Page 839 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 59 Large-Vessel Vasculitides 811

Triggering of innate immune cells (monocytes,
neutrophils, etc) Clinical consequences 7 0
? Site 7 '& 7
? Identity of stimuli Elevated CRP, ESR 7
7 0
Elevation of innate pro-inflammatory cytokines Muscle pain (PMR) 7 0 7 7 '&
-IL-6, IL-8, IL-12p70, MCP-1, MIP-1β, eotaxin, Malaise '& 7 0
Failure-to-thrive
pentraxin 3, etc Fever 0 0 7
Anemia 0 7 7
Thrombocytosis 7
Induction of hepatic acute phase proteins 7 7 7 '& 7
- C-reactive protein, mannose-binding protein, ?? priming of 0 0
ferritin, serum amyloid A, haptoglobin, selected vascular $'9(17,7,$ 0(',$ 7
fibrinogen, von willebrand factor, hepcidin, etc beds 7
'& '& 7
&' &' &KHPRNLQHV ,17,0$
Induction of inflammatory amplification loops 3' / 7 0
- Activation of neutrophils, monocytes, endothelial 3' / &'
cells, fibroblasts, etc 7 FHOOV 7 FHOOV 7 FHOOV 7
,)1 \ ,/ ,)1 \ ,/ ,)1 \ ""
,/ ,/
FIG 59.2 Extravascular Giant-Cell Arteritis (GCA). Circulating ,/ ,/
innate cells (monocytes, neutrophils, etc.) are highly activated 0DF 0DF 0DF
and elicit a hepatic acute-phase response. Several of the acute 7*)% ,/ % 9(*) 3'*) L126
phase proteins serve as biomarkers (C-reactive protein [CRP], ,/ )*)
$OGRVH UHGXFWDVH
erythrocyte sedimentation rate [ESR]) of disease. Extravascular
GCA is explicitly sensitive to corticosteroid therapy and to cytokine FIG 59.3 Vascular Giant-Cell Arteritis (GCA). Adaptive
blockade. Whether the extravascular competent has a direct or immune responses in vascular GCA are supported by trans-
indirect involvement in driving/sustaining granulomatous vasculitis mural granulomatous infiltrates. Dendritic cells (DCs), present
remains unknown. Polymyalgia rheumatic (PMR) may represent in healthy arteries at the adventitia–media border, serve as
an isolated form of extravascular GCA. antigen-presenting cells (APCs) and provide costimulatory signals
but are deficient in the coinhibitory ligand programmed death
ligand 1 (PD-L1). Wall-infiltrating T cells are multifunctional,
producing a broad spectrum of effector cytokines, including
serum amyloid A (SAA), and several other acute-phase proteins. interferon (IFN)-γ, interleukin (IL)-17, IL-9, and IL-21. Macro-
Accordingly, treatment with an IL-6 receptor–blocking antibody, phages, some of which transform into multinucleated giant cells,
effectively reduces the laboratory abnormalities measured in supply a multitude of cytokines, metalloproteinases, reactive
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patients with GCA. Whether IL-6 has additional functions in oxygen species (ROS), growth factors, angiogenesis factors
the disease process, particularly in the inflamed vessel wall, is and inducible nitric oxide synthase (iNOS). Their functional
uncertain. Some acute-phase proteins (e.g., SAA) have proinflam- commitment depends on their geographical location in the
matory functions by themselves, functioning as proinflammatory vessel wall.
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amplifiers. Although abnormal innate immunity dominates
the extravascular component of LVVs, underlying mechanisms composition of the intramural granulomatous infiltrates. Con-
(e.g., what the original triggers are, where the activation occurs, sidering that vital arteries (e.g., the aorta) are protected by immune
how the systemic inflammation interfaces with vascular inflam- privilege, malfunction of endogenous vasDCs may, indeed, be
mation) are essentially unexplored. the pinnacle defect–initiating vasculitis.
Defects in innate immunity contributing to the early and late Other innate immune cells captured in the vasculitic lesions,
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events in the vasculitic lesions are much better understood specifically macrophages, are particularly important as inflam-
18
(Fig. 59.3). A population of vessel wall–residing dendritic cells matory effector cells. Multiple functional domains of macro-
15
(vasDCs) have been identified in normal human arteries, phages have pathogenic relevance. Intriguingly, the functional
localized at the adventitial–medial junction, close to the adventitial commitment of lesional macrophages is closely linked to their
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microvascular network. Given their strategic positioning, they geographical location in the tissue site. Intima-positioned
are believed to guard the artery’s “backdoor.” vasDCs serve a macrophages produce inducible nitric oxide synthase, participat-
gatekeeper function in vasculitis, and stimulation of such vasDCs ing in regulating vascular tone. Adventitial macrophages secrete
is a prerequisite to break the natural immunotolerance (immune cytokines (IL-1β, IL-6, transforming growth factor-β [TGF-β]),
privilege) of the arterial wall. Their activation presages vasculitis, conditioning the local inflammatory environment. Granuloma
as indicated by their transition from the resting state to the formation and giant cells dominate in the media and at the
activated state in PMR arteries, where no vessel wall infiltrates media–intima border. Functional profiling of media-residing
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are as yet detectable. In frank vasculitis, vasDCs undergo macrophages has connected them to tissue damage; they produce
expansion, penetrate deep into the wall, produce chemokines metalloproteinases and reactive oxygen species (ROS), provide
17
and cytokines, and express costimulatory ligands. They have antioxidant regulation, and supply growth factors for myofibro-
been implicated in presenting local antigen to induce T-cell clonal blasts and newly formed microvessels. Essentially they drive the
expansion and, through their chemokine production, shape the hyperplasia of the intimal layer that leads to luminal obstruction