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  • 1. 454  |  AUGUST 2014  |  VOLUME 10 Department of Rheumatic and Immunologic Diseases, A50, 9500 Euclid Avenue, Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, USA (G.S.H., L.H.C.). Correspondence to: G.S.H. Vasculitis: determinants of disease patterns Gary S. Hoffman and Leonard H. Calabrese Abstract | The vasculitides are a large group of heterogeneous diseases for which it has been assumed that pathogenesis is largely autoimmune. As clinicians, we distinguish one form of vasculitis from another on the basis of observed patterns of organ injury, the size of the vessels affected and histopathological findings. The terms ‘small-vessel’, ‘medium-vessel’ and ‘large-vessel’ vasculitis are useful clinical descriptors, but fail to inform us about why vessels of a certain calibre are favoured by one disease and not another. Classification based on vessel size also fails to consider that vessels of a specific calibre are not equally prone to injury. Distinct vulnerabilities undoubtedly relate to the fact that same-size vessels in different tissues may not be identical conduits. In fact, vessels become specialized, from the earliest stages of embryonic development, to suit the needs of different anatomical locations. Vessels of the same calibre in different locations and organs are as different as the organ parenchymal cells through which they travel. The dialogue between developing vessels and the tissues they perfuse is designed to meet special local needs. Added to the story of vascular diversity and vulnerability are changes that occur during growth, development and ageing. An improved understanding of the unique territorial vulnerabilities of vessels could form the basis of new hypotheses for the aetiopathogenesis of the vasculitides. This Review considers how certain antigens, including infectious agents, might become disease-relevant and how vascular diversity could influence disease phenotypes and the spectrum of vascular inflammatory diseases. Hoffman, G. S. Calabrese, L. H. Nat. Rev. Rheumatol. 10, 454–462 (2014); published online 17 June 2014; doi:10.1038/nrrheum.2014.89 Introduction The diagnostic process for complex diseases, including vasculitis, has long depended on meticulous clinical observation, characteristics of imaging abnormalities, histological findings in affected tissues and between- disease comparisons of affected organs. This repeatedly tested process usually leads to a singular diagnosis and treatment strategy for most forms of vasculitis. However, it is only a partially informed approach in regard to aeti- ology and to understanding the many factors that con- tribute to specific anatomic sites being vulnerable while others are often spared. Apart from infectious diseases, endocrinopathies and most malignancies, mechanisms that explain disease aetiology and patterns are mostly unknown. In some autoimmune disorders, we have achieved a good start in understanding pathogenesis; it is from these exam- ples that one might construct hypotheses and methods to problem-solve for the unknown. Before considering how these examples provide insight for vasculitis, it is important to review why differences in vascular beds in different locations should lead us to expect unique territorial vulnerabilities. Vascular development and diversity From the earliest stages of embryonic organ develop- ment, it is apparent that vessels are not merely conduits for blood, nutrients, gas exchange and waste disposal. Vessels of the same calibre in different organs are as dif- ferent as the organ parenchymal cells through which they course (Figures 1 and 2). Indeed, the dialogue between developing microvascular bed components and the tissues they perfuse is designed to meet the special needs of different organs and even unique neighbour- hoods within organs. Endothelial cells within organs often display unique organ-associated antigens. Added to the formulae of vulnerability are changes that occur within organ microvascular components during growth, development and ageing.1–6 Recognition of such diver- sity makes it clear why the terms ‘small-vessel’, ‘medium-­ vessel’ and ‘large-vessel’ vasculitis might be simplistic and misleading. Vessel size distinctions alone fail to recognize diversity within vessels of the same calibre (for example, capillaries in the skin, brain, lungs, renal glomeruli and so on), their specialized roles in different locations and variations in response to stimuli, injury and repair that determine disease patterns. Microvascular diversity Vascular beds in different organs vary in regard to morph­ology and function of endothelial cells, inter­ cellular junctions, subendothelial matrix, and types of pericytes that surround endothelial cells (Figures 1 and 2). Variations in membrane proteins, including adhesion molecules and Toll-like receptors (TLRs), and quantity and types of matrix components (for example, collagens, laminins, nidogens, fibronectin, vitro­nectin, fibrillins) influence cell proliferation, migration, Competing interests The authors declare no competing interests. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 2. NATURE REVIEWS | RHEUMATOLOGY VOLUME 10  |  AUGUST 2014  |  455 differentiation, transvascular passage of solutes and ­leukocytes and injury-response patterns.7–11 Intraorgan microvascular diversity is illustrated within the kidney in Figure 3. Structural and functional diver- sity should be expected when one considers that the renal cortex is involved primarily in filtration and reabsorp- tion, whereas the renal medulla is where urine is concen- trated. In the glomerulus, high permeability to water and small solutes is orchestrated by fenestrated endothelium, its contiguous glycocalyx (extracellular glycoproteins), basement membrane, podocyte foot processes and slit diaphragms, as well as mesangial cells (pericytes for Key points ■■ Vessels are more than merely conduits for blood, nutrients, gas exchange and waste disposal ■■ The dialogue between developing and mature vessels and their resident tissues determines organ form, function, specialization, vulnerability and capacity for repair ■■ Vessels of the same size in different organs are not the same, reflecting specialized functions ■■ Vessels are immunologically competent structures ■■ As with other tissues, growth, development and ageing of vessels are associated with adaptations (and maladaptations) that modify their function and vulnerabilities ■■ The unique features that define vascular diversity provide extraordinary opportunities to explore mechanisms responsible for unique disease patterns in different forms of vasculitis glomerular endothelium). Glomerular pericytes have specialized roles that influence glomerular structure and filtration, and also have a phagocytic function. Filtered blood flows through the efferent arteriole and into peri­ tubular capillaries (in cortical glomeruli) or the hybrid capillary–arteriolar descending vasa recta (in juxta­ medullary glomeruli). The descending vasa recta give rise to a small capillary network which leads in turn to the ascending vasa recta. Notably, the descending vasa recta vessels are not fenestrated, whereas the ascending vessels are. The vasa recta supply oxygen and nutrients to the inner medulla, and are integral to the maintenance of the medullary concentration gradient.12 Diversity in large and medium vessels Diversity in large-vessel territories is conceptually similar to the distinctions noted in different small- vessel beds in regard to adaptation to location and functional requirements. Simple distinctions relate to physical properties, such as the aortic root being thicker, wider and having a greater number of medial lamella units than the distal aorta; the extension of vasa vasora into the media in the thoracic but not the abdominal aorta; and the density of elastic fibres being lower in the abdominal than thora­cic aorta.13 At a functional level, aortic endothelial cells display heterogeneity in binding monocytes when stimulated ex vivo by a variety of ago- nists. In general, distal abdominal aorta endothelial cells bind monocytes more effectively than proximal aorta endothelial cells.14 The embryogenesis of large vessels is another lesson in diversity and specialization. For example, almost the entire vascular tree is the product of embryonic meso- derm. However, vascular smooth muscle cells (VSMCs) within the aortic root, arch and proximal arch vessels are the product of neural crest ectoderm. Neuroectoderm- derived VSMCs and mesoderm-derived VSMCs have different ex vivo responses to transforming growth factor β1.15 In later stages of embryogenesis, those VSMCs that are mesoderm-derived undergo additional differentiation that is responsible for unique physiology and immune capacities in different regions of the large- vessel map (Figure 4).16 Again, diversity within similarly sized vessels illustrates the over-simplification of vas- culitis classification schemes that emphasize vessel size without qualifications. We have also come to appreciate the role of large and medium vessels in immune surveillance. The Weyand– Goronzy lab has demonstrated that muscular ar­teries have unique TLR profiles.17 Dendritic cells located at the adventitia–media border of large and medium vessels have TLRs (pathogen recognition receptors; PRRs) that bind specific pathogen-associated molecu- lar patterns (PAMPs) and stimulate T cells that may be attracted into an evolving large-vessel vasculitis lesion or intramural infection. These TLR ‘portfolios’ differ between vessels, and may determine risk for injury and disease (Figure 5).17 These observations are just part of the reason we observe different disease proclivities in ­different vascular territories. Tight junction Basement membrane Continuous Fenestrated Fenestra Discontinuous Organ Function CNS Lymph node Muscle Endocrine glands Gastrointestinal tract Choroid plexus Kidney glomeruli Liver Bone marrow Spleen BBB Lymphocyte homing Metabolic exchange Secretion Absorption Secretion Filtration Particle exchange Haematopoiesis Blood cell filter Figure 1 | Endothelial microvascular relationships in different organs. Capillaries in different microvascular beds can differ dramatically in permeability and parenchymal-vascular homeostasis functions. In many organs, distinctions are also present within different functional regions. Abbreviations: BBB, blood–brain barrier; CNS, central nervous system. Adapted with permission from Springer © Pries, A. R. Kuebler, W. M. Handbook Exptl Pharmacol. 176, 1–40 (2006).10 FOCUS ON VASCULITIS © 2014 Macmillan Publishers Limited. All rights reserved
  • 3. 456  |  AUGUST 2014  |  VOLUME 10 Infection as a trigger of vasculitis Vasculitis due to infection is the easiest vascular injury model to understand because aetiology is already estab- lished. Less certain is why infectious agents ‘prefer’ to establish residence in specific neighbourhoods. This question is relevant to any affected tissue, not just blood vessels. It has become clear that pathogenic bacteria prefer sites that provide a ‘welcome mat’ in the form of a ligation partner (or partners) for their surface molecules. Cell- wall-anchored proteins, including MSCRAMMs (micro- bial surface components that recognize adhesive matrix molecules), and structures such as fimbriae (attachment pili) are utilized by bacteria to achieve bridged entry into vulnerable cells.18,19 Analogous viral membrane-adhesion molecules have similar selective functions. Modifications in adhesion or binding molecules can profoundly affect cell-targeting and pathogenicity.20 Beyond knowing about the mere presence of complementary ligation partners, it would be important to know whether their density of expression has a role in determining the frequency with which particular organs are affected. These selective binding relationships have been said to reflect tropisms of infectious agents for certain cells; however, if a virus or bacterium is not found bound to cells, a lack of selectivity is probably not the only explanation. Vascular effects of infection Once microbial attachment and even cellular entry is achieved, injury may or may not result. The ultimate effects of infection are likely to depend on the adequacy of the immune response, not only at a systemic level, but