or stress factor in a genetically predisposed subject. Among these factors, pathogen-associated molecular patterns (PAMPs) as well as damage-associated molecular patterns (DAMPs) seem to play an important role. By activating pattern recognition receptors (PRRs) carried by APC, PAMPs and DAMPs act as adjuvants. They promote the maturation of APC leading to the activation of lymphocytes and the production of pro-inflammatory cytokines. Interestingly, EVs can act as DAMPs and/or PAMPs. In fact, it has been shown that cells infected by intracellular pathogens secrete EVs which carry PAMPs [80–83]. Moreover, EVs expressing DAMPs would be released during internal stresses [84–86]. Among these DAMPs, EVs carry RNA that may act as agonists for the endosomal TLR7 [87] leading to the production of IFNα by plasmacytoid dendritic cells, a key cytokine in SLE pathophysiology. Thus, EVs could trigger and sustain the autoimmune response by acting as an adjuvant for APC. Another example is the presence of EVs associated with HMGB1 (high mobility group protein B1) in systemic sclerosis, which might participate to microvascular injury and inflammation [88]. EVs can also participate to innate immune responses to infection including viruses, by carrying metabolite-derived DAMPS. A recent example described that DNA viruses or HIV-1 infected cells secrete EVs containing the second messenger 2′3′-cyclic GMP-AMP (cGAMP) to be delivered to target cells [89]. cGAMP is originally synthetized by cGAS that is the cytosolic sensor of DNA viruses or HIV-1. EVs-containing cGAMP then activate antiviral signaling pathways including Type I Interferon in target cells and ultimately propagate the immune response. Such mechanism might be dysregulated and participate in SLE pathogenesis in which Type I Interferon secretion holds a critical role.

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A third mechanism, characterized by the internalization of exosomes by APC seems to be the most efficient [22]. Once internalized, the complex peptide / MHC carried by the exosomes can be transported to the cell surface [74,75] or the antigenic peptide alone can be transferred at the cell membrane closed to MHC molecule [24,76,77]. This complex can participate in activation of T lymphocytes. This phenomenon of antigen and MHC molecules transfer has also been described for MPs [79].

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antigenic determinants capable of binding anti-DNA and antinucleosome antibodies from lupus mice and some antibodies presents in plasma of patients. Study of MPs from human plasma of SLE patients showed a high number of MPs associated with IgG and this association correlated to plasmatic levels of anti-DNA antibody and to complement activation [65,66]. Nevertheless, it still remains to be proved that these IgG are directed against nuclear material and that they are bound in a specific way by their Fab fragment before being able to conclude in the participation of MPs in the formation of pathogenic immune complexes.

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APS is an autoimmune disorder characterized by the association of thrombosis and/or obstetric complications with biological abnormalities characterized by the presence of antiphospholipid antibodies. Due to their pro-coagulant potential, MPs have been studied in the pathophysiology of this disease. Studies showed an increase of endothelial MPs [121] with a high expression of tissue factor but which seem to be independent from the presence of a personal history of thrombosis [122]. However, it has also been shown an increase of platelet MPs only in patients with a personal history of thrombosis [122]. These results suggest that anti-phospholipid antibodies may lead to chronic activation of endothelial cells responsible for the increased endothelial MPs [123]. Platelet MPs could be a biomarker of the risk of thrombosis or obstetric complications in patients with anti-phospholipid antibodies.

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RA is a chronic inflammatory autoimmune disease characterized by joint destruction but also systemic manifestations. Given the involvement of EVs in many pathophysiological processes, several studies have investigated their role in RA. Several teams have shown an increase in circulating levels of platelet derived MPs in RA patients which are correlated to disease activity [112,113]. However, other studies did not reveal any difference in the number of circulating MPs between patients and healthy controls [114,115]. In the synovial fluid, elevation of platelet MPs was found at a significantly higher concentration than circulating MPs suggesting intense local generation and/or preferential localization of blood platelet MPs [92,116]. In the joint, these MPs can act alone by promoting coagulation so contributing to fibrin deposits in the joints or by causing activation of synovial fibroblasts partly responsible of inflammatory phenomena or by secreting proinflammatory mediators [6,92]. These MPs may also be associated with autoantibodies forming proinflammatory immune complex responsible for leukotriene secretion by neutrophils [52]. An increase in leukocyte derived MPs was also found in the synovial fluid promoting pannus formation [114]. Leukocyte-MPs from T lymphocytes and macrophages could be involved in the secretion by synovial fibroblasts of metalloproteinases and proinflammatory mediators as well as proangiogenic chemokines [6,97].

