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The Aetiology and Pathogenesis of Major Systemic Vasculitides

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The Aetiology and Pathogenesis of Major Systemic Vasculitides Postgraduate Medical Journal (1986) 62, 627-636 Postgrad Med J: first published as 10.1136/pgmj.62.729.627 on 1 July 1986. Downloaded from Mechanisms of Disease The aetiology and pathogenesis ofmajor systemic vasculitides Caroline O.S. Savage and Yin C. Ng Department ofMedicine, Royal Postgraduate Medical School, Hammersmith Hospital, Ducane Road, London W12 OHS, UK. Introduction Systemic vasculitis is an inflammatory disorder of Immuno-pathogenetic mechanisms blood vessels characterized by a perivascular cellular infiltrate around and fibrinoid necrosis within vessel Immune complexes walls. It may accompany a variety ofdiseases and may dominate clinical and pathological findings in polyar- (a) Animalmodels ofimmune complex induced teritis (classical and microscopic), the Churg-Strauss vasculitis syndrome, Wegener's granulomatosis, Henoch- Schonlein purpura, giant cell arteritis and Takayasu's The animal models of serum sickness and of the disease - all 'primary' systemic vasculitides, the clin- Arthus reaction have been useful in elucidating ical and pathological features of which are described mechanisms by which antibody may react with free elsewhere (Cohen et al., 1980; Scott et al., 1982; antigens (to produce circulating immune complexes) copyright. McCluskey & Fienberg, 1983; Savage et al., 1985; or with tissue-associated antigens, to mediate tissue Serra et al., 1984; Churg & Strauss, 1952; Chumbley et injury. However, other good models of vasculitis al., 1977; Pinching et al., 1983; Fauci et al., 1983; which reflect more accurately the human 'primary' Counahan et al., 1977). It is also associated with other systemic vasculitides, particularly those associated well-defined systemic disorders including systemic with granuloma formation, are lacking. lupus erythematosus, rheumatoid arthritis, mixed essential cryoglobulinaemia, subacute bacterial en- Serum sickness Clark & Kaplan (1937) first http://pmj.bmj.com/ docarditis and various types of malignancy (Fauci et associated serum sickness with necrotizing vasculitis in al., 1978; Cupps & Fauci, 1982). The pathological man. Rich & Gregory (1943), Germuth (1953) and features of these 'primary' and 'secondary' vas- Dixon et al. (1958) developed animal models in which culitides form a spectrum in which virtually all types rabbits were injected with horse serum or a large dose and sizes of blood vessels are involved and no organ of a heterologous serum protein. From these studies system is exempt. which are well reviewed elsewhere (Cochrane & Kof- Immunogenetic mechanisms such as passive deposi- fler, 1973) it became evident that circulating and tissue tion ofimmune complexes, direct antibody attack and bound immune complexes form at the time ofimmune on September 27, 2021 by guest. Protected cell mediated immunity, are generally thought to elimination and that their appearance is associated underlie the systemic necrotizing vasculitides, but with the development ofarterial, as well as glomerular, detailed understanding remains poor. Aetiological lesions. Later studies established that circulating com- factors are largely unknown, as are the factors deter- plexes are normally removed by the reticuloendoth- mining organ distribution, size of vessel involved, elial system and other factors must pertain before presence or absence of granulomata and clinical deposition in vessel walls occurs (Cochrane & Koffler, expression of disease. 1973). Such factors include vascular permeability, the size ofthe complexes, the affinity ofthe antibody, local hydrodynamic factors, the state ofthe reticuloendoth- elial system and the local characteristics of each Correspondence: C.O.S. Savage, B.Sc., M.R.C.P., Renal tissue's endothelium and vessel wall architecture. Not Unit, Royal Postgraduate Medical School, Ducane Road, only do multiple factors determine whether immune London W12 OHS. complexes will be deposited, but the subsequent Received: 17 February 1986 pathogenesis of tissue injury triggered by their deposi- ) The Fellowship of Postgraduate Medicine, 1986 628 C.O.S. SAVAGE & Y.C. NG Postgrad Med J: first published as 10.1136/pgmj.62.729.627 on 1 July 1986. Downloaded from tion depends on several mediators including com- (b) Immune complex mediated vasculitis in man plement, neutrophil infiltration and possibly the coagulation and kallikrein-kinin system (Cochrane & The evidence Vasculitis in man often develops in Koffier, 1973). Immune complexes certainly have the diseases with strong immunological associations, sug- potential to interact with numerous humoral and gesting that the vasculitis too may be secondary to cellular recognition systems since they can bind Clq, immunological