J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.3.275 on 1 March 2000. Downloaded from J Neurol Neurosurg Psychiatry 2000;68:271–276 271 EDITORIAL Vasculitic neuropathies Vasculitis—inflammation of the vessel wall with vascular ders suggests that mechanisms present in the CNS for damage or attendant tissue injury— may be a manifesta- minimising vascular inflammation are not present in the tion of diverse diseases. Recent studies of classification, PNS. Another largely unexplored component is the epidemiology, and pathogenic mechanisms of individual intriguing role of the autonomic nervous system in the vasculitides provide a foundation for better understanding regulation of vascular inflammation. Sympathetic innerva- the broad array of clinical features encountered in patients. tion of the lymph nodes and spleen as well as receptors for Intense scrutiny of the cellular components and mediators noradrenaline (norepinephrine) on lymphocytes provides a of vascular inflammation in several diseases has yielded mechanism for central autonomic modulation of systemic details of spatial and temporal distribution of inflammatory immune responses. Sympathetic factors within the periph- molecules, some of which are the subject of new therapies. eral nerve also influence local inflammation. The loss of Many clinical questions remain unresolved. How we define sympathetic fibres in diabetes seems to be a proinflamma- and diagnose vasculitis continues to be debated among cli- tory factor in neuropathies4 nicians and pathologists. Given the pleomorphic expres- Vascular inflammation spans numerous physiological sion of disease, what clinical features are central to a diag- and pathological processes. Accumulation of inflammatory nosis? How do genetically determined responses of the cells in the vessel wall remains the common denominator of host, duration of disease, and type of involved tissue influ- the vasculitides. However, the determinants of tissue dam- ence the histological features? How do we target therapies age are not always clear. Three components can be identi- at inflammation without interfering with healing? fied and targeted for therapeutic intervention: initiation of Neuropathies are a prominent feature of the systemic the injury, recruitment of inflammatory cells and tissue and secondary vasculitides. The reasons for this frequency damage, and regulation of the immune response. Endothe- are not immediately clear. The microvasculature of the lial cells are a focus of inflammatory attack and active par- http://jnnp.bmj.com/ peripheral nerve is comprised of two functionally distinct ticipants in recruitment of cells in most vascular trees. In systems, an extrinsic and an intrinsic system linked by a the CNS vasculature non-endothelial cells, usually micro- complex anastomotic network. The rich blood supply and glia, are the principle antigen presenting cells, provide co- the capacity of nerves to function reasonably well with stimulatory molecules, and contribute proinflammatory anaerobic metabolism normally render the nerve relatively and anti-inflammatory mediators. There is no information resistant to ischaemia. However, other anatomical and about the antigen presenting features of endothelial cells in physiological characteristics such as watershed areas the PNS vasculature. Vascular-immune interactions re- between the distribution of major nutrient arteries and lack volve around sequential expression of a series of cell on September 30, 2021 by guest. Protected copyright. of autoregulation of peripheral nerve blood flow provide an surface molecules on endothelial cells and leucocytes that explanation of the vulnerability of nerve fibres to ischaemia provide for attachment, adhesion, and, usually, migration with certain types of vascular injury.12 The immediate of leucocytes through the blood vessel walls. Expression of cause of the vasculitic neuropathies is inflammation and these molecules, selectins, integrins, and intercellular occlusion of the vasa nervorum resulting in ischaemia of adhesion molecules (ICAMs), and their ligands provide the peripheral nerve. This widespread occlusion of epineu- specificity for the type of cell recruited and some rial, or rarely perineurial and endoneurial, arterioles causes correlation with the location and type of the blood vessel multifocal central fascicular or sector degeneration of involved.5 Certain cytokines produced by activated T cells nerve fibres.3 and macrophages during specific immune responses func- What is the nature of the peripheral nerve vasculature tion to recruit additional cells and amplify the inflamma- that accounts for its frequent involvement in vasculitides tion. The normally transient nature of vascular and caused by disparate immunopathogenic mechanisms? The