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SLE is a systemic autoimmune disease characterized by clinical and biological manifestations highly polymorphic and its severity is associated with the presence of visceral involvement, in particular renal and vascular. Studies related to EV characterization showed an increase in plasma levels of platelet, leukocyte and endothelial derived MPs in patients compared to healthy controls [117,118]. Among these studies, one team explored a potential association between MPs concentration, autoantibody profile and disease activity and found a negative correlation between platelet MPs and levels of anti-DNA antibodies [118]. Other studies have found no differences in the concentration of MPs PS+ and/or platelet MPs between patients and controls [66,119]. Finally, a recent study showed a decrease in the number of MPs PS+, platelet, leukocyte and endothelial MPs [120]. Authors interpret this decreased number of MPs as the result of an increased clearance or as an altered formation of MPs in SLE patients. Therefore, these studies show divergent and even contradictory results which do not allow establishing a particular MP profile in SLE. Such differences between studies are the witness of the difficulties inherent to MPs characterization and enumeration. Nevertheless, the current development of standardization of pre-analytical procedures and the development of new analytical strategies should enable in the future, the realization of standardized and comparable studies. From a pathophysiological point of view, immune complexes are essential elements leading to the production of IFNα by plasmacytoid dendritic cells and participating in the genesis of tissue damage by complement activation within organs. Studies have therefore investigated the possibility for MPs carrying self-antigens to fix autoantibodies and then form immune complexes. As mentioned above, data showed that in vitro produced MPs carry

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Systemic sclerosis is an autoimmune disease characterized by the association of vasculopathy, fibrosis and the presence of autoantibodies. Clinical status is very heterogeneous ranging from localized skin involvement to organ failure in the most severe forms. The vascular injury characterized by an inflammation of vessel wall with activation of the coagulation is an early and central event in the pathogenesis of the disease. As for SLE, the characterization of MPs in systemic sclerosis differs among studies. Some studies have shown an increase of platelet-, endothelial-, monocyte- and T lymphocyte-derived MPs in patients [124,125], while others showed a decrease of these MPs, although with an increase of PS negative MPs [126]. To explain this decrease, authors suggest an increased in the clearance of MPs in this pathology or an increase in their adhesion to inflamed endothelial wall. As already mentioned, these differences point to the difficulties relating to the study of EVs because of variability in their preparation and analysis. These results reinforce the absolute necessity to standardize the methods of isolation and analyze for future studies. Recently, a study showed that in systemic sclerosis oxidized HMGB1 associated to platelet-derived MPs increased neutrophil activation suggesting their implication in microvascular injury and inflammation. In fact, authors found that MPs HMGB1+ purified from patients but not MPs HMGB1− from healthy subjects activated neutrophils in vitro. Interestingly, HMGB1 inhibitors reversed the effects of MPs [88].

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Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are life-threatening auto-immune diseases characterized by necrotizing inflammation of small-to-medium-sized vessels [127]. These diseases, including granulomatosis with polyangeitis, microscopic polyangeitis and eosinophilic granulomatosis with polyangeitis, are characterized by the presence of auto-antibodies (ANCAs) that interact with antigens (myeloperoxidase or proteinase-3)-contained in primary granules of neutrophils. ANCAs induce bloodstream neutrophil activation improperly which results in abnormal neutrophil–endothelium interactions and vasculitis lesions [128].

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molecules and produce growth factors and chemokines involved in leukocytes activation [109]. EVs may act in the three main stages of angiogenesis: matrix degradation, recruitment and differentiation of endothelial progenitors as well as proliferation and migration of endothelial cells. This could be done via their content in metalloproteinases, in tissue factor and in CD40 capable of inducing the production of VEGF or via the release of various chemokines involved in angiogenesis [110, 111].

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By their heterogeneity of action and composition, EVs could be used as vectors or therapeutic agents. First, they could serve as drug delivery system such as liposomes. Some biological drugs are large charged molecules, which are unable to pass through membranes and therefore cannot reach their targets. EVs can carry a variety of molecules and cross biological barriers such as the synovial membrane or the blood–brain barrier; therefore they could be used as potent biological vehicles. They have the advantage to be more stable in blood compared to free drug and, being autologous, they guarantee biological security. Thus, in the context of autoimmune diseases, EVs containing antiinflammatory substances emerge as potential therapeutic agents [133, 134]. Initially, it requires genetic modification of APC by transfer of genes encoding cytokines, enzymes or immunosuppressive molecules. Modified APC release EVs that have the same suppressive properties as their parental cell. For example, in mice models of RA, the injection of exosomes from IL-4, IL-10, FasL, and indoleamine 2,3-dioxygenasemodified DC reduced clinical manifestations of the disease [135–139]. Importantly, strong progress have been made to elucidate molecular mechanisms of EV formation, release and uptake by target cells during the past few years, as well as using the most advanced technologies to thoroughly characterize composition of EVs by using proteomics, nextgen sequencing, and now metabolomics. Tackling post-translational protein modifications are even now being proposed [140] and will undoubtedly leverage our understanding of EV biology in homeostasis and diseases. Some of these components are considered as emerging targets

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EVs are subcellular structures, which carry and may deliver a variety of molecules involved in many biological processes. This explains their involvement in the pathophysiology of autoimmune diseases through their participation in inflammatory and thrombotic phenomena, vascular dysfunction and maintenance of the autoimmune response. In addition to these pleiotropic effects, EVs could serve as biomarkers of disease severity and even illness onset. However, studies on concerning the use of EVs as biomarkers in pathology often present variable or even contradictory results probably because of the difficulties for the characterization of EVs with the use of different techniques of isolation, detection and quantification. It underlines the essential interest of standardization of sampling and analytical techniques for the realization of reproducible and comparable studies. Remarkably, rapid advances in sensitive and high-throughput omics technologies for small and large molecules will expedite our understanding of the full molecular components of EVs in the future, and their potential incidence on immune dysregulation observed in autoimmune diseases. No conflict of interest.