also within the affected cells. We have already noted that unique TLR profiles exist on dendritic cells in dif- ferent muscular arteries. Parenchymal cells have site-­ variable biochemical resources that can limit (or permit) infectious agents’ attempts to thrive. Some chemical mediators, such as host-defense peptides (for example, defensins, cathelicidins) usually thought of as leukocyte products, are also products of parenchymal cells. Host- defense peptides have antibacterial and antiviral potency, as well as immunomodulatory, cancer-inhibiting and wound-healing properties; they are variably expressed in different vascular territories.21,22 The relationship between vasculitis and infection is complex owing to the wide array of pathogens that may be involved and varied expressions of vascular inflam- mation in different tissues.23 In certain instances, the relationship between aetiology and angiocentric inflam- mation and destruction is clear, as in aortitis caused by Mycobacterium tuberculosis or syphilis, for which there is a predilection for the ascending aorta. Perhaps the previ- ously discussed unique embryonic origins of the aortic arch media (neuroectoderm) influence this pattern. Other infections, such as HIV, are associated with a wide variety of vasculitic phenotypes, affecting small or large vessels.24 There are, however, several distinct examples of vasculitis associated with infectious agents that inform us of mechanisms of vascular targeting that may have broader significance in the overall understanding of the immunopathogenesis of vasculitis. Experimental models One experimental model of murine vasculitis is of special interest, as it exemplifies the roles for both pathogen and host defense in the phenotypic expression of vasculitis. Virgin and colleagues have demonstrated in mice carry­ ing defects in the IFN‑γ pathway that infection with either γ‑herpesvirus 6825 or murine cytomegalovirus26 results in arteritis limited to the aortic arch and, specifi- cally, neuroectoderm-derived VSMCs. Importantly, per- sistent viral replication, rather than autoimmunity, was necessary for chronic arteritis. Although organ-specific targeting would seem to be a logical explanation for these findings, the story is Roles in haemostasis Immune and phagocyte functions Contractile function Participation in vascular development Multipotent cells Contribution to BBB properties Endothelial cell Astrocyte end-feet Blood Pericyte a b Figure 2 | Blood–brain barrier. a | Capillary–pericyte relationship in brain parenchyma. The BBB shields the central nervous system from toxic and harmful substances. The BBB endothelial cells have longer tight junctions, sparse pinocytic vesicular transport systems, no fenestrations and other properties that make the BBB microvasculature unique in comparison with all others in the body. Pericyte specialized functions are also unique in the brain, where they are critical to BBB integrity and function in antigen presentation, haemostasis, injury-repair and regulation of blood flow. b | An artist’s rendition of the BBB. Tight continuous junctions comprise endothelial cells, basement membrane (grey circle), pericytes and astrocyte end-feet. Abbreviation: BBB, blood–brain barrier. Adapted with permission from Springer © Sá-Pereira, I. et al. Mol. Neurobiol. 45, 327–347 (2012).11 Glomerular capillary DVR AVR Podocyte Larger, more muscular than AVR Nonfenestrated endothelial cells Smaller than DVR Fenestrated endothelial cells Pericyte Endothelial cell Filtration slit Pedicel Basal lamina Fenestrated endothelial cellGlycocalyx Figure 3 | The renal microvascular structure and function varies with intrarenal location. Vascular heterogeneity in the kidney notably involves variations in fenestration. The glomerulus requires high permeability function, for which fenestrated endothelium is well suited. The DVR vessels are not fenestrated, whereas the AVR vessels are, thus serving to facilitate a medullary concentration gradient. Abbreviations: AVR, ascending vasa recta; DVR, descending vasa recta. Adapted from Molema, G. Aird, W. C. Vascular heterogeneity in the kidney. Semin. Nephrol. 32, 145–155 © (2012),12 with permission from Elsevier. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 4. NATURE REVIEWS | RHEUMATOLOGY VOLUME 10  |  AUGUST 2014  |  457 more complicated. Sequential weekly post-mortems of affected mice revealed the presence of virus in numerous organs and vessels. However, clearance of virus occurred without organ injury within 6 weeks, except in aortic root VSMCs (Figure 6).25–27 Thus, what initially appeared to be injury due to viral tropism could, on further reflec- tion, represent a pattern of injury due to an ineffective site-specific immune response. Human disease Numerous human infectious diseases are implicated in the production of immune-complex-mediated forms of vasculitis. These include bacterial pathogens in endo­ carditis as well as viral pathogens such as hepatitis B virus (HBV) and hepatitis C virus (HCV). For this discussion, HCV with associated cryoglobulinemia is by far the most extensively studied and most informative. HCV vasculitis Evidence that HCV is aetiologically linked to cryo­ globulinaemic vasculitis was provided shortly after the discovery of HCV in 1989.28–30 Epidemiologically, HCV is detected in more than 90% of patients with type 2 cryoglobulinaemic vasculitis. In addition, anti-HCV antibodies are hyperconcentrated in the cryoprecipitate by a factor 10 or more in comparison with the serum, and HCV is hyperconcentrated in the cryoprecipitate by a factor of 1,000 or more.28,31 Finally, clearing of vascu- litis is seen promptly, especially in skin, in the wake of effective antiviral therapy.32 The syndrome is clinically distinctive: in a majority of patients, HCV vasculitis demonstrates a predilection for small-vessel injury of skin, peripheral nerve and renal glomerulus.33 Rarely, vasculitis can affect the brain, lung, gastrointestinal tract and medium-size vessels.34 The mechanisms by which HCV-envelope glyco­ proteins bind to hepatocytes and set the stage for viral entry to host cells determine the organ-specific tropism of HCV.35,36 The