perivascular inflammation correlates with the temporally frequency of involvement of the PNS in the systemic limited expression of proinflammatory cytokines and vasculitides despite the varying underlying pathogenic adhesion molecules as well as autostimulation of anti- mechanism (immune complex deposition, cell mediated inflammatory molecules from the tissue parenchyma and interactions, and antineutrophil cytoplasmic antibody circulation. Persistent inflammation may occur, however, (ANCA) associated neutrophilic processes) suggests a with the enduring presence of an antigen, damage to the general susceptibility or reactivity to inflammatory stimuli. vessel wall with exposure of extracellular matrix proteins, Further, the more frequent involvement of the PNS vascu- or with immune dysregulation such as occurs in some lature compared with the CNS vasculature in these disor- autoimmune disease. Accompanying inflammation of the J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.3.275 on 1 March 2000. Downloaded from 272 Moore vascular wall are several local and systemic processes that matrix metalloproteinase-1 suggesting a role for these mol- contribute to the tissue damage. The alterations in coagu- ecules in the vessel and nerve injury.17 lation and vasomotor tone result from local damage to Autoantibodies are not often pathogenic by themselves. endothelium as well as intrinsic components of the However, the strong association between specific ANCAs cytokine cascade.6 and certain types of vasculitis raised questions about Heterogenous aetiological agents may initiate and potential ANCA initiated vascular damage. sustain vascular inflammation. Several established and Antineutrophil cytoplasmic antibodies recognise con- potential pathogenic mechanisms may act in concert to stituents of neutrophil cytoplasm including proteinase 3 sustain and reinforce vessel damage.78 Well defined (PR3), myeloperoxidase (MPO), and elastase. Transloca- mechanisms that initiate and sustain vascular injury are tion and release of these cytoplasmic components is part of immune complex deposition and T cell mediated processes the physiological response of neutrophils to inflammatory such as those that occur in graft rejection. Other processes mediators such as TNFá.18 In vitro studies show that anti- strongly associated with vascular injury include expression bodies to PC3 (PC3-ANCA) bind to neutrophils and of neoantigens (usually infectious) on the endothelium and induce respiratory bursts and degranulation possibly ANCA. Further, studies are beginning to explore the beyond what is physiologically appropriate. PC3-ANCA potential that eosinophils or mast cells have to initiate the also binds to endothelial cells and may increase expression accrual of inflammation in certain vasculitides.9 of adhesion molecules. The in vivo relevance is supported Immune complexes with certain immunochemical char- by animal models of ANCA induced vasculitis and acteristics activate a complement cascade that induces glomerulonephritis. Although MPO ANCAs are less neutrophil mediated damage to the vessel wall. strongly associated with disease, they could mediate vascu- The presence of granulocytes is usually associated with lar damage in association with either H2O2 or ischaemia/ fibrinoid necrosis as would be expected on the basis of their perfusion injury in one animal model.19 release of toxic enzymes during inflammation. Necrosis in Factors initiating the regulation of inflammation are the vessel wall is a large contributor to scarring and the under renewed scrutiny. Studies of genetic susceptibility delayed sequelae present in vasculitides such as Wegener’s and hormonal modulation of inflammation are particularly granulomatosis and polyarteritis nodosa. germane. Recent animal and human studies support a More recent studies focus on T cells which, often in genetic role in certain inflammatory diseases. Genetic vari- association with macrophages, seem to be major eVector ations may modify components within the human inflam- cells in many of the vasculitides. Several elegant studies in matory eVector pathway (adhesion molecules, cytokines, temporal arteritis (giant cell arteritis) provide insight into and their receptors) in a way that promotes vascular the topography of the cells in the infiltrate. Cells in diVer- inflammation. Reports on hereditary á1-antitrypsin defi- ent regions of the infiltrate acquire distinct functional ciency are among the new data suggesting a genetic predis- capabilities. CD4+ T cells in the adventitia display position to vasculitis.20 21 In mice that develop a spontane- evidence of recent engagement with their antigen on the ous granulomatous arteritis, a hereditary defect in Fas basis of the presence of interleukin-2 receptors