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Multiple sclerosis is an autoimmune demyelinating disease of the central nervous system and responsible for various neurological manifestations. Its pathophysiology is characterized by interactions between endothelial cells, leukocytes, monocytes and cells of the central nervous system. An essential process for the establishment of the pathology is the lesion of the blood–brain barrier allowing the transendothelial migration of leukocytes in the central nervous system. The presence of metalloproteinases in EVs suggests that they could be involved in the degradation of this barrier. EVs in particular from endothelial, leukocyte and platelet origin whose quantity is more or less increased depending on the stage of the disease would promote leukocyte migration into the central nervous system [123] as well as the spread of neuroinflammation phenomena by their content in cytokines, chemokines (CCL5) and their role in antigen presentation [99]. Another interest of EVs is their use as biomarkers of disease severity. Several studies have investigated the link between different clinical and biological criteria for multiple sclerosis and the number of EVs. However, results are variable, sometimes even contradictory, depending of the type of studied EVs, their cellular origin and the analytical conditions.

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in cancer showing some success in both in vitro and in vivo settings [141]. These strategies might be applied to autoimmune diseases to counteract immune-activating EVs described above. However, caution should be made of potential undesirable off-target effects of such strategies due to the important role of EVs in normal biological processes.

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Studies have constantly detected increased levels of circulating MPs originating mainly from platelets and neutrophils in AAV patients [129–132]. Moreover, concentration of neutrophil and platelet-derived MPs has been shown to be higher in patients with active AAV as compared to remittent disease and also to correlate with AAV activity score [129–132]. In vitro, MPs expressing the ANCA antigens (MPO and PR3) and tissue factor are excessively released after neutrophils activation with MPO or PR3 ANCAs [131,132]. These ANCA-induced neutrophil derived-MPs are able to bind to endothelial cell via CD18– ICAM-1 interaction, to induce endothelial cell activation and to trigger the coagulation cascade in a tissue factor dependent manner [131, 132]. Thus, these data not only suggest that neutrophil MPs may be interesting biomarkers of disease activity, but also that they may be active mediators of endothelial injury in AAV thereby constituting attractive therapeutic targets.

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[1] Van der Pol E, Boing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev 2012;64:676–705. [2] György B, Szabó TG, Pásztói M, Pál Z, Misják P, Aradi B, et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 2011;68:2667–88. [3] Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013;200:373–83. [4] Beyer C, Pisetsky DS. The role of microparticles in the pathogenesis of rheumatic diseases. Nat Rev Rheumatol 2010;6:21–9. [5] Burger D, Schock S, Thompson CS, Montezano AC, Hakim AM, Touyz RM. Microparticles: biomarkers and beyond. Clin Sci 2013;124:423–41. [6] Buzas EI, György B, Nagy G, Falus A, Gay S. Emerging role of extracellular vesicles in inflammatory diseases. Nat Rev Rheumatol 2014;10:356–64. [7] Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 2014;30: 255–89. [8] Chaput N, Théry C. Exosomes: immune properties and potential clinical implementations. Semin Immunopathol 2011;33:419–40. [9] Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci 2000;113(Pt 19):3365–74. [10] Simons M, Raposo G. Exosomes — vesicular carriers for intercellular communication. Curr Opin Cell Biol 2009;21:575–81. [11] Bobrie A, Colombo M, Raposo G, Théry C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 2011;12:1659–68. [12] Théry C, Boussac M, Véron P, Ricciardi-Castagnoli P, Raposo G, Garin J, et al. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol 2001;166:7309–18. [13] Muntasell A, Berger AC, Roche PA. T cell-induced secretion of MHC class II–peptide complexes on B cell exosomes. EMBO J 2007;26:4263–72. [14] Arita S, Baba E, Shibata Y, Niiro H, Shimoda S, Isobe T, et al. B cell activation regulates exosomal HLA production. Eur J Immunol 2008;38:1423–34. [15] Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res 2012;40:D1241–4. [16] Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, Askenase P, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol 2012;10, e1001450. http://dx.doi.org/10.1371/journal.pbio.1001450. [17] Laulagnier K, Motta C, Hamdi S, Roy S, Fauvelle F, Pageaux J-F, et al. Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem J 2004;380:161–71. [18] Subra C, Laulagnier K, Perret B, Record M. Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 2007;89:205–12. [19] Dignat-George F, Boulanger CM. The many faces of endothelial microparticles. Arterioscler Thromb Vasc Biol 2011;31:27–33. [20] Batool S, Abbasian N, Burton JO, Stover C. Microparticles and their roles in inflammation: a review. Open Immunol J 2013;6:1–14. [21] Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009;9:581–93.

