Page 841 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 59 Large-Vessel Vasculitides 813

KEY CONCEPtS impact on the density of newly formed microvessels and the
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Large Vessel Vasculitis thickness of the hyperplastic intimal layer. Hyperactive check-
points are now targeted therapeutically to unleash T-cell immunity
• Medium and large arteries in humans have multiple wall layers and in patients with cancer. A role for PD-1–derived negative signaling
a wall structure substantial enough to be the target of transmural in vasculitis predicts that such patients are at risk to develop
inflammation. drug-induced vasculitis.
• Vasculitis causes the rapid and concentric growth of hyperplastic intima,
leading to luminal occlusion and ischemia of dependent tissues.
Intramural inflammation of the aorta can result in wall damage followed CLINICAL FEATURES IN GIANT CELL ARTERITIS
by aneurysm formation and rupture.
• Because of the vital function and nonregenerative nature of large
human arteries, the threshold for the induction and persistence of
innate and adaptive immune responses in the wall structures of such CLINICaL PEarLS
arteries must be explicitly high. Clinical and Epidemiological Clues in
• Inflammatory infiltrates typical for granulomatous vasculitis enter the Giant-Cell Arteritis
vessel from the “back door,” the adventitia, and not from the lumen.
• Besides their critical role in securing blood flow, medium and large • Patient older than 50 years of age
blood vessels also possess immunoregulatory functions mediated by • Female
dendritic cells (DCs) indigenous to the vascular wall. DCs in each • Northern European heritage
vascular territory express a distinctive pattern of Toll-like receptors • Laboratory findings of a highly activated acute-phase response
(TLRs), giving each vessel its own immunological identity. • Insidious onset of nonspecific symptoms (weight loss, night sweats,
malaise, fever)
• Ischemia of ocular structures, cranial muscles, scalp, or upper
extremities
Defective T Regulatory Cells and Insufficient Immune
Checkpoints in Giant Cell Arteritis
Recent data have brought to the forefront that antigen-nonspecific Clinical manifestations of GCA reflect the combination of a
immunoregulatory pathways may have disease relevance in LVVs, systemic inflammatory syndrome with vascular insufficiency
2,26
specifically in enabling unopposed and lasting adaptive immune (Table 59.1). Increased sensitivity of vascular imaging methods
responses to induce and sustain vessel wall inflammation. and longer survival of affected individuals have made it clear
Like in many chronic inflammatory lesions, GCA’s arterial that in most patients medium and large arteries are involved.
wall infiltrates lack sufficient antiinflammatory T regulatory cells In some patients, the disease preferentially targets more peripheral
(Tregs). This may be a consequence of the proinflammatory branches of the aorta (e.g., cranial arteries, such as the temporal
milieu, but recent studies have identified a novel mechanism of artery). In others, the aorta and its proximal branches (e.g.,
Treg-dependent immunosuppression that is nonfunctional in subclavian, axillary arteries) are involved to a major extent. In
GCA. In healthy individuals, secondary lymphoid tissue are a subpopulation of patients, the clinical consequences of arterial
occupied by a population of CD8 Tregs that effectively control inflammation are minimal, and these consequences come to
clonal expansion of CD4 T cells, and thus the overall size of the clinical attention because of failure to thrive.
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CD4 T-cell compartment. Such CD8 Tregs suppress activation In cranial GCA, symptoms result from vascular stenosis of
and expansion of neighboring CD4 T cells by the directed transfer the neck and head arteries, most prominently in the branches
of nicotinamide adenine dinucleotide phosphate (NADPH) of the external carotid artery. Arteritis of the scalp arteries leads
oxidase 2 (Nox2)–containing membrane particles. The population to the typical presentations of headaches and scalp tenderness.
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of Nox2 CD8 Tregs is distinctly low in patients with GCA and Patients report difficulties with wearing glasses or combing their
remains low with antiinflammatory therapy, suggesting a preexist- hair. The headaches are often intense and unresponsive to standard
ing abnormality in the patients’ immune system. Implicating analgesics. Headaches are a nonspecific clinical symptom, yet in
Nox2 expressed on CD8 T cells in the threshold setting of CD4 an older individual with other findings of an inflammatory
T-cell immunity opens an entirely new perspective in vasculitis syndrome, physicians need to rule out GCA. Insufficient blood
research and redirects the focus away from antigenic triggers flow to the masseter muscles and the tongue causes jaw or tongue
that induce protracted macrophage activity. claudication, elicited by prolonged chewing and talking. Although
A second immunoregulatory defect weakening proper control this type of claudication is present in <30% of patients, it is
of CD4 T-cell immunity has been localized to the programmed clinically helpful because it rarely occurs outside of GCA. Similarly,
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death 1 (PD-1) immunoinhibitory checkpoint. Inhibitory painful dysphagia can be a useful clinical clue.
checkpoints are designed to protect tissue from excessive immune The orbits and the optic nerve are strictly dependent on blood
reactivity. PD-1 is expressed on activated T cells, the ligand PD-L1 supply from the external carotid system, particularly the oph-
is expressed on APCs. Triggering of PD-1 sends negative signals thalmic artery. GCA in branches of the ophthalmic artery, specifi-
into T cells and stops their proliferation and polarization. DCs cally the posterior ciliary arteries, leads to anterior ischemic optic
in patients with GCA, both lesional vasDCs and circulating DCs, neuropathy, presenting as sudden and painless vision loss.
low
are PD-L1 . GCA T cells thus lack negative signaling and fail Typically, patients lose vision in the early-morning hours or
to undergo clonal contraction. Indeed, in inflamed temporal wake up blind. Involvement of one eye may be followed by visual
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arteries PD-1 T cells are strongly enriched. In human artery– loss in the partner eye if the disease is not diagnosed and treated
chimeric mice, blocking PD-1 with antibody treatment exacerbates promptly. Besides anterior optic neuropathy, GCA can cause a
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vasculitis, and wall-infiltrating PD-1 T cells produce a spectrum number of ischemic complications in the orbits and along the
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of effector cytokines (IFN-γ, IL-17, IL-9, IL-21, etc.). Most visual axis, which may present as diplopia or partial vision loss.
importantly, PD-1–PD-L1 interactions in the artery have direct If recognized and treated immediately, vasculitis-associated sight