Vasculitis nrrheum.2014.89

454 | AUGUST 2014 | VOLUME 10 www.nature.com/nrrheum
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.
hoffmag@ccf.org
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.
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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

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.
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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

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
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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

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

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
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organ-targeting and disease patterns. Seminal additional
references are included from earlier years.
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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.
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