circulating virus-immune complexes would also be expected to have selective binding affinities that explain organ-targeting. Although the complete path to HCV vasculitis is uncertain, it seems to involve many steps. For example, infection with HCV is not sufficient to develop cryo­globulinaemia, which occurs in 40–60% of infected patients, or vasculitis, which occurs in less than 5% of infected patients.37 Infection can be present and inappar­ent for decades, but yet progresses in over 70% of patients,37 of whom very few develop vasculitis. This implies that once infection is established, change in the virus or the host must occur for disease to become apparent. Co-factors could include viral mutations or host alterations in genome–epigenome, immunologic status, tissue substrate and/or microbiome. HCV in skin and kidney vasculature Detection of HCV antigens, including the replicative strand of HCV-RNA (indicating in situ viral prolifera- tion), has been well documented in skin, although less well documented in the kidney.31,38 The molecular basis for the cryoglobulin (incorporating virus, anti-viral IgG, and genetically and structurally restricted IgM rheuma- toid factor [RF])39 to target skin vasculature is unclear. B‑cell homing chemokines such as CXCL13 might play a role in this process.40 The ability of the cryoglobulin to bind C1q receptors on endothelial cells might also be important.41 The direct role of HCV in skin lesions is supported by the observation that inflammatory purpura is the most sensitive of all target-organ manifestations that improve with effective antiviral therapy.42 The mechanisms responsible for the renal lesions of type 1 membranoproliferative glomerulonephritis involve the deposition of immune complexes within the mesangium and subendothelial spaces.38,43 HCV targeting of these anatomic areas might involve both cellular and matrix determinants. Evidence sup- ports some predilection of the restricted IgM RF for fibronectin within the mesangial matrix.44 There is also evidence that both complement-mediated and antibody-specific mechanisms may lead to upregula- tion of VCAM‑1 and platelet aggregation.45 Finally, viral homing to the renal glomerulus with consequent depo- sition of viral proteins is likely to be important46,47 and may even occur in the absence of clinical manifestations of renal disease.31 A role for cell-mediated immunity is Splanchnic mesoderm Somites Proepicardium Mesoangioblasts Various stem cells Neural crest Secondary heart field Mesothelium Figure 4 | Developmental fate map for VSMCs. Different colours represent differences in embryonic origins of VSMCs. Different vessels, and even different segments of the same vessel, contain VSMC subsets from distinct progenitors. These VSMC subtypes respond to stimuli in lineage-specific ways. Abbreviation: VSMC, vascular smooth muscle cell. Adapted from Majesky, M. W. Developmental basis of vascular smooth muscle diversity. Arterioscler. Thromb. Vasc. Biol. 27, 1248–1258 (2007).16 FOCUS ON VASCULITIS © 2014 Macmillan Publishers Limited. All rights reserved
  • 5. 458  |  AUGUST 2014  |  VOLUME 10 indicated by the frequent detection of lymphocytes and monocytes around pre-capillary arterioles.48 Micro- dissected glomeruli from HCV-infected patients dem- onstrate upregulated expression of TLR3 and increased mRNA for several chemokines that could further serve to attract inflammatory effector cells.49 In contrast to the skin, HCV-RNA is less readily detectable in kidney or peripheral nerve.50 The molecular mechanisms for this apparent compartmentalization remain unclear. HCV in CNS vasculature A more recent development in the understanding of the molecular nature of vascular targeting involves direct infection of the central nervous system (CNS) by HCV, independent of cryoglobulin formation. Using a series of sophisticated immunopathologic techniques, Fletcher and colleagues51 have demonstrated that HCV, which has previously been demonstrated to infect the CNS,52,53 is capable of disrupting the endothelial cells that form the blood–brain barrier (BBB). BBB endothelial cells were shown to display the putative viral entry receptor molecules CD81, claudin‑1, occludin, scavenger recep- tor class B member 1 (SRB1, also known as CD36) and LDL receptor. Indeed, microvascular endothelia were the only cell type in the brain that expressed all the factors required for HCV entry (Figure 7).54,55 Furthermore, two independently derived brain endothelial cell lines were shown to support HCV entry and replication leading to increased endothelial permeability and apoptosis.55 This important new finding adds to prior observations of HCV infection of astrocytes and microglia/macrophages.56 In addition to providing evidence of direct HCV infec- tion of the CNS, Fletcher et al.51 also demonstrated that the BBB was disrupted, with resulting increased per­ meability that may relate to cognitive dysfunction in HCV infection. HCV-associated cognitive dysfunction has been well documented in the absence of vasculi- tis.55–57 Apart from rare instances, vasculitis is not seen in the brain of HCV-infected patients and there is little evi- dence that non-CNS endothelial cells are HCV-infected; this implies that vascular injury is mostly attributable to the effects of cryoglobulins on endothelial cells. Antigens that drive autoimmunity The aetiologies of different forms of idiopathic vasculi- tis are not as well understood as the examples noted of infectious diseases, where the agent and/or the immune responses elicited can mediate tissue injury. Even in those examples, it is not entirely clear what binding part- ners and other factors account for disease patterns. In a number of autoimmune diseases, antigenic targets have been identified, and attempts to specifically block triggers of immune-mediated injury are being explored. Thus, knowledge of the target antigen could explain disease patterns and also provide therapeutic opportunities. Anti-GBM disease In most of these examples in which the targeted antigen(s) has been identified, it is not clear whether the immune response is directed to native antigen for which tolerance has been lost or