Please cite this article as: Turpin D, et al, Role of extracellular vesicles in autoimmune diseases, Autoimmun Rev (2015), http://dx.doi.org/10.1016/ j.autrev.2015.11.004

600 601 602

606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670

[58]

[59]

[60]

[61]

[62]

D

[63]

C

E

R

R

O

C

N

F

[57]

O

[56]

R O

[55]

sample collection and vesicle isolation procedures. J Extracell Vesicles 2014;3. http://dx.doi.org/10.3402/jev.v3.24215. Nomura S, Shouzu A, Taomoto K, Togane Y, Goto S, Ozaki Y, et al. Assessment of an ELISA kit for platelet-derived microparticles by joint research at many institutes in Japan. J Atheroscler Thromb 2009;16:878–87. Revenfeld ALS, Bæk R, Nielsen MH, Stensballe A, Varming K, Jørgensen M. Diagnostic and prognostic potential of extracellular vesicles in peripheral blood. Clin Ther 2014;36:830–46. Dragovic RA, Gardiner C, Brooks AS, Tannetta DS, Ferguson DJP, Hole P, et al. Sizing and phenotyping of cellular vesicles using nanoparticle tracking analysis. Nanomed Nanotechnol Biol Med 2011;7:780–8. Van der Pol E, Coumans FAW, Grootemaat AE, Gardiner C, Sargent IL, Harrison P, et al. Particle size distribution of exosomes and microvesicles determined by transmission electron microscopy, flow cytometry, nanoparticle tracking analysis, and resistive pulse sensing. J Thromb Haemost 2014;12:1182–92. Coumans FAW, van der Pol E, Böing AN, Hajji N, Sturk G, van Leeuwen TG, et al. Reproducible extracellular vesicle size and concentration determination with tunable resistive pulse sensing. J Extracell Vesicles 2014;3:25922. http://dx.doi.org/10. 3402/jev.v3.25922. Maas SLN, de Vrij J, van der Vlist EJ, Geragousian B, van Bloois L, Mastrobattista E, et al. Possibilities and limitations of current technologies for quantification of biological extracellular vesicles and synthetic mimics. J Control Release Off J Control Release Soc 2015;200:87–96. Pizzirani C, Ferrari D, Chiozzi P, Adinolfi E, Sandonà D, Savaglio E, et al. Stimulation of P2 receptors causes release of IL-1beta-loaded microvesicles from human dendritic cells. Blood 2007;109:3856–64. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654–9. Clayton A, Turkes A, Dewitt S, Steadman R, Mason MD, Hallett MB. Adhesion and signaling by B cell-derived exosomes: the role of integrins. FASEB J Off Publ Fed Am Soc Exp Biol 2004;18:977–9. Skokos D, Botros HG, Demeure C, Morin J, Peronet R, Birkenmeier G, et al. Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol Baltim Md 1950 2003;170:3037–45. Admyre C, Johansson SM, Paulie S, Gabrielsson S. Direct exosome stimulation of peripheral human T cells detected by ELISPOT. Eur J Immunol 2006;36:1772–81. Nielsen CT, Østergaard O, Stener L, Iversen LV, Truedsson L, Gullstrand B, et al. Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation. Arthritis Rheum 2012;64:1227–36. Ullal AJ, Reich III CF, Clowse M, Criscione-Schreiber LG, Tochacek M, Monestier M, et al. Microparticles as antigenic targets of antibodies to DNA and nucleosomes in systemic lupus erythematosus. J Autoimmun 2011;36:173–80. Clayton A, Court J, Navabi H, Adams M, Mason MD, Hobot JA, et al. Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. J Immunol Methods 2001;247:163–74. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996;183:1161–72. Admyre C, Bohle B, Johansson SM, Focke-Tejkl M, Valenta R, Scheynius A, et al. B cell-derived exosomes can present allergen peptides and activate allergenspecific T cells to proliferate and produce TH2-like cytokines. J Allergy Clin Immunol 2007;120:1418–24. Luketic L, Delanghe J, Sobol PT, Yang P, Frotten E, Mossman KL, et al. Antigen presentation by exosomes released from peptide-pulsed dendritic cells is not suppressed by the presence of active CTL. J Immunol Baltim Md 1950 2007;179: 5024–32. Utsugi-Kobukai S, Fujimaki H, Hotta C, Nakazawa M, Minami M. MHC class Imediated exogenous antigen presentation by exosomes secreted from immature and mature bone marrow derived dendritic cells. Immunol Lett 2003;89:125–31. Hwang I, Shen X, Sprent J. Direct stimulation of naive T cells by membrane vesicles from antigen-presenting cells: distinct roles for CD54 and B7 molecules. Proc Natl Acad Sci U S A 2003;100:6670–5. Vincent-Schneider H, Stumptner-Cuvelette P, Lankar D, Pain S, Raposo G, Benaroch P, et al. Exosomes bearing HLA–DR1 molecules need dendritic cells to efficiently stimulate specific T cells. Int Immunol 2002;14:713–22. Théry C, Duban L, Segura E, Véron P, Lantz O, Amigorena S. Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol 2002;3: 1156–62. André F, Chaput N, Schartz NEC, Flament C, Aubert N, Bernard J, et al. Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol Baltim Md 1950 2004;172:2126–36. Mallegol J, Van Niel G, Lebreton C, Lepelletier Y, Candalh C, Dugave C, et al. T84intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology 2007;132:1866–76. Montecalvo A, Shufesky WJ, Stolz DB, Sullivan MG, Wang Z, Divito SJ, et al. Exosomes as a short-range mechanism to spread alloantigen between dendritic cells during T cell allorecognition. J Immunol Baltim Md 1950 2008;180:3081–90. Segura E, Nicco C, Lombard B, Véron P, Raposo G, Batteux F, et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood 2005;106:216–23. Obregon C, Rothen-Rutishauser B, Gitahi SK, Gehr P, Nicod LP. Exovesicles from human activated dendritic cells fuse with resting dendritic cells, allowing them to present alloantigens. Am J Pathol 2006;169:2127–36.

