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Clinical Experimental ImmunologyVolume 175, Issue 2 p. 150-166 Review Article Free Access Intravascular immunity as a key to systemic vasculitis: a work in progress, gaining momentum G. A. Ramirez, Istituto Scientifico San Raffaele and Università Vita Salute San Raffaele, Milano, ItalySearch for more papers by this authorN. Maugeri, Istituto Scientifico San Raffaele and Università Vita Salute San Raffaele, Milano, ItalySearch for more papers by this authorM. G. Sabbadini, Istituto Scientifico San Raffaele and Università Vita Salute San Raffaele, Milano, ItalySearch for more papers by this authorP. Rovere-Querini, Istituto Scientifico San Raffaele and Università Vita Salute San Raffaele, Milano, ItalySearch for more papers by this authorA. A. Manfredi, Corresponding Author Istituto Scientifico San Raffaele and Università Vita Salute San Raffaele, Milano, Italy Correspondence to: A. A. Manfredi, San Raffaele Scientific Institute, via Olgettina 58, Milano 20132, Italy. E-mail: manfredi.angelo@hsr.itSearch for more papers by this author The group of large vessel vasculitides comprises giant cell arteritis (GCA) and Takayasu\'s arteritis (TA). GCA has a significant epidemiological impact in the elderly Caucasian population. The involvement of large arteries in GCA is restricted mainly to the supradiaphragmatic space and is segmental. New-onset headache, jaw claudication and scalp tenderness are common symptoms and are often accompanied by systemic inflammation [fatigue, fever, elevated erythrocyte sedimentation rate (ESR)] and by polymyalgia rheumatica (PMR), a related inflammatory disease of unknown cause characterized by pain of the neck, shoulders and hips. Vision loss, aortic aneurysm formation and ischaemic stroke represent typical and frequent complications of GCA. TA affects younger patients, in particular women of childbearing age, with a higher incidence in Asia and Latin America 3. Large vessel involvement is widespread in TA, as the pulmonary artery and the whole subdiaphragmatic arterial tree are frequently involved. A lower rate of progression of vessel wall remodelling and enhanced formation of collateral vessels differentiate TA from GCA 4. Aneurysm formation is more frequent in TA than in GCA, possibly reflecting still uncharacterized features of vessel inflammation in TA 5. Despite epidemiological and clinicopathological dissimilarities, a clinicopathogenic continuum might encompass TA, GCA and some forms of chronic peri-aortitis 6-8. For example, in a recent retrospective study the risk of arterial, but apparently not of venous, thrombosis characterizes both TA and GCA 9, 10, with 10% of TA patients experiencing strokes 11. The molecular correlates of the embolic diathesis are still poorly understood, also considering the epidemiological features of TA patients who, in general, are relatively young and not expected to be at risk of atherosclerosis. High-dose corticosteroids are a mainstay in the therapy of GCA 12, even if a substantial fraction of the patients relapse upon steroid tapering. Steroids are also often used in TA in association with immunosuppressive drugs such as methotrexate or azathioprine 13. Anti-tumour necrosis factor (TNF) agents are also effective in TA, whereas the use of biological agents in GCA is still under investigation and appears less promising 14. Kawasaki\'s disease (KD) and polyarteritis nodosa (PAN) are medium vessel vasculitides. KD is a vasculitis of the childhood, almost invariably affecting patients under 5 years of age, more common in Japanese and Afro-Caribbean ethnic cohorts. Despite its self-limiting course, the disease is severe and potentially life-threatening because of the frequent involvement of coronary arteries. Common clinical signs include fever, cervical (often unilateral) lymphadenopathy, non-exudative conjunctivitis, polymorphic diffused exanthema, reddening and fixuration of lips and tongue, non-pitting oedema of the dorsa of hands and desquamating exanthema of palms and soles. After an early phase of predominant perivasculitis, inflammation of medium-sized artery in KD progresses towards the involvement of the medial and intimal layers 15. Infiltrating macrophages, CD8+ T cells and IgA-secreting plasma cells dominate, with frequent disruption of the vessel architecture and formation of aneurysms. Centripetal activation of the endothelium is associated with frequent thrombosis and end-organ ischaemia. KD late stages include aneurysms and stenoses due to intimal thickening. Myocarditis is almost invariably detectable at autopsy and coronary artery aneurysms and thrombosis occur in 15–25% of untreated patients. KD is, in fact, the primary cause of heart disease in children. Current therapeutic strategies in KD are based on the administration of intravenous immunoglobulins (IVIG) and anti-platelet agents such as aspirin and abiciximab 16. Despite treatment, children with KD still have a 5–10% risk of developing coronary artery lesions, indicating the need for more effective, pathophysiologically targeted therapies 17. A fraction (10–15%) of patients with KD do not respond satisfactorily to IVIG. In these subjects, anti-TNF agents are effective 18. Dendritic cells endowed with a tolerogenic function expand during subacute phases of KD. This event is not apparently influenced by TNF blockade, revealing a somewhat complex remodelling of the immune network that occurs in KD patients responding to therapy 19. PAN is an extremely rare necrotizing vasculitis involving medium arteries, characterized by micro-aneurysmatic and stenosing lesions 20. Fibrinoid necrosis and dense neutrophil and lymphocyte infiltrate are frequent findings 21. The pathogenesis is poorly known: most studies are biased by the lack of differentiation from other vasculitides, in particular microscopic polyangiitis (MPA) and by the epidemiological shift towards non-hepatitis B virus (HBV)-associated PAN 22, 23. Current therapeutic regimens are those employed in small vessel vasculitides 12, 16, 23 (see below). Small vessel vasculitides include immune-complex and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV). IgA vasculitis (Henoch–Schönlein purpura) is a prototypic immune-complex vasculitis, more frequent in children and young adults. Palpable purpura, mainly at lower extremities, arthritis, gastrointestinal involvement (ischaemia, enteric haemorrhage, intussusception) and renal disease with features undistinguishable from isolated IgA nephropathy (Berger\'s disease) are relatively common 20, 24. Long-term kidney involvement can evolve into renal failure, more frequently in adult patients, whereas other manifestations are usually self-limiting or controlled by non-steroid anti-inflammatory drugs or corticosteroids. Severe renal manifestations are usually treated with high-dose corticosteroids, either alone or combined with immunosuppressive agents, plasmapheresis or IVIG 16, 25. The incidence of cryoglobulinaemic vasculitis (essential cryoglobulinaemia, mixed cryoglobulinaemia, CV) peaks in middle age and in areas with a high incidence of hepatitis C virus (HCV) infection. Cryoglobulins are formed by a combination of mono- or oligoclonal immunoglobulins with rheumatoid factor in the context of humoral responses associated with chronic infection (mainly HCV), autoimmunity (e.g. Sjögren\'s syndrome) or B cell malignancies. Purpura, mainly in the lower limbs, and skin ulcers, possibly with arthralgias or arthritis, are common features at presentation. Peripheral nerve involvement is usually mild and glomerulonephritis less frequent 26. Treatments for HCV-related CV are based on anti-viral agents such as peg-interferon (IFN) plus ribavirin 27, whereas in non-viral CV AAV-like regimens are recommended 12. Anti-B cell agents such as rituximab are being added to anti-viral agents as the standard of care treatment of CV, given their apparent safety and efficacy 28. Autoantibodies directed against antigens usually contained in the neutrophil primary granules characterize AAV. These antibodies, which could be involved directly in the pathogenesis of the disease 29-31, are referred to as ANCA because of their target intracellular distribution at immunofluorescence analysis of fixed samples. Anti-proteinase 3 antibodies (cANCA) and destructive granulomatous lesions of the upper and lower respiratory tract, of the eye and of the ear, necrotizing crescentic glomerulonephritis and systemic vasculitis are hallmarks of granulomatosis with polyangiitis (GPA, formerly Wegener\'s granulomatosis 32). Systemic features such as fever and arthromyalgias are frequent, while skin and nervous system involvement are less common. Persistent exposure to respiratory infectious and irritant agents might be involved in the natural history of the disease 33. Pulmonary and renal involvements occur in both GPA and MPA. An epidemiological complementation exists, with MPA being more rare and severe in Europe and GPA less frequent in Japan 34. Anti-myeloperoxidase (MPO) antibodies (pANCA) characterize MPA, and granulomatous lesions and the involvement of upper respiratory tract are less frequent. Skin, peripheral nerve, gastrointestinal and lung involvements are, in fact, exquisitely vasculitic in MPA. Renal involvement in MPA is frequent and often severe. Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg–Strauss\' syndrome) is part of a wider clinicopathological continuum that includes allergy, asthma and eosinophilic syndromes. Clinical features include hypereosinophilia, nasal polyposis, palpable purpura, peripheral neuropathy and a history of allergic asthma, usually improving just before the onset of vasculitis. Cardiac, pulmonary and gastrointestinal involvement with either vasculitic lesions or granulomatous and eosinophilic infiltration are also common 35. Renal involvement is less frequent than in other AAV. pANCA, often recognizing MPO, are detectable in 40–50% of patients. ANCA-positive patients apparently have a higher incidence of vasculitic manifestations, renal and peripheral nervous system involvement and higher relapse rates. ANCA-negative patients are at increased risk of heart and pulmonary involvement 36. An increased incidence of venous thrombo-embolism in GPA has been established in the Wegener\'s Clinical Occurrence of Thrombosis (WeCLOT) study 37. Results were confirmed and extended to all AAV (but not to patients with PAN) in a large retrospective analysis 38. AAV patients also are at higher risk of arterial thrombosis, with 14% of patients experiencing a cardiovascular event within 5 years of GPA or MPA diagnosis 39. Apparently, antibodies recognizing MPO are associated with a higher cardiovascular risk than antibodies against proteinase 3 (PR3) 39. Venous and arterial thrombosis often occur during active phases of vasculitis and are not apparently associated with conventional pro-thrombotic risk factors, rather suggesting a potential link with inflammation and defective regulation of the thrombogenic action of leucocytes 10, 40. Significant efforts are being employed in AAV genetics, pathophysiology and therapeutics 41, 42. Current treatment approaches are