a modified antigen that no longer is recog- nized as native or ‘self’. Anti-glomerular basement mem- brane (anti-GBM) disease, also known as Goodpasture syndrome, stands out in this regard. Although this disease is not a classic form of vasculitis, it does derive from anti- body-mediated capillary injury in the alveoli and glo­ meruli. The anti-GBM disease antigen is known: it is the non-collagenous domain (NC1) of the α3 chain of type IV collagen (Figure 8). Its antigenicity has been attributed to disruption of sulphilimine bonds that reinforce the struc- ture of the α345 NC1 hexamer in basement membrane collagen. The critical epi­topes within this neoantigen for B cells are the peptide sequences α317–31 and α3127–141 , and for T-cell-mediated specific reactivity it is α3136–146 .58 A change in collagen IV structure reveals cryptic antigens of the α3 chain that are most abundant in glo- merular and alveolar basement membranes—the prin- cipal target tissues in anti-GBM disease. Studies that have explored the causes of antigen modifications have implicated infection, inhaled hydrocarbons, smoking, cocaine use and lithotripsy.59 Obviously, the vast majority of patients exposed to these risk factors do not develop anti-GBM disease. Exploration of genetic factors have revealed that patients who are HLA DRB1*15:01-positive have an 8.5-fold greater relative risk of developing Temporal Subclavian Mesenteric Aorta Carotid Illiac Relative expression 5.0 1.0 0.1 TLR1 TLR2 TLR3 TLR4 TLR5 TLR6 TLR7 TLR8 TLR9 Figure 5 | Vessel-specific TLR gene expression profiles in human medium and large vessels. Red fields represent above-average transcript expression levels and green fields represent below-average expression. Note that TLR2 and TLR4 are consistently expressed in the six different vessels studied, whereas TLR7 and TLR9 are infrequent. Considerable variability is noted in expression of TLR1, TLR3, TLR5, TLR6 and TLR8. Abbreviation: TLR, Toll-like receptor. Reproduced from Pryshchep, O. et al. Vessel-specific Toll-like receptor profiles in human medium and large arteries. Circulation 118, 1276–1284 (2008).17 a b M Adv I L 25μm M I L25μm Adv Ag Figure 6 | Mice lacking IFN‑γ or the IFN-γR inoculated with murine herpesvirus develop aortic root/arch site-specific aortitis. Specific antibody (immunohistochemistry) identifies viral antigen within VSMCs of the aortic root/ arch, at a | low-power and b | high-power magnification. Whereas virus is cleared from other organs and other aortic sites, the ability to clear virus seems to be inadequate in VSMCs of the aortic root/arch of IFNγ or IFNγR deficient mice. Abbreviations: Adv, adventitia; Ag, γHV68 antigen immunoreactivity; I, intima; IFN, interferon; IFN-γR, IFN-γ receptor; L, lumen; M, media; VSMC, vascular smooth muscle cell; γHV68, γ‑herpesvirus 68. Reproduced from Nat. Med. 3, 1346–1353 (1997) © NPG.25 REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 6. NATURE REVIEWS | RHEUMATOLOGY VOLUME 10  |  AUGUST 2014  |  459 anti-GBM disease compared with those who do not carry this allele.60,61 These elegant studies urge further investi- gation into the identification of target antigens and into antigen modification versus loss of selective tolerance. Post-translational protein modifications The term ‘autoantigenesis’ was coined to describe changes that arise in self-proteins as they break self-tolerance and trigger autoimmune responses.62 For example, tolerance can be lost through post-translational modifications (PTMs), which are acquired by 50–90% of human pro- teins. In some cases, modifications are necessary for the biological functions of proteins. However, some PTMs create new self-antigens that may then become subject to altered immunologic processing and presentation. In numerous subspecialties, ongoing studies are exploring the involvement of loss of tolerance in dis- eases for which one or more antigens have been identi- fied as common targets of the immune system, including myasthenia gravis (acetylcholine receptor), Graves disease (thyrotropin receptor), type I dia­betes mellitus (insulin, proinsulin, zinc transporter 8), pemphigus (desmogleins, desmoplakin), coeliac disease (protein- glutamine γ‑glutamyltransferase 2), idiopathic membra- nous nephropathy (M-type phospholipase A2 receptor), neuromyelitis optica (aquaporin 4) and multiple sclero- sis (myelin-oligodendrocyte glycoprotein, myelin basic protein, proteolipid protein). Single-organ versus multisystem vasculitis In the field of vasculitis, the simplest disease pattern that might lend itself to discovery of antigens that drive the immune response is single-organ vasculitis. Just as in other organ-specific immune-mediated diseases in the fields of endocrinology, neurology, nephrology, gastro­ enterology and so on, studies of vasculitis aetiology would seem much easier with a narrow scope of affected tissue than with more complex systemic diseases.63–65 Multisystem autoimmunity or vasculitis is a much more complex puzzle to solve compared with organ- specific autoimmune disease, including single-organ vas- culitis. Multisystem requirements may involve affected organs sharing antigens (as in anti-GBM disease) or spe- cific circulating antigens being deposited in each affected organ; target tissues could have molecular identity or be highly homologous; and disease patterns might be deter- mined by affected sites sharing ligands that bind antigen (or immune complexes) and elicit an injury programme. Over the past 30 years, opportunities to understand organ-targeting have evolved from studies of anti-­ neutrophil cytoplasmic antibody (ANCA; specifically myeloperoxidase–ANCA or proteinase 3–ANCA) associ­ated vasculitides (AAV).66 The term AAV has been applied to the diseases granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, also known as Churg–Strauss syndrome). Whether ANCA is essential for each disease is doubtful, as 10–20% of patients with either GPA or MPA and about 60% of patients with EGPA may be ANCA-negative.67–69 Although this finding may be claimed to be a matter of inadequate performance of ANCA testing for GPA and MPA, that argument would be less convincing for EGPA. Regardless