P

[54]

[64] [65]

T

[22] Morelli AE, Larregina AT, Shufesky WJ, Sullivan MLG, Stolz DB, Papworth GD, et al. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 2004;104:3257–66. [23] Urbanelli L, Magini A, Buratta S, Brozzi A, Sagini K, Polchi A, et al. Signaling pathways in exosomes biogenesis, secretion and fate. Genes 2013;4:152–70. [24] Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2002;2:569–79. [25] Hugel B, Martínez MC, Kunzelmann C, Freyssinet J-M. Membrane microparticles: two sides of the coin. Physiology (Bethesda) 2005;20:22–7. [26] Piccin A, Murphy WG, Smith OP. Circulating microparticles: pathophysiology and clinical implications. Blood Rev 2007;21:157–71. [27] Zwaal RF, Schroit AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 1997;89:1121–32. [28] Morel O, Toti F, Hugel B, Freyssinet J-M. Cellular microparticles: a disseminated storage pool of bioactive vascular effectors. Curr Opin Hematol 2004;11:156–64. [29] Distler JHW, Huber LC, Gay S, Distler O, Pisetsky DS. Microparticles as mediators of cellular cross-talk in inflammatory disease. Autoimmunity 2006;39:683–90. [30] Bevers EM, Comfurius P, van Rijn JL, Hemker HC, Zwaal RF. Generation of prothrombin-converting activity and the exposure of phosphatidylserine at the outer surface of platelets. Eur J Biochem FEBS 1982;122:429–36. [31] Schroit AJ, Tanaka Y, Madsen J, Fidler IJ. The recognition of red blood cells by macrophages: role of phosphatidylserine and possible implications of membrane phospholipid asymmetry. Biol Cell Auspices Eur Cell Biol Organ 1984;51:227–38. [32] Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA. Phosphatidylserine receptor is required for clearance of apoptotic cells. Science 2003;302:1560–3. [33] Pisetsky DS, Ullal AJ, Gauley J, Ning TC. Microparticles as mediators and biomarkers of rheumatic disease. Rheumatology (Oxford) 2012;51:1737–46. [34] Shet AS. Characterizing blood microparticles: technical aspects and challenges. Vasc Health Risk Manag 2008;4:769–74. [35] Arraud N, Linares R, Tan S, Gounou C, Pasquet J-M, Mornet S, et al. Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J Thromb Haemost 2014;12:614–27. [36] Cocucci E, Racchetti G, Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol 2009;19:43–51. [37] Horstman LL, Jy W, Jimenez JJ, Bidot C, Ahn YS. New horizons in the analysis of circulating cell-derived microparticles. Keio J Med 2004;53:210–30. [38] Lacroix R, Judicone C, Poncelet P, Robert S, Arnaud L, Sampol J, et al. Impact of preanalytical parameters on the measurement of circulating microparticles: towards standardization of protocol: pre-analytics influence on microparticles analysis. J Thromb Haemost 2012;10:437–46. [39] Witwer KW, Buzás EI, Bemis LT, Bora A, Lässer C, Lötvall J, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles 2013;2. http://dx.doi.org/10.3402/jev.v2i0.20360. [40] Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. In: Bonifacino Juan, editor. Curr Protoc Cell Biol; 2006 (Al, Chapter 3:Unit 3.22). [41] Jy W, Horstman LL, Jimenez JJ, Ahn YS, Biró E, Nieuwland R, et al. Measuring circulating cell-derived microparticles. J Thromb Haemost 2004;2:1842–51. [42] Van Der Pol E, Van Gemert MJC, Sturk A, Nieuwland R, Van Leeuwen TG. Single vs. swarm detection of microparticles and exosomes by flow cytometry. J Thromb Haemost 2012;10:919–30. [43] Arraud N, Gounou C, Turpin D, Brisson AR. Fluorescence triggering: a general strategy for enumerating and phenotyping extracellular vesicles by flow cytometry: phenotyping of EVs by fluorescence triggering in FCM. Cytometry A 2015. http://dx.doi.org/10.1002/cyto.a.22669. [44] Chandler WL, Yeung W, Tait JF. A new microparticle size calibration standard for use in measuring smaller microparticles using a new flow cytometer. J Thromb Haemost 2011;9:1216–24. [45] Van der Vlist EJ, Nolte-'t Hoen ENM, Stoorvogel W, Arkesteijn GJA, Wauben MHM. Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry. Nat Protoc 2012;7:1311–26. [46] Nolan JP, Stoner SA. A trigger channel threshold artifact in nanoparticle analysis. Cytom Part J Int Soc Anal Cytol 2013;83:301–5. [47] Arraud N, Gounou C, Linares R, Brisson AR. A simple flow cytometry method improves the detection of phosphatidylserine-exposing extracellular vesicles. J Thromb Haemost 2015;13:237–47. [48] Zhu S, Ma L, Wang S, Chen C, Zhang W, Yang L, et al. Light-scattering detection below the level of single fluorescent molecules for high-resolution characterization of functional nanoparticles. ACS Nano 2014;8:10998–1006. [49] Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol 1967;13:269–88. [50] Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 1999;94: 3791–9. [51] Aalberts M, van Dissel-Emiliani FMF, van Adrichem NPH, van Wijnen M, Wauben MHM, Stout TAE, et al. Identification of distinct populations of proteasomes that differentially express prostate stem cell antigen, annexin A1, and GLIPR2 in humans. Biol Reprod 2012;86:82. [52] Cloutier N, Tan S, Boudreau LH, Cramb C, Subbaiah R, Lahey L, et al. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes: Immune complexes contain microparticles. EMBO Mol Med 2013;5:235–49. [53] Zonneveld MI, Brisson AR, van Herwijnen MJC, Tan S, van de Lest CHA, Redegeld FA, et al. Recovery of extracellular vesicles from human breast milk is influenced by