damage. Evidence for immune com- C4b and C3b complement components, fibronectin, plex mediated disease is derived from detection of rheumatoid factor and anti-idiotypic antibodies: these circulating immune complexes using a variety of proteins can in turn interact with corresponding cell techniques, from demonstrations of their presence as surface receptors (Nydegger, 1985). Immune com- cryoglobulins, from the development of hypocom- plexes may also impair the function of suppressor T plementaemia and from the demonstration ofimmune cells and alter their expression of cell surface markers reactants in tissue by direct immunofluorescence. For allowing the development of procoagulant activities example, circulating immune complexes (often accom- which can initiate intravascular coagulation (Rothber- panied by hypocomplementaemia) are detectable in ger et al., 1977). most patients with vasculitis associated with hepatitis B infection (described in more detail below), systemic The Arthus reaction The Arthus reaction is a localized lupus erythematosus, rheumatoid arthritis, or bac- acute immune complex vasculitis which develops in terial endocarditis (Theofilopoulos & Dixon, 1979). the skin of sensitized animals 4-10 hours after the Cryoglobulins are associated with vasculitis in various local injection of antigen (Cochrane, 1965). His- infections, lymphoproliferative and collagen diseases tologically, the vessel walls show marked infiltration (Franklin, 1980); patients with Type II mixed essential of red cells into the extravascular space. Early on, cryoglobulinaemia may also develop severe vasculitis complexes can be identified by immunofluorescence (Gorevic et al., 1980). Immunofluorescence studies but are removed by neutrophils within 24-48 hours of have detected complement and immunoglobulin in antigen injection (Cochrane et al., 1959). vessel walls, as in the dermal vessels of patients with The Arthus reaction follows binding of preformed rheumatoid arthritis (Rapoport et al., 1980), mixed antibody to antigen, with subsequent activation of essential cryoglobulinaemia (Gorevic et al., 1980) and complement which initiates various immune ad- systemic lupus erythematosus (Tan & Kunkel, 1966). copyright. herence reactions, release of chemotactic factors, Further evidence for an association between immune release ofanaphylatoxins (C3a and C5a) which trigger complexes and vasculitis is derived from the observa- mast cell degranulation, and the formation of the tion that extra-articular disease in rheumatoid arth- membrane attack complex (Soter & Austen, 1980). ritis is associated with increased concentrations of Infiltrating neutrophils bind to the complexes via their circulating immune complexes (Zubler et al., 1976). C3b receptors (CR1); phagocytosis and release of Several investigators have found a connection between enzymes, inflammatory peptides and oxygen radicals the level of immune complexes and disease activity is triggered by binding to antibody Fc determinants (Scott et al., 1982) and improvement has been reported http://pmj.bmj.com/ (Henson, 1982). The generation of hydrogen peroxide following the removal of these and other factors by and the hydroxyl radical by activated neutrophils may plasma exchange (Lockwood et al., 1979). Further, the be particularly important in mediating tissue injury strong association between immune complexes, and (Fligiel et al., 1984); iron may potentiate injury, and clinical symptoms was recently demonstrated in a catalase or iron chelators may have a protective effect. prospective study in which heterologous anti- The acute serum sickness model and the Arthus thymocyte globulin was injected in 11 patients, 8 of reaction suggest that immune complexes form and are whom developed serum sickness (Lawley et al., 1984). on September 27, 2021 by guest. Protected then deposited, or that antibody may react with fixed Studies like these which have been reported by tissue antigen. However, these concepts are not ex- multiple centres, provide reasonable evidence that clusive. Firstly, other methods ofimmune aggregation immune complexes are present in secondary vas- can be envisaged such as 'planting' ofan antigen which culitides such as systemic lupus erythematosus, has a particular affinity for a tissue by virtue ofcharge rheumatoid arthritis, cryoglobulinaemia and bacterial or other molecular interactions. Izui et al. (1976) endocarditis. Yet despite their presence, it remains reported that DNA may preferentially localize to the difficult to determine precisely the pathogenetic glomerular basement membrane. Secondly, a combin- potential of immune complexes in systemic vasculitis ation of processes may operate. Matsuo et al. (1985) since they are rarely detectable in 100% of these demonstrated that antibody induces redistribution patients (Pussell et al., 1978), they may be present
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