of test sensi­ tivity, an important secondary role for ANCA might exist in modifying disease expression. For example, patients with these diseases who are ANCA-positive are more likely to have renal involvement and, in general, more severe disease. Whether these observations are a reflec- tion of ANCA influencing organ-targeting or amplifying injury pathways has not been explored. Effects of age on disease patterns The effects of growth, development and ageing on tissue substrates are immediately apparent to any of us enjoying old pictures from our infancy to adolescence, adulthood HCV Tight junction Infected cells CD81 SRB1 LDLR Occludin Claudin Brain Endothelial cell Astrocyte end-feet Pericyte Capillary Microglial cell Basal membrane Neuron Liver Hepatocytes Figure 7 | HCV infection targeting the BBB. All of the known HCV receptor molecules (CD81, claudin‑1, occludin, LDLR and SRB1) are expressed at the surface of hepatocytes and BBB ECs. SRB1 expression is restricted to the microvascular endothelium. Other receptors are expressed by astrocytes. The altered permeability and function of BBB ECs results from HCV CNS infection, with consequences that can include fatigue, neurocognitive dysfunction and depression. Abbreviations: BBB, blood–brain barrier; CNS, central nervous system; EC, endothelial cell; HCV, hepatitis C virus; LDLR, LDL receptor; SRB1, scavenger receptor class B member 1. Adapted from Feray, C. Is HCV infection a neurologic disorder? Gastroenterology 142, 428–431 © (2012),54 with permission from Elsevier. FOCUS ON VASCULITIS © 2014 Macmillan Publishers Limited. All rights reserved
  • 7. 460  |  AUGUST 2014  |  VOLUME 10 and, for some readers, the ‘senior’ periods of our lives. Less apparent than surface characteristics are the bio- chemical, physiologic and immunologic features of ageing or ‘senescence’. In regard to the vasculature, embryonic endothelial cells remain plastic and can adapt readily to changes within their microenvironment, whereas adult, special- ized endothelial cells are less able to respond to a variety of stimuli such as growth factors and other cytokines.70 Ageing leads endothelial cells to become more per­ meable, have diminished nitric oxide production and vasodilate. There is spontaneous increased production of metalloproteinases, which enhances matrix degradation. Increasing degrees of matrix cross-linking by advanced glycation end-products contribute to vascular stiffness, wall thickening and loss of elasticity. Add to these effects those of immunosenescence, including impaired dendritic-cell trafficking and TLR responses, increased autoantibody formation and altera- tions in our microbiome, and it becomes obvious why the same stimulus might elicit a modified response (or disease phenotype) in different periods of one’s life.71 These observations have led some to suggest that Takayasu arteritis and giant cell arteritis of the elderly are in fact the same disease with modified age-related phenotypes.72,73 Precedents for similar observations have been made for the modified disease profiles seen in systemic lupus erythematosus (SLE) and dermato- myositis during the periods of childhood, reproductive years and advanced age. In myasthenia gravis, as in SLE, female gender bias becomes less striking with age, ocular features are more severe in the young, thymectomy is usually successful in the young but not the elderly, and comorbidities increase the risk of death in the elderly.74,75 Conclusions Clinicians have found it convenient to use vessel size as one characteristic to help distinguish different forms of vasculitis from each other. This classification scheme has been a useful starting point for description and differ- ential diagnosis. However, the specialization of vessels of the same calibre in different locations is associated with distinctions in form and function that can be very informative in understanding organ-targeting and disease patterns. The selective affinity of injury-producing mediators for specific substrate has been best illustrated by the discovery of complementary ligation partners between affected tissues and infectious agents. Identifying ligation partners and agents that block their linkage has obvious therapeutic implications. The methods applied in the infectious diseases learning experience have been used to b S-hydroxylysyl-methionine crosslink S-lysyl-methionine crosslinkα345 NC1 hexamer Anti-GBM Ab Anti-GBM Ab Dissociation Non-crosslinked hexamer a Hyl-211 CHC O NH C O NHC O CH HO N S NH CH NHC O CH C O α3 chain CH CHC O NH α5 chainNH Met-93 Met-93 CH C O NHC O NH C O CH N S NHCHNH C O CHC O α4 chain CHCH C O NH α4 chainNH Lys-211 Crosslinked hexamer Inert α3 α4 α5 α4 α3 α4 α5 EA EB sHM EA EB Figure 8 | Anti-GBM disease (Goodpasture syndrome) involves modification of native antigen. a | Native type IV basement membrane collagen is stabilized by sulphilimine bonds that reinforce the structure of the α345 NC1 hexamer. b | Antigenicity in anti-GBM disease has been attributed to disruption of sulphilimine crosslinking that stabilizes the α345 NC1 hexamer. In the absence of collagen IV disruption, anti-GBM antibody cannot bind its antigen. However, when the sulphilimine bonds are compromised, the hexamer dissociates and cryptic epitopes of the α3 chain are exposed to pathogenic antibodies. Abbreviation: Ab, antibody; GBM, glomerular basement membrane; NC1, non-collagenous domain; sHM, s‑hydroxyl-methionine. Reproduced with permission from John Wiley Sons, Inc. © Vanacore, R. et al. Clin. Exp. Immunol. 