based on disease severity (i.e. extension to vital organs or refractoriness to therapies 12, 43). A combination of oral or intravenous cyclophosphamide with glucocorticoids is often used for induction of remission in patients with generalized or severe AAV or with a five-factor score ≥ 1 44) 12, 45. Encouraging results from the Rituximab for ANCA-associated Vasculitis (RAVE) and Rituximab in Vasculitis (RITUXVAS) trials 46-48 suggest that rituximab might represent an alternative to cyclophosphamide, and as such it might be introduced in the standard of care treatment 49, 50. High-dose glucocorticoids plus methotrexate could be employed for remission induction in non-organ or non-life-threatening AAV. Plasma exchange is recommended in addition to standard treatment of patients with severe renal involvement, although it does not apparently influence the overall survival 12. Various agents, including azathioprine, methotexate and rituximab, are used to maintain remission 51. Behçet\'s disease is currently included in a group of ‘variable-vessel’ vasculitides: it involves arterial and venous vessels of variable dimensions, a feature that is somewhat unique, and is often associated with the development of arterial aneurysms. Recurrent mucocutaneous manifestations (including oral and genital ulcers), uveitis and endothelial activation characterize the disease. Joints, gastrointestinal tract and central nervous system are also involved 52. Thrombotic events in Behçet\'s disease occur in 10–30% of patients and include superficial thrombophlebitis and deep vein, cerebral venous sinus, pulmonary artery and intracardiac thrombosis. Budd–Chiari syndrome and thrombosis of the vena cava are responsible for at least part of the disease morbidity 40. Thrombosis and vasculitis appear intermingled, with diffuse neutrophilic inflammation of the vascular wall often being found in association with tightly adherent thrombi and activation of circulating leucocytes 53-55: venous occlusion and arterial wall aneurysmatic remodelling are common outcomes, while embolism is relatively rare 40. Enhanced T cell responses, due possibly to facilitating effects of human leucocyte antigen (HLA)-B51 and to genetically determined imbalances in the interleukin (IL)-10/IL-23 network 56-58), and co-existing autoinflammatory processes are implicated 59, 60. Recent studies suggest that variants in ERAP1, an aminopeptidase that trims peptides for proper loading onto major histocompatibility complex (MHC) class I antigens, are associated with Behçet\'s disease, sustaining the contention that peptide–MHC class I interactions contribute to the pathogenesis of the disease 61. There is consensus on the use of azathioprine and corticosteroids for eye disease 52. Cyclosporin A, infliximab or interferon (IFN)-α are used in severe cases, colchicine in Behçet\'s disease-related arthritis and erythema nodosum and corticosteroids for dural sinus thrombosis 62. By contrast, the management of vascular disease as well as gastro-Behçet\'s disease or neuro-Behçet\'s disease is based largely on expert opinion and includes conventional immunosuppressants, TNF-antagonists and thalidomide 52. Of interest, immunosuppressive agents appear to substantially decrease the risk of thrombosis relapses 63, while anti-coagulants do not appear effective 64, highlighting the importance of the deregulated immune response in driving cardiovascular events in Behçet\'s disease. The blood transports oxygen and nutrients throughout the body. Pathogens or toxins also spread through blood vessels. As a consequence, the circulatory system must be able to sense potential threats to the organism integrity and to react. Intravascular immunity refers to the interaction between humoral and cellular constituents of the immune system and microbes 65. Successful microbes have evolved strategies that divert and confuse the immune response by interfering with the chemotactic recruitment and the various functions of effector leucocytes by adhering to endothelial cells and thus avoiding clearance in the spleen, or by escaping detection by interference with humoral innate immunity 65. Conversely, an exquisitely sensitive and tightly regulated immune patrolling system has evolved in higher eukaryotes. Patrolling cells detect not only direct signs of microbial invasion (pathogen-associated molecular patterns, PAMPs), but also signs of vascular injury that might indirectly reveal infection (damage-associated molecular patterns, DAMPs). More than 60 trillion endothelial cells line vascular lumens, accounting in the human body for an approximate 4 km2 surface 66. Changes on the surface of endothelial cells, which in physiological conditions are confined to relatively small areas, initiate the key event in vascular inflammation, i.e. the recruitment of blood leucocytes to the vessel wall. These changes reflect: (i) the activation of endothelium innate immune receptors, which are differentially distributed in the vasculature 67 and are apparently responsible for the pathological outcomes of vessel inflammation (e.g. panarteritis versus perivasculitis) 68; and (ii) the paracrine action of a family of sentinel cells, which are strategically located in the vessels to detect potential or actual threats to the vessel integrity. These sentinels include constitutively rolling/crawling neutrophils and monocytes and innate lymphocyte populations, invariant natural killer (NK) T cells in particular, and even mast cells 69. Immobilized populations of phagocytes that reside in specialized vascular districts also play a role. Küpffer cells in liver sinusoids are the best-characterized vessel guardians, specialized in purging the circulating blood from opsonized particulate substrates. Platelets also express innate pattern recognition receptors and interact with leucocytes in the blood and at sites of vessel injury 70. Platelets respond to lower amounts of selected PAMPs, such as bacterial endotoxin, than most leucocytes, releasing a wide array of activatory signals. As such leucocyte sensitivity to potentially harmful agents is much higher in the presence of platelets 71, 72. The interaction might have dangerous outcomes 73, even considering the ability of platelet-derived microparticles, which extend the reach of platelets even to quite distant districts, to elicit, amplify and maintain vascular inflammation (see also below) 74. Sentinel cells react to PAMPs and DAMPs by generating various mediators that act on endothelia, including cytokines, histamine and cysteinyl–leukotrienes 65, 71 and even functional microRNA 75. Endothelial cells react by up-regulating the expression of P-selectin, which is stored in Weibel–Palade bodies, and of E-selectin, which is synthesized de novo. Selectins engage the leucocyte PSGL1 leucocyte receptor, enforcing the tethering of flowing leucocytes to the endothelium and initiating their subsequent rolling along the vessels in the direction of the blood flow. Long tethers are formed under shear at the rear of the rolling neutrophils that ‘catapult’ to the front of the cell 71. PSGL1 activation determines a conformational change of leucocyte integrins, which interact with higher affinity with their counterparts on the endothelium. As a consequence, leucocytes progressively slow down, adhere firmly to endothelial cells and eventually arrest. The endothelium surface is enriched in negatively charged residues, such as heparan sulphates, that anchor positively charged chemokines. Chemoattractant signals, specifically including formylated moieties derived from mitochondria, organelles with a putative endosymbiotic origin 76-79, appear to play a key role in directing neutrophils towards transmigration sites in inflamed vessels. PSGL1 activation also results in the redistribution of the primary granules content to the neutrophil plasma membrane, including MPO and PR3 that are targeted by ANCA (see above). The redistribution of oxidizing and proteolytic activities at the membrane may facilitate transendothelial migration and the further movement of leucocytes away from the chemokines on the endothelial cells and within the extracellular matrix, even if this contention has not been demonstrated formally in in-vivo systems. Reactive oxygen species (ROS) generation is a hallmark of immune cell activation. ROS are required to cope with invading microorganisms in the blood and in the peripheral tissues. In zebrafish the wound response entails a localized rise in hydrogen peroxide concentration at the margins of the wound, which is necessary for the swift recruitment of leucocytes at the site of injury 80, where they are likely to be in charge both of restricting microbe proliferation and of delivering appropriate signals to stem/progenitor cells which, in turn, reconstitute damaged tissues 81. Subendothelial vessel wall cells/constituents contribute to vessel homeostasis under inflammatory conditions. For example, leucocytes that have extravasated from post-capillary venules crawl along processes of pericytes, mural cells of blood vessels, in a β2 integrin-dependent manner. This event enables them to reach gaps between adjacent pericytes 82. Traffic through the subendothelial matrix in inflamed tissues is facilitated by enlargement of these gaps 82 and by the remodelling of the cytoskeleton of pericytes interacting with the leucocytes 83. Once extravasated, leucocytes receive migratory and survival signals from pericytes associated with nearby capillaries and arterioles. Pericytes broadcast the news of ongoing vessel injury and attract extravasated neutrophils and monocytes at the site of vascular inflammation 84, 85. So far, the actual implications of these events for maintained small vessel inflammation in AAV and other systemic vasculitis have not been investigated. In-vivo microscopy studies have also indicated that the density of the interstitial collagen network controls its ability to provide physical guidance to extravasated neutrophils. Neutrophil migration through the interstitial matrix depends upon the integrity of the actin-based cytoskeleton and on metalloproteinase (MMP)-sensitive adhesion/signalling molecules on neutrophils. In contrast, it does not apparently require pericellular degradation of the collagen network 86. Mechanisms that enable inflamed vessels to cope with microbial and non-microbial threats and to heal The mechanisms involved in the defence against microbes and in the reconstitution of vessel integrity largely overlap: this possibly reflects an evolutionary process initiated at the level of an ancestral unspecialized haemolymphatic system 87. Aberrant deployment and/or maintenance of responses, that have probably been selected evolutionarily because they are advantageous, constitute a priming event of vasculitis leading to vessel wall disruption (with subsequent haemorrhage) and thrombosis, on one hand, and on deregulated vessel wall remodelling on the other hand. After detection of a potential threat to vessel integrity, counter-regulatory responses contrast the injurious activity and the diffusion of pathogens or toxins in the acute phase and at later times promote the reversal of vessel damage through neoangiogenesis and repair responses. Arterial and venous thrombosis can also occur as processes that are triggered by the active participation of immune cells, which are dispensable for haemostasis or vessel repair. Immune-mediated thrombosis, or immunothrombosis 88, might have a homeostatic role in protection against microbial threats in the vasculature. Thrombi might contribute to the capture of blood microbes, preventing their spreading into tissues and entrapping them in a microenvironment that is enriched in microbicidal activities. Neutrophil extracellular traps (NETs), threads of deconsensed chromatin released by activated neutrophils and decorated with microbicidal signals (Fig. 1), represent crucial structural constituents of immune-elicited thrombi 89. Neutrophils generate NETs as a response to stimuli that cannot be removed easily by phagocytosis. NETs are known: (i) to be implicated in AAV 90; and (ii) to contribute to the organization of venous thrombi 91, 92. As such, they represent intriguing candidates to link paroxysmal neutrophil activation and thrombosis in AAV. Neutrophils of patients with active AAV appear to express high amounts of tissue factor (TF), a critical signal for the activation of the coagulation cascade. Moreover, they generate TF-expressing NETs and microparticles which can be detected in the blood, the bronchoalveolar lavage and the patient\'s kidney 93. NET generation is possibly associated with the direct effect of ANCA on primed neutrophils 93. However, direct clinical evidence of NET involvement in atherothrombosis is lacking, and the limitations associated with the available animal models of vasculitis for the study of thrombotic events 94 make experimental proof of a cause–effect relationship difficult. Neutrophils degranulate and generate neutrophils extracellular traps (NETs) in response to sterile stimuli. Neutrophils freshly purified from a healthy donor were either left untreated (a) or challenged with purified human P-selectin (b). The expression of pentraxin (PTX)3 (red) and myeloperoxidase (MPO) was analysed by confocal microscopy. (c,d) The generation of NETs upon challenge of adherent neutrophils with the N-formylated formyl-methionyl-leucyl-phenylalanine (fMLP) peptide, which mimics microbial of mitochondrial protein degradation products or interleukin (IL)-8. Hoechst (blue) was used for counterstaining nuclei and extracellular DNA. NETs promote thrombosis by activating factor XII, by neutralizing endogenous anti-coagulants (e.g. tissue factor pathway inhibitor: TFPI) and by promoting platelet recruitment and activation through captured von-Willebrand factor and histone proteins 88. In turn, activated platelets commit neutrophils to NET generation with unusual efficacy 95. During sepsis, NETs play a critical role in the capture of circulating bacteria, thus preventing their dissemination to distant sites. This represents a formal proof of the protective role of intravascular immunity 96. These pathways might also be involved in the response to sterile vessel injury. Neutrophils that are involved in immune-mediated thrombosis are likely to be activated, even if the extent of the activation is not sufficient to licence them for migration to extravascular districts. The expression of ANCA antigens, such as PR3 and MPO, on the surface of neutrophils is a genetically determined event, possibly enhanced further by inflammatory stimuli 41, 97. Membrane PR3 and MPO interact with ANCA which, in turn, activate the alternative complement pathway. As a consequence, neutrophils undergo degranulation and respiratory burst and release NETs 24, 90, 98, 99. ANCA-induced NET generation increases the autoantigen burden due to the exposure of PR3 and MPO along NETs. Recent studies have indicated that antigen-presenting dendritic cells challenged with NET components reproduce ANCA and autoimmunity when injected into healthy experimental animals, implicating the cross-presentation of NET-associated antigens in the in-vivo maintenance of AAV 100. Neointimal and medial thickening are part of a stereotyped response to the injury of large vessels 101-103. Enhanced recruitment of inflammatory cells, disruption of the vessel wall architecture due to proteolytic activities and deregulated activation of the repair programme of the vessel wall contribute to the vessel wall remodelling. The adventitial layer has a privileged role in the natural history of large vessel vasculitis 4. The current pathogenic model implicates a biased activation of polarized T helper type 1 (Th1)/Th17 lymphocytes by adventitial dendritic cells within the vessel wall, release of cytokines and of IFN-γ in particular from activated T cells, with ensuing macrophage recruitment and activation. In turn, macrophages infiltrate the adventitial and medial layers and secrete cytokines such as IL-1β and IL-6 and growth factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) 101, 104, 105. Late events include medial smooth muscle cells proliferation, intima invasion and deposition of poorly structurally organized extracellular matrix, on one hand, and neoangiogenesis on the other hand. The generation and release of growth factors, including VEGF and PDGF, from platelets and circulating or infiltrating immune cells is critical for the remodelling of the vessel wall in medium and large vessel vasculitides 106-109. Levels of VEGF are high in patients with large vessel vasculitides 107, particularly in GCA patients with recent optic nerve ischaemia 108. Vessel-associated macrophages are a possible source of the signal 104. PDGF co-operates with VEGF in sustaining neoangiogenesis 110, with pericyte and smooth muscle cell recruitment and myofibroblast proliferation 110. The balance between angiopoietins 1 (Ang1) and 2 (Ang2) is critical to regulate angiogenesis and tissue remodelling 111, 112. Ang2 expression is restricted to inflammatory 113, 114 or to physiological and non-physiological pro-angiogenic conditions 115, 116. Persistent hypoxia or high levels of growth factors are associated with Ang1 expression which, in turn, participates in a vasoprotective response. In contrast, upon release from Weibel–Palade bodies, Ang2 initiates the neoangiogenic process by promoting endothelial destabilization, an event which is critical for vessel sprouting, possibly via interference with the activation of the Tie2 receptor 117. Little is known about the pathogenic role of angiopoietins in systemic vasculitides: higher levels of Ang1 and Ang2 have been detected in Behçet\'s disease and AAVs, without a clear correlation with disease activity 114, 118. A recent study 17 reports an association between single nucleotide polymorphisms (SNPs) in the VEGFA and ANGPT1 gene and KD susceptibility as well as between SNPs in VEGFR2 and ANGPT2 and coronary artery disease. Ang1 was significantly lower in the serum of patients with active disease and scarcely expressed in tissue samples of affected arteries, while Ang2 was detected only at sites of post-thrombotic neovascularization, suggesting that Ang1/Ang2 deregulation was involved in KD subendothelial oedema, gap formation, fenestration of endothelial cells and eventual inflammatory cells infiltration 17, 119. The hypoxia-associated response is a target to limit the progression of aneurysmal lesions associated to systemic vasculitides 114, 115, 120, 121. Ang2 blockade has yielded promising results in cancer preclinical models when combined with anti-neoplastic and anti-VEGF agents 122. This approach could have additional advantages in an Ang1/TGF-β-rich anti-angiogenic/profibrotic environment 123, 124. Selective Ang2 blockade and Ang1/Ang2 dual blockers such as trebananib proved clinically efficacious in ovarian cancer in a Phase II study 125, and several trials are ongoing for other solid (NCT01664182, NCT01538095, NCT01553188, NCT01666977) or haematological malignancies (NCT01555268). A dual anti-VEGF–Ang2 CrossMab is currently being tested at a preclinical stage 122. The long pentraxin PTX3 is a prototypic innate pattern recognition receptor, highly conserved through evolution 126, 127. In contrast to short pentraxins such as C-reactive protein, that are usually produced in the liver, PTX3 is mainly generated and released at sites of inflammation. Neutrophils store a large and non-renewable reservoir of preformed PTX3 in the specific granules (Fig. 1). As such, neutrophils are responsible for the prompt release of PTX3 in response to acute vessel and tissue injury 128, 129. In this context, PTX3 represents a regulator of the inflammatory response: it regulates neutrophil access to inflamed vessels negatively by interfering with the P-selectin/PSGL1 system 130, binds to activated platelets and quenches their inflammatory activities 129. Indeed, activated platelets in the presence of PTX3 interact less effectively with leucocytes, aggregate less and bind with lower efficacy to fibrinogen 129. Vessel cells, including endothelial cells and macrophages, produce PTX3, which possibly has a role in the persisting vessel remodelling and inflammation associated with systemic vasculitis 108, 131, 132. PTX3 interacts with cell remnants, regulating their clearance 133 and controlling the immunogenicity of antigens associated with dying cells 134, events that could be implicated in the persistence of cell remnants at sites of inflammation, a hallmark of AAV 131, 132, 135, 136. Interestingly, the action of PTX3 on the clearance of cell debris depends upon its physical interaction with other inflammatory molecules such as ficolins 137, 138, highlighting the role of PTX3 as a critical regulator of apoptotic cell phagocytosis in inflammatory conditions. PTX3 concentration is associated with cardiovascular risk factors but apparently not with subclinical atherosclerosis 139, and the molecule accumulates at sites of active vessel remodelling in patients with GCA 108 and TA 140. PTX3 physical association with various matrix components modifies the biological characteristics of the matrix. PTX3-assisted reorganization is required for the cumulus matrix organization 141 and for effective smooth muscle cell migration. Moreover, PTX3 acts as a selective inhibitor of neovascularization triggered by fibroblast growth factor (FGF)2, without influencing physiological angiogenesis 142. Other inflammatory molecules, such as TNF-stimulated gene 6 protein (TSG-6), are able to compete with PTX3 for the binding and thus to revert the inhibitory effects exerted by PTX3 on FGF2-mediated angiogenesis, suggesting that the relative levels of interacting inflammatory molecules generated at inflammatory sites are crucial to fine-tune the angiogenic outcome of the process 143. Further studies in patients with systemic vasculitis are necessary to verify whether or not PTX3-assisted organization of the matrix influences the functions of leucocytes that have extravasated and the outcome of the vessel wall remodelling 101, 109. Exogenous administration of soluble pattern recognition receptors has been proposed to have therapeutic potential 144-146. A single injection of a viral vector carrying the PTX3 gene inhibited intimal thickening after balloon injury in rat carotid arteries 147, 148, suggesting that PTX3 delivery might prove valuable in large vessel vasculitides and especially TA, in which angioplasty is commonly used. The high mobility group box 1 (HMGB1) protein has well-characterized functions in the nucleus and in the cytosol of living cells. It is released as a consequence of cell and tissue necrosis and further secreted actively by activated immune cells, broadcasting the news that active inflammatory responses are needed to prompt long-term repair and defence programmes 149, 150. HMGB1 enhances and accelerates the action of multiple stressors, endogenous inflammatory signals (e.g. DNA and chromatin components), microbial constituents and cytokines 150, 151. HMGB1 blood concentration increases as a consequence of localized ischaemia-associated tissue injury. This is the case of acute myocardial infarction, where circulating levels of HMGB1 predict the extension of ischaemia and the residual contractile function of the myocardium 152 and of diseases characterized by the extensive involvement of the microcirculation and systemic peripheral ischaemia. In patients with SSc, platelet-derived, bioactive HMGB1 release correlates with platelet activation 153 and serum HMGB1 concentrations are associated with disease activity 154. Elevated concentrations of HMGB1 in the blood have been found in patients with medium vessel vasculitis, KD in particular 155, 156, and with small vessel vasculitis, including IgA vasculitis and AAV 157-162. Plasma HMGB1 concentration increases in the vasculitis active phase 159, 162. Moreover, the concentration of HMGB1 is higher in patients with GPA with a mostly granulomatous disease 160. In contrast, the accepted disease activity score, Birmingham Vasculitis Activity Score (BVAS) or other inflammatory markers do not discriminate between patients with a predominantly vasculitic or granulomatous involvement 160. Because HMGB1 is expressed preferentially in the granulomatous tissue 160, systemic levels might reflect local production within granulomas. High HMGB1 levels also identify patients with renal involvement, either active or quiescent. The latter result possibly reflects a low-grade inflammatory response that continues even in the absence of overt clinical manifestations 162. HMGB1 plays an apparently non-redundant role in controlling the inflammatory response to necrosis, sustaining the repair of injured tissues, on one hand, and controlling the establishment of acquired immune responses on the other hand 149, 163-165. HMGB1 pharmacological blockade in rheumatological diseases is being thoroughly investigated 151, and might prove valuable in the setting of systemic vasculitis. Inflammasomes are intracellular machineries, assembled on demand after stimulation of innate pattern recognition receptors. Caspases 1 and 5 are ultimately recruited to process and activate cytokines, in particular to convert pro-IL-1β to active IL-1β 166, 167 and to regulate cytokine-independent events, such as the acidification of phagosomes that contain bacteria 168. Several drugs modulate the inflammasome. Colchicine eventually limits the inflammasome-elicited caspase 1 activation 169-171. Anakinra (a recombinant IL-1-receptor antagonist), canakinumab (an anti-IL-1β humanized antibody) and rilonacept (a decoy IL-1-receptor) act downstream of the activation of the inflammasome. IFN-α has a dual inhibitory effect on the inflammasome: direct inhibition occurs through a signal transducer and activator of transcription (STAT)-1-dependent pathway, while the IFN-α-induced IL-10 increase down-regulates pro-IL-1β levels 172. Inflammasome activation plays a prominent role in autoinflammatory disorders 166. Low-density lipoprotein receptor-related protein 1 (LRP1) provides a scaffold necessary for the assembly of the inflammasome that activates caspases 1 and 5, required for processing and activation of various inflammatory cytokines: it has been identified as a novel GCA susceptibility gene, information that might hint at a deregulated recruitment of inflammasome in large vessel vasculitis, and suggests that it might represent a therapeutic target 173. Abnormal expression and circulating levels of IL-1β has also been detected in patients with KD, in particular in those who do not respond to IVIG 174. A non-redundant role of IL-1β and caspase-1 in coronary arteritis has been established in a mouse model of KD 175. Genetic and pharmacological evidence supports the issue that IL-1β maturation and secretion are dependent upon the non-obese diabetic (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome and are required for the development of coronary lesions. In this model, coronaritis was partially corrected by anakinra 175, providing a rationale for the use of anti-IL-1β treatments to prevent coronary disease in KD patients, even if caution should be used when translating such information in humans. Elevated levels of IL-1β have been detected in the sera and synovial fluid of patients with Behcet\'s disease 60 and IL-1β production dominates the response to microbial stimuli of macrophages of patients with active disease 176, possibly providing a clue to the deregulated anti-bacterial response in Behçet\'s disease. However, caspase-independent pathways might also be involved 177. Colchicine is recommended for the management of erythema nodosum and arthritis, and IFN-α for a wide range of manifestations of Behcet\'s disease, including eye, CNS and mucocutaneous involvement. Anakinra and canakinumab have proved to be efficacious in refractory Behcet\'s disease 178, 179 and a pilot study evaluating safety and efficacy of anakinra against placebo is ongoing (NCT01441076). Immune complex deposition and ANCA generation play a role in the recruitment and activation of innate immune response at sites of vessel inflammation 20, 33. In AAV a positive feedback loop possibly sustains neutrophil and B cell activation 180. Activated neutrophils are a source of the B cell activating factor BAFF (also known as BLyS, a member of the TNF family) 181, 182, whose levels are apparently associated with cryoglobulinaemia in the setting of HCV infection 183. Marginal zone (MZ) innate-like B lymphocytes potently respond to inflammatory stimuli and their cross-talk with neutrophils results in an enhanced generation of antibodies against conserved microbial antigens, highlighting a B lymphocyte helper activity of neutrophils 184. Conversely, innate-like CD5+ B cells appear to play a homeostatic role in AAV: they are reduced in the blood of patients with active disease, and low numbers after blood repopulation upon depletion with rituximab predict future relapse 185. The selective expansion of MZ-like B cell clones might play a role in the progression to malignant lymphoproliferation in CV 186. Factors involved in the regulation of MZ-like B cells such as the Fc receptor-like 5 (FCRL5) pathway 187 are currently under investigation as pathogenic players and potential therapeutic targets in CV 188. B cell-depleting strategies have been tested extensively in clinical settings. A randomized controlled trial and two open-label studies have demonstrated the efficacy of rituximab in CV 28, 189, 190. The RAVE and RITUXVAS trials recognized the equivalence of rituximab and cyclophosphamide in inducing remission in AAV 46-48. According to the RAVE trial, rituximab was significantly more efficient than cyclophosphamide in those patients who relapsed 47, 48, and some case reports showed the efficacy of rituximab in four patients with severe and/or refractory IgA vasculitis. Belimumab is an anti-B cell agent with a selective effect on naive B cells and plasma cells, due to blockade of BAFF. Belimumab is currently under investigation in combination with azathioprine for maintenance of remission in GPA and MPA (BREVAS trial: NCT01663623). A randomized placebo-controlled trial is going to begin to evaluate Blisibimod, another BAFF-antagonist, in the setting of AAV (BIANCA-SC trial: NCT01598857). B cell-depleting strategies appear less effective on granulomatous and in general non-vasculitic manifestations of AAV 191, 192, pointing to the need for novel therapies targeted at mechanisms responsible for macrophage and eosinophil recruitment and granuloma maintenance, such as T lymphocytes 193. Besides neutrophils, T lymphocytes constitute the predominant leucocyte subgroup in the vascular infiltrate of Behçet\'s disease 59. Patients with active Behçet\'s disease show expansion of the Th1 and Th17 compartment, increased Th17/Treg ratio in the blood and cerebrospinal fluid 59, lower IL-10 levels and enhanced expression of the receptor for IL-23. The IL-23 pathway stimulates Th17 cells 56, 204 which, in turn, promote neutrophil recruitment 205. GCA is a T cell-dependent disease 206. Adventitial-recruited Th1 and Th17 cells co-operate to promote 207 macrophage activation and vessel wall remodelling. Corticosteroids are probably only effective on the Th17 branch, whereas IFN-γ-producing Th1 cells are spared 207. The latter cells could sustain vessel inflammation in refractory disease or induce relapse in apparently remitted patients. A selective cyclo-oxygenase-independent anti-IFN-γ effect has been described for aspirin in a model of GCA 208, possibly providing support for controversial clinical findings 209, 210. Innate-like γδ T cells are highly responsive to TNF 211 and show tropism for the recognition of heat shock proteins (HSP) 212. Cross-reactivity between human and bacterial HSP could facilitate γδ T cell autoreactivity 213. Increased expression of HSP occurs in the skin and endothelium of patients with Behçet\'s disease and TA, respectively 5, 214 and is associated with expansion of the γδ T cell subset in the peripheral blood and at sites of inflammatory involvement 5, 215-217. Furthermore, autoreactive γδ T cells exert spontaneous cytotoxicity against aortic endothelial cells in TA 5. A significant γδ T cell infiltrate has also been reported in GPA with renal involvement and in the skin of patients with cutaneous necrotizing vasculitis 218. Several studies have tested the role of anti-T drugs in AAV, in particular in the setting of relapsing, refractory or persistent disease, where therapeutic indications are less defined. Anti-thymocyte globulin and 15-deoxypergualin (gusperimus) showed efficacy in open-label trials 219-221. Alemtuzumab (Campath-1H), an anti-CD52 agent, showed controversial results in an open-label study 222. A randomized trial (NCT01405807) is ongoing. IFN-α is effective in remission induction in EGPA, possibly by a selective dampening effect on Th2 responses (as well as on eosinophil degranulation) 36. Productive interactions between adventitial DCs and T lymphocytes are crucial in the pathogenic cascade of large vessel vasculitides, and modulators of lymphocyte activation such as the cytotoxic T lymphocyte antigen (CTLA)-4 analogue abatacept are currently being tested in GCA and TA (NCT00556439). An open-label trial for the efficacy of abatacept in GPA has recently been completed (NCT00468208) and another involving Behçet\'s disease is expected to end by 2014 (NCT01693640). Blockade of IL-2 signalling (e.g. with the anti-IL-2Rα antibody daclizumab 223) could perhaps find some application in analogous clinical settings. Anti-Th17-targeted therapies (e.g. the anti-IL-12/IL-23 monoclonal antibody ustekinumab) could prove beneficial in GCA, AAV and Behçet\'s disease, given the emerging role of Th17 in the pathogenesis of these diseases. In the setting of Behçet\'s disease, further rationale is provided by the efficacy of anti-Th17 agents in autoimmune diseases with a shared immunogenetic background 224, 225. TNF has a central role in a wide range of inflammatory conditions, including fever, neutrophil priming, endothelial activation and granuloma formation, which are all key events in the pathogenesis of vasculitis. TNF blockade has been tested extensively. An action on granulomatous lesions could be involved in the efficacy of anti-TNF agents in TA 226, 227 and in naive or refractory AAV 51. In the latter conditions, inhibition of neutrophil and endothelial activation could also occur. A similar mechanism could also be active in severe Behçet\'s disease, PAN and in the acute phase of KD. A study of the safety and effectiveness of infliximab in GCA (NCT00076726) was terminated, due to an interim analysis showing that infliximab did not reduce the number of first relapses in GCA or cumulative glucocorticosteroid dosage. IL-5 and IL-25 are key players in EGPA 36. IL-5, a well-characterized eosinophilic stimulating factor, is part of the Th2-associated cytokine array that characterizes EGPA. Conversely, eosinophil-derived IL-25, which is increased in the blood of patients with EGPA and expressed selectively in the vasculitic lesions, sustains Th2 responses 228. Mepolizumab, an anti-IL-5 monoclonal antibody appears promising in EGPA 42, 229, and anti-IL-25 agents are under development. IL-6 is a pleiotropic cytokine secreted by monocytes and T cells and acts as a major inducer of systemic inflammation and local neoangiogenesis. Increased levels of IL-6 are detectable in the serum and cerebrospinal fluid of patients with neuro-Behçet and correlate with disease activity 60. Serum concentrations of IL-6 are raised in GCA and correlate with disease activity. Moreover, IL-6 is expressed by infiltrating macrophages and promotes Th17 polarization 207, suggesting a direct involvement of the cytokine in the pathogenesis of the disease even if a protective effect of IL-6 in GCA could not be excluded 230. Some studies have reported the efficacy of IL-6 blockade in Behçet\'s disease 231-233, in GCA 234, 235 and in TA 13, 236-238. Randomized placebo-controlled trials are now ongoing (NCT01791153, NCT01450137, NCT01693653). IL-21 is produced by activated central memory CD4+ T cells and promotes Th17 and Th1 in spite of Treg differentiation 59. High levels of IL-21 are present in circulating blood of patients with Behçet\'s disease and active GCA 239, 240 and IL-21 blockade influences the Th17/Treg balance in vitro 239, 240, suggesting that anti-IL-21 agents (currently under development) might be effective 59. A novel generation of agents has enhanced our ability to regulate the humoral and cellular immune response. As a consequence, better clinical outcomes and reduced drug-related toxicities have been obtained. However, we are just beginning to decipher the events associated with the persistent, self-maintaining vessel inflammation that is the hallmark of most systemic vasculitis. Specifically, we are just beginning to be aware of the protective role of vessel remodelling, necrosis and thrombosis in immune physiology that are the key features of most systemic vasculitis. Extinguishing the priming events in vessel inflammation could be achieved by targeting the mechanisms involved in intravascular immunity, including inflammasome activation, leucocyte recruitment, cytokine- or thrombin-mediated endothelial and platelet activation. DAMPs, PAMPs and the innate receptor machinery involved in their recognition represent a particularly attractive area of work in which strategies aimed at eliciting even relatively subtle changes in the microenvironmental conditions might impact substantially on the outcome of the immune response. NETs are attracting growing interest, both as structures endowed with direct biological actions involved in vasculitis and as relevant sources of autoantigens, which could be involved in maintaining the vicious circle leading to unrelenting vascular inflammation. The identification of the immunoregulatory properties of various subpopulations of innate leucocytes, and specifically innate B lymphoctes, and pericytes could further extend our ability to reset vascular inflammatory processes from their very beginning. Multiple pathways are also potentially involved in the remodelling of the vessel wall, and evidence derived from vasculitic and non-vasculitic settings suggests the potential efficacy of agents either with a direct neutralizing or agonist effect towards cytokines/growth factors that are implicated at a pre- and post-receptor level. Finally, identification of the protective action of molecules involved in the humoral innate immune response on vascular integrity and in guiding effective vascular repair suggests that we could rely upon the signals involved in the physiological homeostatic response of the vessels to injury as a novel frontier in drug development. The authors gratefully acknowledge the support of the Italian Ministry of Health (Ministero della Salute), RF2009 to A. A. M. and P. R.-Q.; of the Italian Ministry of University and Research (MIUR), PRIN 2010 to A. A. M. and FIRB-IDEAS to P. R.-Q.; and of the Associazione Italiana per la Ricerca sul Cancro (AIRC) to A. A. M. The authors wish to thank Dr Maria Carla Panzeri and Dr Cesare Covino for the excellent confocal microscopy that has been carried out in ALEMBIC, an advanced microscopy laboratory established by the San Raffaele Scientific Institute and the Vita-Salute San Raffaele University. Luqmani RA, Suppiah R, Grayson PC, Merkel PA, Watts R. Nomenclature and classification of vasculitis – update on the ACR/EULAR diagnosis and classification of vasculitis study (DCVAS). Clin Exp Immunol 2011; 164 (Suppl. 1): 11– 13. Wiley Online Library Jennette JC, Falk RJ, Bacon PA et al. 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum 2013; 65: 1– 11. Wiley Online Library Langford C. Takayasu\'s arteritis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, eds. Rheumatology. Oxford: Elsevier, 2010: 1567– 1573. Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med 2003; 349: 160– 169. Chauhan SK, Singh M, Nityanand S. Reactivity of gamma/delta T cells to human 60-kd heat-shock protein and their cytotoxicity to aortic endothelial cells in Takayasu arteritis. Arthritis Rheum 2007; 56: 2798– 2802. Wiley Online Library Vaglio A, Pipitone N, Salvarani C. Chronic periaortitis: a large-vessel vasculitis? Curr Opin Rheumatol 2011; 23: 1– 6. Grayson PC, Maksimowicz-McKinnon K, Clark TM et al. Distribution of arterial lesions in Takayasu\'s arteritis and giant cell arteritis. Ann Rheum Dis 2012; 71: 1329– 1334. Vaglio A, Catanoso MG, Spaggiari L et al. Interleukin-6 as an inflammatory mediator and target of therapy in chronic periaortitis. Arthritis Rheum 2013; 65: 2469– 2475. doi: 10.1002/art.38032. Wiley Online Library Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Takayasu arteritis and giant cell arteritis: a spectrum within the same disease? Medicine (Balt) 2009; 88: 221– 226. Springer J, Villa-Forte A. Thrombosis in vasculitis. Curr Opin Rheumatol 2013; 25: 19– 25. Hwang J, Kim SJ, Bang OY et al. Ischemic stroke in Takayasu\'s arteritis: lesion patterns and possible mechanisms. J Clin Neurol 2012; 8: 109– 115. Mukhtyar C, Guillevin L, Cid MC et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009; 68: 318– 323. Tombetti E, Franchini S, Papa M, Sabbadini MG, Baldissera E. Treatment of refractory Takayasu arteritis with tocilizumab: seven Italian patients from a single referral center. J Rheumatol 2013. Mekinian A, Neel A, Sibilia J et al. Efficacy and tolerance of infliximab in refractory Takayasu arteritis: French multicentre study. Rheumatology (Oxf) 2012; 51: 882– 886. Burns JC. Kawasaki disease. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, eds. Rheumatology. Oxford: Elsevier, 2010: 1583– 1586. Chan M, Luqmani R. Pharmacotherapy of vasculitis. Expert Opin Pharmacother 2009; 10: 1273– 1289. Breunis WB, Davila S, Shimizu C et al. Disruption of vascular homeostasis in patients with Kawasaki disease: involvement of vascular endothelial growth factor and angiopoietins. Arthritis Rheum 2012; 64: 306– 315. Wiley Online Library Burns JC, Best BM, Mejias A et al. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr 2008; 153: 833– 838. Burns JC, Song Y, Bujold M et al. Immune-monitoring in Kawasaki disease patients treated with infliximab and intravenous immunoglobulin. Clin Exp Immunol 2013; 174: 337– 344. Wiley Online Library Ishiguro N, Kawashima M. Cutaneous polyarteritis nodosa: a report of 16 cases with clinical and histopathological analysis and a review of the published work. J Dermatol 2010; 37: 85– 93. Wiley Online Library Lidar M, Lipschitz N, Langevitz P, Shoenfeld Y. The infectious etiology of vasculitis. Autoimmunity 2009; 42: 432– 438. de Menthon M, Mahr A. Treating polyarteritis nodosa: current state of the art. Clin Exp Rheumatol 2011; 29: S110– 116. Jennette JC, Falk RJ, Hu P, Xiao H. Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Annu Rev Pathol 2013; 8: 139– 160. Pillebout E, Alberti C, Guillevin L, Ouslimani A, Thervet E. Addition of cyclophosphamide to steroids provides no benefit compared with steroids alone in treating adult patients with severe Henoch Schonlein purpura. Kidney Int 2010; 78: 495– 502. Quartuccio L, Isola M, Corazza L et al. Performance of the preliminary classification criteria for cryoglobulinaemic vasculitis and clinical manifestations in hepatitis C virus-unrelated cryoglobulinaemic vasculitis. Clin Exp Rheumatol 2012; 30: S48– 52. Fabrizi F, Dixit V, Messa P. Antiviral therapy of symptomatic HCV-associated mixed cryoglobulinemia: meta-analysis of clinical studies. J Med Virol 2013; 85: 1019– 1027. Wiley Online Library Saadoun D, Rosenzwajg M, Landau D, Piette JC, Klatzmann D, Cacoub P. Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis. Blood 2008; 111: 5334– 5341. Savage CO. Pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. Clin Exp Immunol 2011; 164 (Suppl. 1): 23– 26. Wiley Online Library Kettritz R. How anti-neutrophil cytoplasmic autoantibodies activate neutrophils. Clin Exp Immunol 2012; 169: 220– 228. Wiley Online Library Kallenberg CG, Heeringa P. Complement is crucial in the pathogenesis of ANCA-associated vasculitis. Kidney Int 2013; 83: 16– 18. Jennette JC. Nomenclature and classification of vasculitis: lessons learned from granulomatosis with polyangiitis (Wegener\'s granulomatosis). Clin Exp Immunol 2011; 164 (Suppl. 1): 7– 10. Wiley Online Library Kallenberg CG. Pathogenesis of ANCA-associated vasculitides. Ann Rheum Dis 2011; 70 (Suppl. 