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[66]

[67]

[68] [69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

Please cite this article as: Turpin D, et al, Role of extracellular vesicles in autoimmune diseases, Autoimmun Rev (2015), http://dx.doi.org/10.1016/ j.autrev.2015.11.004

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[110] Rautou P-E, Vion A-C, Amabile N, Chironi G, Simon A, Tedgui A, et al. Microparticles, vascular function, and atherothrombosis. Circ Res 2011;109:593–606. [111] Reich N, Beyer C, Gelse K, Akhmetshina A, Dees C, Zwerina J, et al. Microparticles stimulate angiogenesis by inducing ELR(+) CXC-chemokines in synovial fibroblasts. J Cell Mol Med 2011;15:756–62. [112] Knijff-Dutmer EAJ, Koerts J, Nieuwland R, Kalsbeek-Batenburg EM, van de Laar MA. Elevated levels of platelet microparticles are associated with disease activity in rheumatoid arthritis. Arthritis Rheum 2002;46:1498–503. [113] Umekita K, Hidaka T, Ueno S, Takajo I, Kai Y, Nagatomo Y, et al. Leukocytapheresis (LCAP) decreases the level of platelet-derived microparticles (MPs) and increases the level of granulocytes-derived MPs: a possible connection with the effect of LCAP on rheumatoid arthritis. Mod Rheumatol Jpn Rheum Assoc 2009;19:265–72. [114] Berckmans RJ, Nieuwland R, Tak PP, Böing AN, Romijn FPHTM, Kraan MC, et al. Cell-derived microparticles in synovial fluid from inflamed arthritic joints support coagulation exclusively via a factor VII-dependent mechanism. Arthritis Rheum 2002;46:2857–66. [115] Pamuk GE, Vural O, Turgut B, Demir M, Pamuk ON, Cakir N. Increased platelet activation markers in rheumatoid arthritis: are they related with subclinical atherosclerosis? Platelets 2008;19:146–54. [116] Boilard E, Blanco P, Nigrovic PA. Platelets: active players in the pathogenesis of arthritis and SLE. Nat Rev Rheumatol 2012;8:534–42. [117] Pereira J, Alfaro G, Goycoolea M, Quiroga T, Ocqueteau M, Massardo L, et al. Circulating platelet-derived microparticles in systemic lupus erythematosus. Association with increased thrombin generation and procoagulant state. Thromb Haemost 2006;95:94–9. [118] Sellam J, Proulle V, Jungel A, Ittah M, Miceli Richard C, Gottenberg J-E, et al. Increased levels of circulating microparticles in primary Sjogren's syndrome, systemic lupus erythematosus and rheumatoid arthritis and relation with disease activity. Arthritis Res Ther 2009;11:R156. [119] Joseph JE, Harrison P, Mackie IJ, Isenberg DA, Machin SJ. Increased circulating platelet–leucocyte complexes and platelet activation in patients with antiphospholipid syndrome, systemic lupus erythematosus and rheumatoid arthritis. Br J Haematol 2001;115:451–9. [120] Nielsen CT. Circulating microparticles in systemic lupus erythematosus. Dan Med J 2012;59:B4548–. [121] Dignat-George F, Camoin-Jau L, Sabatier F, Arnoux D, Anfosso F, Bardin N, et al. Endothelial microparticles: a potential contribution to the thrombotic complications of the antiphospholipid syndrome. Thromb Haemost 2004;91:667–73. [122] Jy W, Tiede M, Bidot CJ, Horstman LL, Jimenez JJ, Chirinos J, et al. Platelet activation rather than endothelial injury identifies risk of thrombosis in subjects positive for antiphospholipid antibodies. Thromb Res 2007;121:319–25. [123] Ardoin SP, Shanahan JC, Pisetsky DS. The role of microparticles in inflammation and thrombosis. Scand J Immunol 2007;66:159–65. [124] Nomura S, Inami N, Ozaki Y, Kagawa H, Fukuhara S. Significance of microparticles in progressive systemic sclerosis with interstitial pneumonia. Platelets 2008;19: 192–8. [125] Guiducci S, Distler JHW, Jüngel A, Huscher D, Huber LC, Michel BA, et al. The relationship between plasma microparticles and disease manifestations in patients with systemic sclerosis. Arthritis Rheum 2008;58:2845–53. [126] Iversen LV, Østergaard O, Ullman S, Nielsen CT, Halberg P, Karlsmark T, et al. Circulating microparticles and plasma levels of soluble E- and P-selectins in patients with systemic sclerosis. Scand J Rheumatol 2013;42:473–82. [127] Jennette JC, Falk RJ, Hu P, Xiao H. Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Annu Rev Pathol 2013;8:139–60. [128] Halbwachs L, Lesavre P. Endothelium–neutrophil interactions in ANCA-associated diseases. J Am Soc Nephrol 2012;23:1449–61. [129] Daniel L, Fakhouri F, Joly D, Mouthon L, Nusbaum P, Grunfeld J-P, et al. Increase of circulating neutrophil and platelet microparticles during acute vasculitis and hemodialysis. Kidney Int 2006;69:1416–23. [130] Erdbruegger U, Grossheim M, Hertel B, Wyss K, Kirsch T, Woywodt A, et al. Diagnostic role of endothelial microparticles in vasculitis. Rheumatol Oxf Engl 2008; 47:1820–5. [131] Hong Y, Eleftheriou D, Hussain AAK, Price-Kuehne FE, Savage CO, Jayne D, et al. Anti-neutrophil cytoplasmic antibodies stimulate release of neutrophil microparticles. J Am Soc Nephrol 2012;23:49–62. [132] Kambas K, Chrysanthopoulou A, Vassilopoulos D, Apostolidou E, Skendros P, Girod A, et al. Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease. Ann Rheum Dis 2014;73:1854–63. [133] Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther J Am Soc Gene Ther 2010;18:1606–14. [134] Yin W, Ouyang S, Li Y, Xiao B, Yang H. Immature dendritic cell-derived exosomes: a promise subcellular vaccine for autoimmunity. Inflammation 2013; 36:232–40. [135] Bianco NR, Kim SH, Ruffner MA, Robbins PD. Therapeutic effect of exosomes from indoleamine 2,3-dioxygenase-positive dendritic cells in collagen-induced arthritis and delayed-type hypersensitivity disease models. Arthritis Rheum 2009; 60:380–9. [136] Kim SH, Bianco N, Menon R, Lechman ER, Shufesky WJ, Morelli AE, et al. Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol Ther J Am Soc Gene Ther 2006;13:289–300. [137] Yang C, Robbins PD. Immunosuppressive exosomes: a new approach for treating arthritis. Int J Rheumatol 2012;2012:573528.