164, 4–6 (2011).59 REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 8. NATURE REVIEWS | RHEUMATOLOGY VOLUME 10  |  AUGUST 2014  |  461 study autoimmunity: selective targeting in auto­immunity has begun to be understood through dis­coveries of site-specific antigen targets. The next critical steps will involve determining whether target antigens are native proteins, to which tolerance has been breached, or are modified proteins (neoantigens) that elicit an ‘appropri- ate’ immune response to foreign antigens. Co-factors, such as age, sex, comorbidities and genetic and micro- biomic influences, add additional levels of complexity to understanding host-site vulnerability and disease pat- terns. The tools to help us understand disease patterns have never been better and should make the process of continued discovery increasingly rewarding. Review criteria Since 1992, G.S.H. has maintained a monthly MEDLINE search for all full length articles including the term “vasculitis” and all individual forms of vasculitis, as well as ANCA; since 2006 he has done the same for single- organ autoimmunity, MSCRAMM, vascular development and embryogenesis (restricted to vascular references). Only papers in English were reviewed. References not captured in the search strategy were selectively read. This Review emphasizes findings from references published since 1995, selected for their relevance to organ-targeting and disease patterns. Seminal additional references are included from earlier years. 1. Rocha, S. F. Adams, R. H. Molecular differentiation and specialization of vascular beds. Angiogenesis 12, 139–147 (2009). 2. Cleaver, O. Melton, D. A. Endothelial signaling during development. Nat. Med. 9, 661–668 (2003). 3. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005). 4. Swift, M. R. Weinstein, B. M. Arterial-venous specification during development. Circ. Res. 104, 576–588 (2009). 5. Larrivée, B., Freitas, C., Suchting, S., Brunet, I. Eichmann, A. Guidance of vascular development: lessons from the nervous system. Circ. Res. 104, 428–441 (2009). 6. Ribatti, D., Nico, B. Crivellato, E. Morphological and molecular aspects of physiological vascular morphogenesis. Angiogenesis 12, 101–111 (2009). 7. Davis, G. E. Senger, D. R. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ. Res. 97, 1093–1107 (2005). 8. Hallmann, R. et al. Expression and function of laminins in the embryonic and mature vasculature. Physiology Rev. 85, 979–1000 (2005). 9. Stan, R. V. Endothelial stomatal and fenestral diaphragms in normal vessels and angiogenesis. J. Cell. Mol. Med. 11, 621–643 (2007). 10. Pries, A. R. Kuebler, W. M. Normal endothelium. Handbook Exptl Pharmacol. 176, 1–40 (2006). 11. Sá-Pereira, I., Brites, D. Brito, M. A. Neurovascular unit: a focus on pericytes. Mol. Neurobiol. 45, 327–347 (2012). 12. Molema, G. Aird, W. C. Vascular heterogeneity in the kidney. Semin. Nephrol. 32, 145–155 (2012). 13. Okuyama, K., Yaginuma, G., Takahashi, T., Sasaki, H. Mori, S. The development of vasa vasorum of the human aorta in various conditions. A morphometric study. Arch. Pathol. Lab. Med. 112, 721–725 (1988). 14. Margolin, D. A. et al. Differential monocytic cell adherence to specific anatomic regions of the canine aorta. J.Vasc. Res. 32, 266–274 (1995). 15. Topouzis, S. Majesky, M. W. Smooth muscle lineage diversity in the chick embryo: two types of aortic smooth muscle cell differ in growth and receptor-mediated transcriptional responses to transforming growth factor‑β. Dev. Biol. 178, 430–445 (1996). 16. Majesky, M. W. Developmental basis of vascular smooth muscle diversity. Arterioscler.Thromb. Vasc. Biol. 27, 1248–1258 (2007). 17. Pryshchep, O., Ma-Krupa, W., Younge, B. R., Goronzy, J. J. Weyand, C. M. Vessel-specific Toll-like receptor profiles in human medium and large arteries. Circulation 118, 1276–1284 (2008). 18. Foster, T. J., Geoghegan, J. A., Ganesh, V. K. Höök, M. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat. Rev. Microbiol. 12, 49–62 (2014). 19. Vengadesan, K. Narayana, V. L. Structural biology of Gram-positive bacterial adhesins. Protein Sci. 20, 759–772 (2011). 20. Belouzard, S., Millet, J. K., Licitra, B. N. Whittaker, G. R. Mechanisms of Coronavirus cell entry mediated by the viral spike protein. Viruses 4, 1011–1033 (2012). 21. Cuperus, T., Coorens M, van Dijk, A. Haagsman, H. P. Avian host defense peptides. Dev. Comp. Immunol. 41, 352–369 (2013). 22. Zhao, L. Lu, W. Defensins in innate immunity. Curr. Opin. Hematol. 21, 37–42 (2014). 23. Guillevin, L. Infections in vasculitis. Best Pract. Res. Clin. Rheumatol. 27, 19–31 (2013). 24. Calabrese, L. H. Infection with the human immunodeficiency virus type 1 and vascular inflammatory disease. Clin. Exp. Rheumatol. 22 (Suppl. 36), S87–S93 (2004). 25. Weck, K. E. et al. Murine γ‑herpesvirus 68 causes severe large-vessel arteritis in mice lacking interferon-γ responsiveness: a new model for virus-induced vascular disease. Nat. Med. 3, 1346–1353 (1997). 26. Presti, R. M., Pollock, J. L., Dal Canto, A. J., O’Guin, A. K. Virgin, H. W. Interferon γ regulates acute and latent murine cytomegalovirus infection and chronic disease of the great vessels. J. Exp. Med. 188, 577–588 (1998). 27. Dal Canto, A. J., Swanson, P. E., O’Guin, A. K., Speck, S. H. Virgin, H. W. IFN‑γ action in the media of the great elastic arteries, a novel immunoprivileged site. J. Clin. Invest. 107, R15–R22 (2001). 28. Agnello, V., Chung, R. T. Kaplan, L. M. A role for hepatitis C virus infection in type II cryoglobulinemia. N. Engl. J. Med. 327, 1490–1495 (1992). 29. Antonelli, A. et al. Serum concentrations of interleukin 1β, CXCL10, and interferon-γ in mixed cryoglobulinemia associated with hepatitis C infection. J. Rheumatol. 37, 91–97 (2013). 30. Sansonno, D. Dammacco, F. Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infect. Dis. 5, 227–236 (2005). 31. Fabrizi, F. et al. Hepatitis C virus infection, mixed cryoglobulinemia, and kidney disease. Am. J. Kidney Dis. 61, 623–637 (2013). 32. Cacoub, P., Terrier, B. Saadoun, D. Hepatitis C virus-induced vasculitis: therapeutic options. Ann. Rheum. Dis. 73, 24–30 (2014). 33. Ferri, C. et al. HCV-related autoimmune and neoplastic disorders: the HCV syndrome. Dig. Liver Dis. 39 (Suppl. 1), S13–S21 (2007). 34. Saadoun, D. et al. Hepatitis C virus-associated polyarteritis nodosa. Arthritis Care Res. (Hoboken) 63, 427–435 (2011). 35. Zeisel, M. B., Felmlee, D. J. Baumert, T. F. Hepatitis C viral entry. Curr.Topics Microbiol. Immunol. 369, 86–112 (2013). 36. Catanese, M. T. et al. Different requirements for scavenger receptor class B type I in hepatitis C virus cell-free versus cell‑to‑cell transmission. J. Virol. 87, 8282–8293 (2013). 37. Ferri, C., Zignego, A. L. Pileri, S. A. Cryoglobulins. J. Clin. Pathol. 55, 4–13 (2002). 