1): i59– 63. Fujimoto S, Watts RA, Kobayashi S et al. Comparison of the epidemiology of anti-neutrophil cytoplasmic antibody-associated vasculitis between Japan and the U.K. Rheumatology (Oxf) 2011; 50: 1916– 1920. Sinico RA, Bottero P, Guillevin L. Antineutrophil cytoplasmic autoantibodies and clinical phenotype in patients with Churg–Strauss syndrome. J Allergy Clin Immunol 2012; 130: 1440. author reply, 1. Vaglio A, Buzio C, Zwerina J. Eosinophilic granulomatosis with polyangiitis (Churg–Strauss): state of the art. Allergy 2013; 68: 261– 273. Wiley Online Library Merkel PA, Lo GH, Holbrook JT et al. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener\'s Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann Intern Med 2005; 142: 620– 626. Allenbach Y, Seror R, Pagnoux C, Teixeira L, Guilpain P, Guillevin L. High frequency of venous thromboembolic events in Churg–Strauss syndrome, Wegener\'s granulomatosis and microscopic polyangiitis but not polyarteritis nodosa: a systematic retrospective study on 1130 patients. Ann Rheum Dis 2009; 68: 564– 567. Suppiah R, Judge A, Batra R et al. A model to predict cardiovascular events in patients with newly diagnosed Wegener\'s granulomatosis and microscopic polyangiitis. Arthritis Care Res (Hoboken) 2011; 63: 588– 596. Wiley Online Library Gaffo AL. Thrombosis in vasculitis. Best Pract Res Clin Rheumatol 2013; 27: 57– 67. Lyons PA, Rayner TF, Trivedi S et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med 2012; 367: 214– 223. Holle JU, Gross WL. Treatment of ANCA-associated vasculitides (AAV). Autoimmun Rev 2013; 12: 483– 486. Guillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, Le Toumelin P. The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Balt) 2011; 90: 19– 27. Cohen P, Pagnoux C, Mahr A et al. Churg–Strauss syndrome with poor-prognosis factors: a prospective multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty-eight patients. Arthritis Rheum 2007; 57: 686– 693. Wiley Online Library Langford CA. Cyclophosphamide as induction therapy for Wegener\'s granulomatosis and microscopic polyangiitis. Clin Exp Immunol 2011; 164 (Suppl. 1): 31– 34. Wiley Online Library Jones RB, Tervaert JW, Hauser T et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010; 363: 211– 220. Stone JH, Merkel PA, Spiera R et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010; 363: 221– 232. Specks U, Merkel PA, Seo P et al. Efficacy of remission–induction regimens for ANCA-associated vasculitis. N Engl J Med 2013; 369: 417– 427. Niles J. Rituximab in induction therapy for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Clin Exp Immunol 2011; 164 (Suppl. 1): 27– 30. Wiley Online Library Guerry MJ, Brogan P, Bruce IN et al. Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxf) 2012; 51: 634– 643. Luqmani R. Maintenance of clinical remission in ANCA-associated vasculitis. Nat Rev Rheumatol 2013; 9: 127– 132. Haznedaroglu IC, Ozcebe OI, Ozdemir O, Celik I, Dundar SV, Kirazli S. Impaired haemostatic kinetics and endothelial function in Behçet\'s disease. J Intern Med 1996; 240: 181– 187. Wiley Online Library Takeno M, Kariyone A, Yamashita N et al. Excessive function of peripheral blood neutrophils from patients with Behçet\'s disease and from HLA-B51 transgenic mice. Arthritis Rheum 1995; 38: 426– 433. Wiley Online Library Caliskan M, Yilmaz S, Yildirim E et al. Endothelial functions are more severely impaired during active disease period in patients with Behçet\'s disease. Clin Rheumatol 2007; 26: 1074– 1078. Remmers EF, Cosan F, Kirino Y et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet\'s disease. Nat Genet 2010; 42: 698– 702. Mizuki N, Meguro A, Ota M et al. Genome-wide association studies identify IL23R–IL12RB2 and IL10 as Behçet\'s disease susceptibility loci. Nat Genet 2010; 42: 703– 706. Shimizu J, Takai K, Fujiwara N et al. Excessive CD4+ T cells co-expressing interleukin-17 and interferon-gamma in patients with Behçet\'s disease. Clin Exp Immunol 2012; 168: 68– 74. Wiley Online Library Pineton de Chambrun M, Wechsler B, Geri G, Cacoub P, Saadoun D. New insights into the pathogenesis of Behçet\'s disease. Autoimmun Rev 2012; 11: 687– 698. Zhou ZY, Chen SL, Shen N, Lu Y. Cytokines and Behçet\'s disease. Autoimmun Rev 2012; 11: 699– 704. Kirino Y, Bertsias G, Ishigatsubo Y et al. Genome-wide association analysis identifies new susceptibility loci for Behçet\'s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 2013; 45: 202– 207. Hatemi G, Silman A, Bang D et al. EULAR recommendations for the management of Behçet\'s disease. Ann Rheum Dis 2008; 67: 1656– 1662. Desbois AC, Wechsler B, Resche-Rigon M et al. Immunosuppressants reduce venous thrombosis relapse in Behçet\'s disease. Arthritis Rheum 2012; 64: 2753– 2760. Wiley Online Library Hatemi G, Silman A, Bang D et al. Management of Behçet\'s disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behçet\'s disease. Ann Rheum Dis 2009; 68: 1528– 1534. Hickey MJ, Kubes P. Intravascular immunity: the host-pathogen encounter in blood vessels. Nat Rev Immunol 2009; 9: 364– 375. Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 2007; 100: 158– 173. Pryshchep O, Ma-Krupa W, Younge BR, Goronzy JJ, Weyand CM. Vessel-specific Toll-like receptor profiles in human medium and large arteries. Circulation 2008; 118: 1276– 1284. Deng J, Ma-Krupa W, Gewirtz AT, Younge BR, Goronzy JJ, Weyand CM. Toll-like receptors 4 and 5 induce distinct types of vasculitis. Circ Res 2009; 104: 488– 495. Smith DD, Tan X, Raveendran VV, Tawfik O, Stechschulte DJ, Dileepan KN. Mast cell deficiency attenuates progression of atherosclerosis and hepatic steatosis in apolipoprotein E-null mice. Am J Physiol Heart Circ Physiol 2012; 302: H2612– 2621. Maugeri N, Rovere-Querini P, Evangelista V et al. An intense and short-lasting burst of neutrophil activation differentiates early acute myocardial infarction from systemic inflammatory syndromes. PLOS ONE 2012; 7: e39484. Phillipson M, Kubes P. The neutrophil in vascular inflammation. Nat Med 2011; 17: 1381– 1390. Maugeri N, Baldini M, Ramirez GA, Rovere-Querini P, Manfredi AA. Platelet–leukocyte deregulated interactions foster sterile inflammation and tissue damage in immune-mediated vessel diseases. Thromb Res 2012; 129: 267– 273. Manfredi AA, Rovere-Querini P, Maugeri N. Dangerous connections: neutrophils and the phagocytic clearance of activated platelets. Curr Opin Hematol 2010; 17: 3– 8. Cloutier N, Tan S, Boudreau LH et al. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes. EMBO Mol Med 2013; 5: 235– 249. Wiley Online Library Laffont B, Corduan A, Ple H et al. Activated platelets can deliver mRNA regulatory Ago2{middle dot}microRNA complexes to endothelial cells via microparticles. Blood 2013; 122: 253– 261. Zhang Q, Raoof M, Chen Y et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464: 104– 107. Manfredi AA, Rovere-Querini P. The mitochondrion – a Trojan horse that kicks off inflammation? N Engl J Med 2010; 362: 2132– 2134. McDonald B, Pittman K, Menezes GB et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 2010; 330: 362– 366. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13: 159– 175. Niethammer P, Grabher C, Look AT, Mitchison TJ. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 2009; 459: 996– 999. Bosurgi L, Manfredi AA, Rovere-Querini P. Macrophages in injured skeletal muscle: a perpetuum mobile causing and limiting fibrosis, prompting or restricting resolution and regeneration. Front Immunol 2011; 2: 62. Proebstl D, Voisin MB, Woodfin A et al. Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J Exp Med 2012; 209: 1219– 1234. Wang S, Cao C, Chen Z et al. Pericytes regulate vascular basement membrane remodeling and govern neutrophil extravasation during inflammation. PLOS ONE 2012; 7: e45499. Stark K, Eckart A, Haidari S et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and ‘instruct’ them with pattern-recognition and motility programs. Nat Immunol 2013; 14: 41– 51. Alon R, Nourshargh S. Learning in motion: pericytes instruct migrating innate leukocytes. Nat Immunol 2013; 14: 14– 15. Lerchenberger M, Uhl B, Stark K et al. Matrix metalloproteinases modulate ameboid-like migration of neutrophils through inflamed interstitial tissue. Blood 2013; 122: 770– 780. Loof TG, Morgelin M, Johansson L et al. Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense. Blood 2011; 118: 2589– 2598. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13: 34– 45. Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin? J Cell Biol 2012; 198: 773– 783. Kessenbrock K, Krumbholz M, Schonermarck U et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 2009; 15: 623– 625. Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol 2012; 32: 1777– 1783. von Bruhl ML, Stark K, Steinhart A et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819– 835. Kambas K, Chrysanthopoulou A, Vassilopoulos D 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 2013. Coughlan AM, Freeley SJ, Robson MG. Animal models of anti-neutrophil cytoplasmic antibody-associated vasculitis. Clin Exp Immunol 2012; 169: 229– 237. Wiley Online Library Clark SR, Ma AC, Tavener SA et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13: 463– 469. McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 2012; 12: 324– 333. Rarok AA, Stegeman CA, Limburg PC, Kallenberg CG. Neutrophil membrane expression of proteinase 3 (PR3) is related to relapse in PR3–ANCA-associated vasculitis. J Am Soc Nephrol 2002; 13: 2232– 2238. Nakazawa D, Tomaru U, Suzuki A et al. Abnormal conformation and impaired degradation of propylthiouracil-induced neutrophil extracellular traps: implications of disordered neutrophil extracellular traps in a rat model of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2012; 64: 3779– 3787. Wiley Online Library Knight JS, Carmona-Rivera C, Kaplan MJ. Proteins derived from neutrophil extracellular traps may serve as self-antigens and mediate organ damage in autoimmune diseases. Front Immunol 2012; 3: 380. Sangaletti S, Tripodo C, Chiodoni C et al. Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood 2012; 120: 3007– 3018. Maugeri N, Rovere-Querini P, Baldini M, Sabbadini MG, Manfredi AA. Translational mini-review series on immunology of vascular disease: mechanisms of vascular inflammation and remodelling in systemic vasculitis. Clin Exp Immunol 2009; 156: 395– 404. Wiley Online Library Tervaert JW. Translational mini-review series on immunology of vascular disease: accelerated atherosclerosis in vasculitis. Clin Exp Immunol 2009; 156: 377– 385. Wiley Online Library Ward JR, Wilson HL, Francis SE, Crossman DC, Sabroe I. Translational mini-review series on immunology of vascular disease: inflammation, infections and Toll-like receptors in cardiovascular disease. Clin Exp Immunol 2009; 156: 386– 394. Wiley Online Library Kaiser M, Younge B, Bjornsson J, Goronzy JJ, Weyand CM. Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells. Am J Pathol 1999; 155: 765– 774. Weyand CM, Ma-Krupa W, Pryshchep O, Groschel S, Bernardino R, Goronzy JJ. Vascular dendritic cells in giant cell arteritis. Ann NY Acad Sci 2005; 1062: 195– 208. Wiley Online Library Cid MC, Hernandez-Rodriguez J, Esteban MJ et al. Tissue and serum angiogenic activity is associated with low prevalence of ischemic complications in patients with giant-cell arteritis. Circulation 2002; 106: 1664– 1671. Arnaud L, Haroche J, Mathian A, Gorochov G, Amoura Z. Pathogenesis of Takayasu\'s arteritis: a 2011 update. Autoimmun Rev 2011; 11: 61– 67. Baldini M, Maugeri N, Ramirez GA et al. Selective up-regulation of the soluble pattern-recognition receptor pentraxin 3 and of vascular endothelial growth factor in giant cell arteritis: relevance for recent optic nerve ischemia. Arthritis Rheum 2012; 64: 854– 865. Wiley Online Library Baldini M, Manfredi AA, Maugeri N. Targeting platelet–neutrophil interactions in giant-cell arteritis. Curr Pharm Des 2013. Liakouli V, Cipriani P, Marrelli A, Alvaro S, Ruscitti P, Giacomelli R. Angiogenic cytokines and growth factors in systemic sclerosis. Autoimmun Rev 2011; 10: 590– 594. Dallabrida SM, Ismail NS, Pravda EA et al. Integrin binding angiopoietin-1 monomers reduce cardiac hypertrophy. FASEB J 2008; 22: 3010– 3023. Wiley Online Library Kugathasan L, Ray JB, Deng Y, Rezaei E, Dumont DJ, Stewart DJ. The angiopietin-1-Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice. J Exp Med 2009; 206: 2221– 2234. Agrawal A, Matthay MA, Kangelaris KN et al. Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med 2013; 187: 736– 742. Monach PA, Kumpers P, Lukasz A et al. Circulating angiopoietin-2 as a biomarker in ANCA-associated vasculitis. PLOS ONE 2012; 7: e30197. Trollope AF, Golledge J. Angiopoietins, abdominal aortic aneurysm and atherosclerosis. Atherosclerosis 2011; 214: 237– 243. Tsuzuki T, Okada H, Cho H et al. Divergent regulation of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor by hypoxia and female sex steroids in human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol 2013; 168: 95– 101. Eklund L, Saharinen P. Angiopoietin signaling in the vasculature. Exp Cell Res 2013; 319: 1271– 1280. Choe JY, Park SH, Kim SK. Serum angiopoietin-1 level is increased in patients with Behcet\'s disease. Joint Bone Spine 2010; 77: 340– 344. Scholz A, Lang V, Henschler R et al. Angiopoietin-2 promotes myeloid cell infiltration in a beta(2)-integrin-dependent manner. Blood 2011; 118: 5050– 5059. David S, Kumpers P, Lukasz A, Kielstein JT, Haller H, Fliser D. Circulating angiopoietin-2 in essential hypertension: relation to atherosclerosis, vascular inflammation, and treatment with olmesartan/pravastatin. J Hypertens 2009; 27: 1641– 1647. Kumpers P, David S, Haubitz M et al. The Tie2 receptor antagonist angiopoietin 2 facilitates vascular inflammation in systemic lupus erythematosus. Ann Rheum Dis 2009; 68: 1638– 1643. Gerald D, Chintharlapalli S, Augustin HG, Benjamin LE. Angiopoietin-2: an attractive target for improved antiangiogenic tumor therapy. Cancer Res 2013; 73: 1649– 1657. Dunne JV, Keen KJ, Van Eeden SF. Circulating angiopoietin and Tie-2 levels in systemic sclerosis. Rheumatol Int 2013; 33: 475– 484. Mauviel A. Transforming growth factor-beta: a key mediator of fibrosis. Methods Mol Med 2005; 117: 69– 80. Karlan BY, Oza AM, Richardson GE et al. Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol 2012; 30: 362– 371. Manfredi AA, Rovere-Querini P, Bottazzi B, Garlanda C, Mantovani A. Pentraxins, humoral innate immunity and tissue injury. Curr Opin Immunol 2008; 20: 538– 544. Bottazzi B, Doni A, Garlanda C, Mantovani A. An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu Rev Immunol 2010; 28: 157– 183. Jaillon S, Peri G, Delneste Y et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med 2007; 204: 793– 804. Maugeri N, Rovere-Querini P, Slavich M et al. Early and transient release of leukocyte pentraxin 3 during acute myocardial infarction. J Immunol 2011; 187: 970– 979. Deban L, Russo RC, Sironi M et al. Regulation of leukocyte recruitment by the long pentraxin PTX3. Nat Immunol 2010; 11: 328– 334. Fazzini F, Peri G, Doni A et al. PTX3 in small-vessel vasculitides: an independent indicator of disease activity produced at sites of inflammation. Arthritis Rheum 2001; 44: 2841– 2850. Wiley Online Library van Rossum AP, Pas HH, Fazzini F et al. Abundance of the long pentraxin PTX3 at sites of leukocytoclastic lesions in patients with small-vessel vasculitis. Arthritis Rheum 2006; 54: 986– 991. Wiley Online Library Rovere P, Peri G, Fazzini F et al. The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells. Blood 2000; 96: 4300– 4306. Baruah P, Propato A, Dumitriu IE et al. The pattern recognition receptor PTX3 is recruited at the synapse between dying and dendritic cells, and edits the cross-presentation of self, viral, and tumor antigens. Blood 2006; 107: 151– 158. van Rossum AP, Fazzini F, Limburg PC et al. The prototypic tissue pentraxin PTX3, in contrast to the short pentraxin serum amyloid P, inhibits phagocytosis of late apoptotic neutrophils by macrophages. Arthritis Rheum 2004; 50: 2667– 2674. Wiley Online Library Ohlsson SM, Pettersson A, Ohlsson S et al. Phagocytosis of apoptotic cells by macrophages in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. Clin Exp Immunol 2012; 170: 47– 56. Wiley Online Library Gout E, Moriscot C, Doni A et al. M-ficolin interacts with the long pentraxin PTX3: a novel case of cross-talk between soluble pattern-recognition molecules. J Immunol 2011; 186: 5815– 5822. Ma YJ, Doni A, Romani L et al. Ficolin-1-PTX3 complex formation promotes clearance of altered self-cells and modulates IL-8 production. J Immunol 2013; 191: 1324– 1333. Jylhava J, Haarala A, Kahonen M et al. Pentraxin 3 (PTX3) is associated with cardiovascular risk factors: the Health 2000 Survey. Clin Exp Immunol 2011; 164: 211– 217. Wiley Online Library Dagna L, Salvo F, Tiraboschi M et al. Pentraxin-3 as a marker of disease activity in Takayasu arteritis. Ann Intern Med 2011; 155: 425– 433. Ievoli E, Lindstedt R, Inforzato A et al. Implication of the oligomeric state of the N-terminal PTX3 domain in cumulus matrix assembly. Matrix Biol 2011; 30: 330– 337. Rusnati M, Camozzi M, Moroni E et al. Selective recognition of fibroblast growth factor-2 by the long pentraxin PTX3 inhibits angiogenesis. Blood 2004; 104: 92– 99. Leali D, Inforzato A, Ronca R et al. Long pentraxin 3/tumor necrosis factor-stimulated gene-6 interaction: a biological rheostat for fibroblast growth factor 2-mediated angiogenesis. Arterioscler Thromb Vasc Biol 2012; 32: 696– 703. Moalli F, Paroni M, Veliz Rodriguez T et al. The therapeutic potential of the humoral pattern recognition molecule PTX3 in chronic lung infection caused by Pseudomonas aeruginosa. J Immunol 2011; 186: 5425– 5434. D\'Angelo C, De Luca A, Zelante T et al. Exogenous pentraxin 3 restores antifungal resistance and restrains inflammation in murine chronic granulomatous disease. J Immunol 2009; 183: 4609– 4618. Rodriguez W, Mold C, Kataranovski M, Hutt J, Marnell LL, Du Clos TW. Reversal of ongoing proteinuria in autoimmune mice by treatment with C-reactive protein. Arthritis Rheum 2005; 52: 642– 650. Wiley Online Library Presta M, Camozzi M, Salvatori G, Rusnati M. Role of the soluble pattern recognition receptor PTX3 in vascular biology. J Cell Mol Med 2007; 11: 723– 738. Wiley Online Library Camozzi M, Zacchigna S, Rusnati M et al. Pentraxin 3 inhibits fibroblast growth factor 2-dependent activation of smooth muscle cells in vitro and neointima formation in vivo. Arterioscler Thromb Vasc Biol 2005; 25: 1837– 1842. Bianchi ME, Manfredi AA. Immunology. Dangers in and out. Science 2009; 323: 1683– 1684. Castiglioni A, Canti V, Rovere-Querini P, Manfredi AA. High-mobility group box 1 (HMGB1) as a master regulator of innate immunity. Cell Tissue Res 2011; 343: 189– 199. Harris HE, Andersson U, Pisetsky DS. HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nat Rev Rheumatol 2012; 8: 195– 202. Andrassy M, Volz HC, Riedle N et al. HMGB1 as a predictor of infarct transmurality and functional recovery in patients with myocardial infarction. J Intern Med 2011; 270: 245– 253. Wiley Online Library Maugeri N, Franchini S, Campana L et al. Circulating platelets as a source of the damage-associated molecular pattern HMGB1 in patients with systemic sclerosis. Autoimmunity 2012; 45: 584– 587. Yoshizaki A, Komura K, Iwata Y et al. Clinical significance of serum HMGB-1 and sRAGE levels in systemic sclerosis: association with disease severity. J Clin Immunol 2009; 29: 180– 189. Eguchi T, Nomura Y, Hashiguchi T et al. An elevated value of high mobility group box 1 is a potential marker for poor response to high-dose of intravenous immunoglobulin treatment in patients with Kawasaki syndrome. Pediatr Infect Dis J 2009; 28: 339– 341. Hoshina T, Kusuhara K, Ikeda K, Mizuno Y, Saito M, Hara T. High mobility group box 1 (HMGB1) and macrophage migration inhibitory factor (MIF) in Kawasaki disease. Scand J Rheumatol 2008; 37: 445– 449. Taira T, Matsuyama W, Mitsuyama H et al. Increased serum high mobility group box-1 level in Churg–Strauss syndrome. Clin Exp Immunol 2007; 148: 241– 247. Wiley Online Library Sato F, Maruyama S, Hayashi H et al. High mobility group box chromosomal protein 1 in patients with renal diseases. Nephron Clin Pract 2008; 108: c194– 201. Wibisono D, Csernok E, Lamprecht P, Holle JU, Gross WL, Moosig F. Serum HMGB1 levels are increased in active Wegener\'s granulomatosis and differentiate between active forms of ANCA-associated vasculitis. Ann Rheum Dis 2010; 69: 1888– 1889. Henes FO, Chen Y, Bley TA et al. Correlation of serum level of high mobility group box 1 with the burden of granulomatous inflammation in granulomatosis with polyangiitis (Wegener\'s). Ann Rheum Dis 2011; 70: 1926– 1929. de Souza AW, Westra J, Limburg PC, Bijl M, Kallenberg CG. HMGB1 in vascular diseases: its role in vascular inflammation and atherosclerosis. Autoimmun Rev 2012; 11: 909– 917. Bruchfeld A, Wendt M, Bratt J et al. High-mobility group box-1 protein (HMGB1) is increased in antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations. Mol Med 2011; 17: 29– 35. Rovere-Querini P, Capobianco A, Scaffidi P et al. HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep 2004; 5: 825– 830. Wiley Online Library Bianchi ME, Manfredi AA. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev 2007; 220: 35– 46. Wiley Online Library Vezzoli M, Castellani P, Corna G et al. High-mobility group box 1 release and redox regulation accompany regeneration and remodeling of skeletal muscle. Antioxid Redox Signal 2011; 15: 2161– 2174. Menu P, Vince JE. The NLRP3 inflammasome in health and disease: the good, the bad and the ugly. Clin Exp Immunol 2011; 166: 1– 15. Wiley Online Library Mankan AK, Kubarenko A, Hornung V. Immunology in clinic review series; focus on autoinflammatory diseases: inflammasomes: mechanisms of activation. Clin Exp Immunol 2012; 167: 369– 381. Wiley Online Library Sokolovska A, Becker CE, Ip WK et al. Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function. Nat Immunol 2013; 14: 543– 553. Dbouk HA, Uthman IW. An overview of familial Mediterranean fever with emphasis on pyrin and colchicine. J Med Liban 2008; 56: 35– 41. Mansfield E, Chae JJ, Komarow HD et al. The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood 2001; 98: 851– 859. Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum 2009; 38: 411– 419. Guarda G, Braun M, Staehli F et al. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity 2011; 34: 213– 223. Serrano A, Carmona FD, Castaneda S et al. Evidence of association of the NLRP1 gene with giant cell arteritis. Ann Rheum Dis 2013; 72: 628– 630. Fury W, Tremoulet AH, Watson VE et al. Transcript abundance patterns in Kawasaki disease patients with intravenous immunoglobulin resistance. Hum Immunol 2010; 71: 865– 873. Lee Y, Schulte DJ, Shimada K et al. Interleukin-1beta is crucial for the induction of coronary artery inflammation in a mouse model of Kawasaki disease. Circulation 2012; 125: 1542– 1550. Liang L, Tan X, Zhou Q et al. IL-1beta triggered by peptidoglycan and lipopolysaccharide through TLR2/4 and ROS-NLRP3 inflammasome-dependent pathways is involved in ocular Behçet\'s disease. Invest Ophthalmol Vis Sci 2013; 54: 402– 414. Ture-Ozdemir F, Tulunay A, Elbasi MO et al. Pro-inflammatory cytokine and caspase-1 responses to pattern recognition receptor activation of neutrophils and dendritic cells in Behçet\'s disease. Rheumatology (Oxf) 2013; 52: 800– 805. Botsios C, Sfriso P, Furlan A, Punzi L, Dinarello CA. Resistant Behçet\'s disease responsive to anakinra. Ann Intern Med 2008; 149: 284– 286. Ugurlu S, Ucar D, Seyahi E, Hatemi G, Yurdakul S. Canakinumab in a patient with juvenile Behçet\'s syndrome with refractory eye disease. Ann Rheum Dis 2012; 71: 1589– 1591. Hinze CH, Colbert RA. B-cell depletion in Wegener\'s granulomatosis. Clin Rev Allergy Immunol 2008; 34: 372– 379. Scapini P, Carletto A, Nardelli B et al. Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases. Blood 2005; 105: 830– 837. Holden NJ, Williams JM, Morgan MD et al. ANCA-stimulated neutrophils release BLyS and promote B cell survival: a clinically relevant cellular process. Ann Rheum Dis 2011; 70: 2229– 2233. Lake-Bakaar G, Jacobson I, Talal A. B cell activating factor (BAFF) in the natural history of chronic hepatitis C virus liver disease and mixed cryoglobulinaemia. Clin Exp Immunol 2012; 170: 231– 237. Wiley Online Library Cerutti A, Cols M, Puga I. Activation of B cells by non-canonical helper signals. EMBO Rep 2012; 13: 798– 810. Wiley Online Library Bunch DO, McGregor JG, Khandoobhai NB et al. Decreased CD5+ B cells in active ANCA vasculitis and relapse after rituximab. Clin J Am Soc Nephrol 2013; 8: 382– 391. Terrier B, Joly F, Vazquez T et al. Expansion of functionally anergic CD21−/low marginal zone-like B cell clones in hepatitis C virus infection-related autoimmunity. J Immunol 2011; 187: 6550– 6563. Zhu Z, Li R, Li H, Zhou T, Davis RS. FCRL5 exerts binary and compartment-specific influence on innate-like B-cell receptor signaling. Proc Natl Acad Sci USA 2013; 110: E1282– 1290. Cacoub P, Terrier B, Saadoun D. Hepatitis C virus mixed cryoglobulinemia vasculitis: therapeutic options. Presse Med 2013; 42 (4 Pt 2): 523– 527. doi: 10.1016/j.lpm.2013.01.011. Sneller MC, Hu Z, Langford CA. A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis Rheum 2012; 64: 835– 842. Wiley Online Library Zaja F, De Vita S, Mazzaro C et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 2003; 101: 3827– 3834. Holle JU, Dubrau C, Herlyn K et al. Rituximab for refractory granulomatosis with polyangiitis (Wegener\'s granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Ann Rheum Dis 2012; 71: 327– 333. Aries PM, Hellmich B, Voswinkel J et al. Lack of efficacy of rituximab in Wegener\'s granulomatosis with refractory granulomatous manifestations. Ann Rheum Dis 2006; 65: 853– 858. Berden AE, Kallenberg CG, Savage CO et al. Cellular immunity in Wegener\'s granulomatosis: characterizing T lymphocytes. Arthritis Rheum 2009; 60: 1578– 1587. Wiley Online Library Lamprecht P, Wieczorek S, Epplen JT, Ambrosch P, Kallenberg CG. Granuloma formation in ANCA-associated vasculitides. APMIS Suppl 2009; 127: 32– 36. Wiley Online Library Abdulahad WH, Kallenberg CG, Limburg PC, Stegeman CA. Urinary CD4+ effector memory T cells reflect renal disease activity in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2009; 60: 2830– 2838. Wiley Online Library Abdulahad WH, Stegeman CA, van der Geld YM, Doornbos-van der Meer B, Limburg PC, Kallenberg CG. Functional defect of circulating regulatory CD4+ T cells in patients with Wegener\'s granulomatosis in remission. Arthritis Rheum 2007; 56: 2080– 2091. Wiley Online Library Tsurikisawa N, Saito H, Tsuburai T et al. Differences in regulatory T cells between Churg–Strauss syndrome and chronic eosinophilic pneumonia with asthma. J Allergy Clin Immunol 2008; 122: 610– 616. Jagiello P, Aries P, Arning L et al. The PTPN22 620W allele is a risk factor for Wegener\'s granulomatosis. Arthritis Rheum 2005; 52: 4039– 4043. Wiley Online Library Chen M, Kallenberg CG. ANCA-associated vasculitides – advances in pathogenesis and treatment. Nat Rev Rheumatol 2010; 6: 653– 664. Abdulahad WH, Stegeman CA, Limburg PC, Kallenberg CG. Skewed distribution of Th17 lymphocytes in patients with Wegener\'s granulomatosis in remission. Arthritis Rheum 2008; 58: 2196– 2205. Wiley Online Library Nogueira E, Hamour S, Sawant D et al. Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis. Nephrol Dial Transplant 2010; 25: 2209– 2217. Jakiela B, Sanak M, Szczeklik W et al. Both Th2 and Th17 responses are involved in the pathogenesis of Churg–Strauss syndrome. Clin Exp Rheumatol 2011; 29: S23– 34. Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Defining the human T helper 17 cell phenotype. Trends Immunol 2012; 33: 505– 512. Chi W, Zhu X, Yang P et al. Upregulated IL-23 and IL-17 in Behçet patients with active uveitis. Invest Ophthalmol Vis Sci 2008; 49: 3058– 3064. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature 2008; 453: 1051– 1057. Brack A, Geisler A, Martinez-Taboada VM, Younge BR, Goronzy JJ, Weyand CM. Giant cell vasculitis is a T cell-dependent disease. Mol Med 1997; 3: 530– 543. Deng J, Younge BR, Olshen RA, Goronzy JJ, Weyand CM. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 2010; 121: 906– 915. Weyand CM, Kaiser M, Yang H, Younge B, Goronzy JJ. Therapeutic effects of acetylsalicylic acid in giant cell arteritis. Arthritis Rheum 2002; 46: 457– 466. Wiley Online Library Narvaez J, Bernad B, Gomez-Vaquero C et al. Impact of antiplatelet therapy in the development of severe ischemic complications and in the outcome of patients with giant cell arteritis. Clin Exp Rheumatol 2008; 26: S57– 62. Nesher G, Berkun Y, Mates M, Baras M, Rubinow A, Sonnenblick M. Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum 2004; 50: 1332– 1337. Wiley Online Library Accardo-Palumbo A, Giardina AR, Ciccia F et al. Phenotype and functional changes of Vgamma9/Vdelta2 T lymphocytes in Behcet\'s disease and the effect of infliximab on Vgamma9/Vdelta2 T cell expansion, activation and cytotoxicity. Arthritis Res Ther 2010; 12: R109. Haregewoin A, Soman G, Hom RC, Finberg RW. Human gamma delta+ T cells respond to mycobacterial heat-shock protein. Nature 1989; 340: 309– 312. Hirsh MI, Junger WG. Roles of heat shock proteins and gamma delta T cells in inflammation. Am J Respir Cell Mol Biol 2008; 39: 509– 513. Ergun T, Ince U, Eksioglu-Demiralp E et al. HSP 60 expression in mucocutaneous lesions of Behçet\'s disease. J Am Acad Dermatol 2001; 45: 904– 909. Hamzaoui K, Hamzaoui A, Hentati F et al. Phenotype and functional profile of T cells expressing gamma delta receptor from patients with active Behçet\'s disease. J Rheumatol 1994; 21: 2301– 2306. Yasuoka H, Yamaguchi Y, Mizuki N, Nishida T, Kawakami Y, Kuwana M. Preferential activation of circulating CD8+ and gammadelta T cells in patients with active Behçet\'s disease and HLA-B51. Clin Exp Rheumatol 2008; 26: S59– 63. Ling E, Shubinsky G, Press J. Increased proportion of CD3+CD4–CD8– double-negative T cells in peripheral blood of children with Behçet\'s disease. Autoimmun Rev 2007; 6: 237– 240. Kabelitz D, Fazio J, Adam-Klages S et al. Gammadelta T-cells: basic features and potential role in vasculitis. Clin Exp Rheumatol 2010; 28: 104– 109. Schmitt WH, Hagen EC, Neumann I, Nowack R, Flores-Suarez LF, van der Woude FJ. Treatment of refractory Wegener\'s granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients. Kidney Int 2004; 65: 1440– 1448. Flossmann O, Baslund B, Bruchfeld A et al. Deoxyspergualin in relapsing and refractory Wegener\'s granulomatosis. Ann Rheum Dis 2009; 68: 1125– 1130. Birck R, Warnatz K, Lorenz HM et al. 15-Deoxyspergualin in patients with refractory ANCA-associated systemic vasculitis: a six-month open-label trial to evaluate safety and efficacy. J Am Soc Nephrol 2003; 14: 440– 447. Walsh M, Chaudhry A, Jayne D. Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H). Ann Rheum Dis 2008; 67: 1322– 1327. Allen PB, Peyrin-Biroulet L. Moving towards disease modification in inflammatory bowel disease therapy. Curr Opin Gastroenterol 2013; 29: 397– 404. Goldminz AM, Gottlieb AB. Ustekinumab for psoriasis and psoriatic arthritis. J Rheumatol Suppl 2012; 89: 86– 89. Calderon R, Estrada S, Ramirez de la Piscina P et al. Infliximab therapy in a patient with refractory ileocolic Crohn\'s disease and Takayasu arteritis. Rev Esp Enferm Dig 2010; 102: 145– 146. Maffei S, Di Renzo M, Santoro S, Puccetti L, Pasqui AL. Refractory Takayasu arteritis successfully treated with infliximab. Eur Rev Med Pharmacol Sci 2009; 13: 63– 65. Terrier B, Bieche I, Maisonobe T et al. Interleukin-25: a cytokine linking eosinophils and adaptive immunity in Churg–Strauss syndrome. Blood 2010; 116: 4523– 4531. Moosig F, Gross WL, Herrmann K, Bremer JP, Hellmich B. Targeting interleukin-5 in refractory and relapsing Churg–Strauss syndrome. Ann Intern Med 2011; 155: 341– 343. Hernandez-Rodriguez J, Segarra M, Vilardell C et al. Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant-cell arteritis: angiogenic activity of interleukin-6 as a potential protective mechanism. Circulation 2003; 107: 2428– 2434. Hirano T, Ohguro N, Hohki S et al. A case of Behçet\'s disease treated with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Mod Rheumatol 2012; 22: 298– 302. Shapiro LS, Farrell J, Haghighi AB. Tocilizumab treatment for neuro- Behçet\'s disease, the first report. Clin Neurol Neurosurg 2012; 114: 297– 298. Urbaniak P, Hasler P, Kretzschmar S. Refractory neuro-Behçet treated by tocilizumab: a case report. Clin Exp Rheumatol 2012; 30: S73– 75. Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 2000; 43: 1041– 1048. Wiley Online Library Salvarani C, Magnani L, Catanoso M et al. Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology (Oxford) 2012; 51: 151– 156. Salvarani C, Magnani L, Catanoso MG et al. Rescue treatment with tocilizumab for Takayasu arteritis resistant to TNF-alpha blockers. Clin Exp Rheumatol 2012; 30: S90– 93. Nishimoto N, Nakahara H, Yoshio-Hoshino N, Mima T. Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. Arthritis Rheum 2008; 58: 1197– 1200. Wiley Online Library Unizony S, Stone JH, Stone JR. New treatment strategies in large-vessel vasculitis. Curr Opin Rheumatol 2013; 25: 3– 9. Geri G, Terrier B, Rosenzwajg M et al. Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease. J Allergy Clin Immunol 2011; 128: 655– 664. Terrier B, Geri G, Chaara W et al. Interleukin-21 modulates Th1 and Th17 responses in giant cell arteritis. Arthritis Rheum 2012; 64: 2001– 2011. 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