E

T

[80] Bhatnagar S, Shinagawa K, Castellino FJ, Schorey JS. Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood 2007;110:3234–44. [81] Nakao R, Hasegawa H, Ochiai K, Takashiba S, Ainai A, Ohnishi M, et al. Outer membrane vesicles of Porphyromonas gingivalis elicit a mucosal immune response. PLoS One 2011;6, e26163. http://dx.doi.org/10.1371/journal.pone.0026163. [82] Hong S-W, Kim M-R, Lee E-Y, Kim JH, Kim Y-S, Jeon SG, et al. Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation. Allergy 2011;66:351–9. [83] Prados-Rosales R, Baena A, Martinez LR, Luque-Garcia J, Kalscheuer R, Veeraraghavan U, et al. Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. J Clin Invest 2011;121:1471–83. [84] Théry C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, et al. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 1999;147:599–610. [85] Beninson LA, Maslanik T, Murphy MJ, Fleshner M. 116. The functional role of exosome associated extracellular heat shock protein 72 following exposure to acute stress. Brain Behav Immun 2012;26(Suppl. 1):S32–3. [86] Zhang B, Yin Y, Lai RC, Lim SK. Immunotherapeutic potential of extracellular vesicles. Front Immunol 2014;5:518. [87] Pisetsky DS, Lipsky PE. Microparticles as autoadjuvants in the pathogenesis of SLE. Nat Rev Rheumatol 2010;6:368–72. [88] Maugeri N, Rovere-Querini P, Baldini M, Baldissera E, Sabbadini MG, Bianchi ME, et al. Oxidative stress elicits platelet/leukocyte inflammatory interactions via HMGB1: a candidate for microvessel injury in sytemic sclerosis. Antioxid Redox Signal 2014;20:1060–74. [89] Gentili M, Kowal J, Tkach M, Satoh T, Lahaye X, Conrad C, et al. Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science 2015;349:1232–6. [90] Nickel W, Rabouille C. Mechanisms of regulated unconventional protein secretion. Nat Rev Mol Cell Biol 2009;10:148–55. [91] Peterson DB, Sander T, Kaul S, Wakim BT, Halligan B, Twigger S, et al. Comparative proteomic analysis of PAI-1 and TNF-alpha-derived endothelial microparticles. Proteomics 2008;8:2430–46. [92] Boilard E, Nigrovic PA, Larabee K, Watts GFM, Coblyn JS, Weinblatt ME, et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010;327:580–3. [93] Berckmans RJ, Nieuwland R, Kraan MC, Schaap MCL, Pots D, Smeets TJM, et al. Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes. Arthritis Res Ther 2005;7:R536–44. [94] Zhang H-G, Liu C, Su K, Su K, Yu S, Zhang L, et al. A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell death. J Immunol Baltim Md 1950 2006;176:7385–93. [95] Barry OP, Pratico D, Lawson JA, FitzGerald GA. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J Clin Invest 1997;99:2118–27. [96] Esser J, Gehrmann U, D'Alexandri FL, Hidalgo-Estévez AM, Wheelock CE, Scheynius A, et al. Exosomes from human macrophages and dendritic cells contain enzymes for leukotriene biosynthesis and promote granulocyte migration. J Allergy Clin Immunol 2010;126:1032–40. [97] Distler JHW, Jüngel A, Huber LC, Seemayer CA, Reich CF, Gay RE, et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. Proc Natl Acad Sci U S A 2005;102:2892–7. [98] Lo Cicero A, Majkowska I, Nagase H, Di Liegro I, Troeberg L. Microvesicles shed by oligodendroglioma cells and rheumatoid synovial fibroblasts contain aggrecanase activity. Matrix Biol J Int Soc Matrix Biol 2012;31:229–33. [99] Sáenz-Cuesta M, Osorio-Querejeta I, Otaegui D. Extracellular vesicles in multiple sclerosis: what are they telling us? Front Cell Neurosci 2014;8. http://dx.doi.org/ 10.3389/fncel.2014.00100. [100] EL Andaloussi S, Mäger I, Breakefield XO, Wood MJA. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 2013;12:347–57. [101] Silvariño R, Danza Á, Mérola V, Bérez A, Méndez E, Espinosa G, et al. Venous thromboembolic disease in systemic autoimmune diseases: an association to keep in mind. Autoimmun Rev 2012;12:289–94. [102] Michelson AD, Rajasekhar D, Bednarek FJ, Barnard MR. Platelet and platelet-derived microparticle surface factor V/Va binding in whole blood: differences between neonates and adults. Thromb Haemost 2000;84:689–94. [103] Müller I, Klocke A, Alex M, Kotzsch M, Luther T, Morgenstern E, et al. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets. FASEB J Off Publ Fed Am Soc Exp Biol 2003;17:476–8. [104] Scholz T, Temmler U, Krause S, Heptinstall S, Lösche W. Transfer of tissue factor from platelets to monocytes: role of platelet-derived microvesicles and CD62P. Thromb Haemost 2002;88:1033–8. [105] Teixeira PC, Ferber P, Vuilleumier N, Cutler P. Biomarkers for cardiovascular risk assessment in autoimmune diseases. Proteomics Clin Appl 2015;9:48–57. [106] Brodsky SV, Zhang F, Nasjletti A, Goligorsky MS. Endothelium-derived microparticles impair endothelial function in vitro. Am J Physiol Heart Circ Physiol 2004;286: H1910–5. [107] Pfister SL. Role of platelet microparticles in the production of thromboxane by rabbit pulmonary artery. Hypertension 2004;43:428–33. [108] Mezentsev A, Merks RMH, O'Riordan E, Chen J, Mendelev N, Goligorsky MS, et al. Endothelial microparticles affect angiogenesis in vitro: role of oxidative stress. Am J Physiol Heart Circ Physiol 2005;289:H1106–14. [109] Zhou L, Lu G, Shen L, Wang L, Wang M. Serum levels of three angiogenic factors in systemic lupus erythematosus and their clinical significance. BioMed Res Int 2014; 2014:627126.

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[140] Kreimer S, Belov AM, Ghiran I, Murthy SK, Frank DA, Ivanov AR. Mass-spectrometrybased molecular characterization of extracellular vesicles: lipidomics and proteomics. J Proteome Res 2015;14:2367–84. [141] Vader P, Breakefield XO, Wood MJA. Extracellular vesicles: emerging targets for cancer therapy. Trends Mol Med 2014;20:385–93.

N

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O

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R

E

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D

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R O

O

F

[138] Kim SH, Bianco NR, Shufesky WJ, Morelli AE, Robbins PD. Effective treatment of inflammatory disease models with exosomes derived from dendritic cells genetically modified to express IL-4. J Immunol Baltim Md 1950 2007;179:2242–9. [139] Kim S-H, Lechman ER, Bianco N, Menon R, Keravala A, Nash J, et al. Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis. J Immunol Baltim Md 1950 2005;174:6440–8.

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