38. Alpers, C. E. Smith, K. D. Cryoglobulinemia and renal disease. Curr. Opin. Nephrol. Hypertens. 17, 243–249 (2008). 39. Gorevic, P. D. Rheumatoid factor, complement, and mixed cryoglobulinemia. Clin. Dev. Immunol. 2012, 439018 (2012). 40. Sansonno, D. et al. Increased serum levels of the chemokine CXCL13 and up-regulation of its gene expression are distinctive features of HCV-related cryoglobulinemia and correlate with active cutaneous vasculitis. Blood 112, 1620–1627 (2008). 41. Sansonno, D. B. et al. Role of the receptor for the globular domain of C1q protein in the pathogenesis of hepatitis C virus-related cryoglobulin vascular damage. J. Immunol. 183, 6013–6020 (2009). 42. Dammacco, F. Sansonno, D. Therapy for hepatitis C virus-related cryoglobulinemic vasculitis. N. Engl. J. Med. 369, 1035–1045 (2013). 43. Fabrizi, F. et al. Biological dynamics of hepatitis B virus load in dialysis population. Am. J. Kidney Dis. 41, 1278–1285 (2003). 44. Fornasieri, A. D’Amico, G. Type II mixed cryoglobulinaemia, hepatitis C virus infection, and glomerulonephritis. Nephrol. Dial.Transplant. 11 (Suppl. 4), 25–30 (1996). 45. Cacoub, P. et al. Anti-endothelial cell auto- antibodies in hepatitis C virus mixed cryoglobulinemia. J. Hepatol. 31, 598–603 (1999). 46. Barsoum, R. S. Hepatitis C virus: from entry to renal injury—facts and potentials. Nephrol. Dial. Transplant. 22, 1840–1848 (2007). 47. Sansonno, D. et al. Hepatitis C virus RNA and core protein in kidney glomerular and tubular structures isolated with laser capture microdissection. Clin. Exp. Immunol. 140, 498–506 (2005). 48. Saadoun, D. et al. Involvement of chemokines and type 1 cytokines in the pathogenesis of hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy. Arthritis Rheum. 52, 2917–2925 (2005). FOCUS ON VASCULITIS © 2014 Macmillan Publishers Limited. All rights reserved
  • 9. 462  |  AUGUST 2014  |  VOLUME 10 49. Wornle, M. et al. Novel role of Toll-like receptor 3 in hepatitis C‑associated glomerulonephritis. Am. J. Pathol. 168, 370–385 (2006). 50. Authier, F. J. et al. Detection of genomic viral RNA in nerve and muscle of patients with HCV neuropathy. Neurology 60, 808–812 (2003). 51. Fletcher, N. F. et al. Hepatitis C virus infects the endothelial cells of the blood–brain barrier. Gastroenterology 142, 634–643 (2012). 52. Forton, D. M., Karayiannis, P., Mahmud, N., Taylor-Robinson, S. D. Thomas, H. C. Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants. J. Virol. 78, 5170–5183 (2004). 53. Sabahi, A. Hepatitis C virus entry: the early steps in the viral replication cycle. Virol. J. 6, 117 (2009). 54. Feray, C. Is HCV infection a neurologic disorder? Gastroenterology 142, 428–431 (2012). 55. Burlone, M. E. Budkowska, A. Hepatitis C virus cell entry: role of lipoproteins and cellular receptors. J. Gen.Virol. 90, 1055–1070 (2009). 56. Wilkinson, J., Radkowski, M. Laskus, T. Hepatitis C virus neuroinvasion: identification of infected cells. J.Virol. 83, 1312–1319 (2009). 57. Fletcher, N. F. et al. Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor-dependent manner. Hepatology 59, 1320–1330 (2014). 58. Jia, X. Y., Cui, Z., Yang, R., Hu, S. Y. Zhao, M. H. Antibodies against linear epitopes on the Goodpasture autoantigen and kidney injury. Clin. J.Am. Soc. Nephrol. 7, 926–933 (2012). 59. Vanacore, R., Pedchenko, V., Bhave, G. Hudson, B. G. Sulphilimine cross-links in Goodpasture’s disease. Clin. Exp. Immunol. 164, 4–6 (2011). 60. Peto, P. Salama, A. D. Update on antiglomerular basement membrane disease. Curr. Opin. Rheumatol. 23, 32–37 (2011). 61. Ooi, J. D. et al. The HLA-DRB1*15:01-restricted Goodpasture’s T cell epitope induces GN. J.Am. Soc. Nephrol. 24, 419–431 (2013). 62. Doyle, H. A. Mamula, M. J. Autoantigenesis: the evolution of protein modifications in autoimmune disease. Curr. Opin. Immunol. 24, 112–118 (2012). 63. Hernández-Rodriguez, J. et al. Vasculitis involving the breast: a clinical and histological analysis of 34 patients. Medicine (Baltimore) 87, 61–69 (2008). 64. Hernández-Rodríguez, J., Tan, C. D., Rodríguez, R. E. Hoffman, G. S. Gynecologic vasculitis: an analysis of 163 patients. Medicine (Baltimore) 88, 169–181 (2009). 65. Hernández-Rodríguez, J. Hoffman, G. S. Updating single-organ vasculitis. Curr. Opin. Rheumatol. 24, 38–45 (2012). 66. Jennette, J. C. et al. Revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum. 65, 1–11 (2013). 67. Falk, R. J. Hoffman, G. S. Controversies in small vessel vasculitis—comparing rheumatology and nephrology views. Curr. Opin. Rheumatol. 19, 1–9 (2007). 68. Sablé-Fourtassou, R. et al. Antineutrophil cytoplasm antibodies and the Churg–Strauss syndrome. Ann. Intern. Med. 143, 632–638 (2005). 69. Sinico, R. A. et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg–Strauss syndrome. Arthritis Rheum. 52, 2926–2935 (2005). 70. Ribatti, D., Nico, B., Vacca, A., Roncali, L. Dammacco, F. Endothelial cell heterogeneity and organ specificity. J. Hematother. Stem Cell Res. 11, 81–90 (2002). 71. Mohan, S., Liao, Y., Kim, J., Goronzy, J. Weyand, C. Giant cell arteritis: immune and vascular aging as disease risk factors. Arthritis Res.Ther. 13, 231 (2011). 72. Maksimowicz-McKinnon, K., Clark, T. M. Hoffman, G. S. Takayasu arteritis and giant cell arteritis: a spectrum within the same disease? Medicine (Baltimore) 88, 221–226 (2009). 73. Grayson, P. C. et al. Distribution of arterial lesions in Takayasu’s arteritis and giant cell arteritis. Ann. Rheum. Dis. 71, 1329–1334 (2012). 74. Zivkovic, S. A., Clemens, P. R. Lacomis, D. Characteristics of late-onset myasthenia gravis. J. Neurol. 259, 2167–2171 (2012). 75. Aarli, J. A. Myasthenia gravis in the elderly: is it different? Ann. N. Y.Acad. Sci. 1132, 238–243 (2008). Acknowledgements G.S.H. has received partial research support from the Harold C. Schott Foundation and the Konigsberg Family Fund for Vasculitis Research. L.H.C. is in part supported by the R. J. Fasenmyer Foundation. Author contributions G.S.H. conceived the article’s content, researched data for the article, wrote the first draft and reviewed/ edited the manuscript before submission. L.H.C. researched data for and wrote the section on viral-associated vasculitis. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved