The Aetiology and Pathogenesis of Major Systemic Vasculitides

Home , Arthus reaction

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 reticuloendothelial 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 in of surface antigen on rabbit oocytes which results in otherwise normal tissues (Baart de la Faille-Kuyper et extrusion of antigen-antibody complexes into the al., 1973) or, conversely, undetectable in tissues with adjacent zona pellucida where they become trapped. typical vasculitic lesions (Conn et al., 1972), and disease activity may not correlate with measured levels MAJOR SYSTEMIC VASCULITIDES 629 Postgrad Med J: first published as 10.1136/pgmj.62.729.627 on 1 July 1986. Downloaded from

(Inman et al., 1980). Problems in interpretation also on factors such as the time elapsed before separation arise since levels of immune complexes measured by of the sample, changes in complement function, the different methods correlate poorly (Lambert et al., nature of the immune complex (Horgan et al., 1984) 1978). and the density of CR1 on erythrocytes. The number Understanding of immune complex mediated path- of CR1 sites per erythrocyte is highly variable in the ogenetic mechanisms gained from animal studies normal population (Ida et al., 1982) and is significant- partly explains these inconsistencies: thus, immune ly reduced in systemic lupus erythematosus (Iida et al., complexes may circulate for a limited time (Dixon et 1982; Miyakawa et al., 1981; Walport et al., 1985) and al., 1958), may be rapidly removed from tissues (Fye et rheumatoid arthritis (lida et al., 1982). al., 1977) and other factors such as complement and Evidence linking immune complexes with primary neutrophils may be required for tissue injury. In systemic vasculitides is even more tenuous than for the addition, measurement of fluid phase immune com- secondary vasculitides. Circulating or deposited plexes may be misleading: the methods for immune immune complexes, cryoglobulinaemia or hypocom- complex detection are numerous and are mostly plementaemia are the exception rather than the rule. indirect, using antigen-nonspecific methods which For example, a recent study examined the incidence of depend on changes in either physicochemical (e.g. these abnormalities in 43 patients with polyarteritis or polyethylene glycol precipitation) or biological Wegener's granulomatosis (Ronco et al., 1983). characteristics (e.g. Clq or rheumatoid factor binding Cryoglobulins were detectable in about 20% and assays) (Theofilopoulos & Dixon, 1979). Further- hypocomplementaemia was not found. Immune com- more, recent advances in the understanding of the plexes were detectable in less than one third ofpatients normal handling ofimmune complexes suggest that in using a Raji cell assay but in most patients using a Clq primates, immune complexes which have activated binding assay. Deposits of immunoglobulin or com- complement to become coated with C3b and C4b will plement in renal arterial walls and glomeruli were bind to the C3b receptor (CR1) on erythrocytes. scant. These studies suggest that immune complexes This erythrocyte-mediated carriage of immune com- may not be the primary pathogenetic mechanism plexes to the reticuloendothelial system has been inducing these types of vasculitis. demonstrated in baboons and monkeys (Cornacoff et al., 1983). However, there is also in vitro evidence that Host factors which affect deposition of immune com- copyright. erythrocyte-bound immune complexes are released by plexes andpathogenesis oftissue injury It is likely that the action of factor I (Medof et al., 1982), a the potential pathogenicity of immune complexes will physiological inhibitor of the complement system, partly depend on the physicochemical and biological which cleaves the C3b on the immune complex to properties of the antigen, the antibody and the com- C3dg. Since C3dg has no affinity for CR1, the immune plex - factors which have been discussed in detail in complex is released from the erythrocyte (Figure 1). other reviews (Nydegger & Lambert, 1980). Briefly, This process occurring in whole blood before sample the molecular size of the antigen, the number of http://pmj.bmj.com/ separation (Y.C. Ng, unpublished) results in the antigenic sites recognized by antibody, the affinity and detection of immune complexes that are altered in concentration of antibody, and the ratio of antigen to some biological properties including their phlogistic antibody concentrations, influence the characteristics potential, and hence may be pathogenetically of the immune complex generated. Host factors, such irrelevant. Furthermore, any single measurement of as the state of the reticuloendothelial system, abnor- immune complexes will be affected by the percentage malities of the complement system and local tissue ofcomplexes in the fluid phase, which in turn depends factors (ultrastructure, cellular receptors etc.) are also on September 27, 2021 by guest. Protected

IC IC .C3b. IC IC + C3b Factor * iC3b Factr I ..,. -* . .

Figure1 Ibetw o comph;x CR1 and ;Facto L KIC iMetom_o p

... . ,~~~~... .. ertzcte CR...... ,I...... ,...... -: 630 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 likely to be of major importance in determining the (Czop & Nussenzweig, 1976). In addition, the ineffec- susceptibility of the host and of individual organs to tive generation ofC3b and C4b on immune complexes immune complex mediated tissue injury and in dictat- may result in inefficient CR1-mediated transport to ing the pathological and clinical manifestations. the reticuloendothelial system. Defects in these func- The effect of abnormalities of the reticuloendoth- tions of complement may favour deposition of highly elial system on clearance and thereby, deposition, of phlogistic immune complexes in these patients. immune complexes has been investigated in patients Other host factors which may determine the pattern with vasculitis by measuring the rate of removal of of immune complex deposition include tissue ultras- heat damaged or antibody-coated red cells by the tructure and cell surface receptors. For example (i) spleen. Most of the studies have been performed on glomerular capillaries which are frequently involved in patients with systemic lupus erythematosus or vasculitic processes. receive a high blood flow, are rheumatoid arthritis. Some investigators have found under pressure and have a fenestrated endothelium defective removal of erythrocytes which have which may facilitate immune complex trapping. (ii) correlated with levels of circulating immune com- Cell surface receptors may be altered by, for example, plexes or disease activity (Lockwood et al., 1979; injury which can induce endothelial cells to express Fc Frank et al., 1979; Williams et al., 1979; Hamburger et receptors and C3 receptors (Ryan et al., 1981; Cines et al., 1982). An association between immune clearance al., 1982), thereby promoting active binding of defects and HLA-B8 DR3 (Lawley et al., 1981) or immune complexes to these cells. Renal epithelial cells HLA-DR2 (Kimberley et al., 1983) has also been have been found to express CR1 (Fearon, 1984) and reported. It has been suggested that these associations both CR1 and Fc receptors have been detected in could arise from a direct blocking effect ofcirculating human choroid plexus (Peress et al., 1981; Braathen et immune complexes on reticuloendothelial Fc receptor al., 1979), although the function of receptors in these function (Lockwood et al., 1979) or, alternatively, that sites is unknown. some patients may have a genetically determined Fc receptor defect that predisposes to immune dysregula- (c) Antigens tion (Lawley et al., 1981; Kimberley et al., 1983). In responsiblefor immune complex vasculitis support of an acquired reticuloendothelial system dysfunction is the demonstration of reversibility with Identification of the nature of the antigens in immunecopyright. plasma exchange (Lockwood et al., 1979). However, complexes is potentially of value in determining the others have failed to demonstrate defective clearance precise disease aetiology and in allowing the adminis- of IgG coated or heat damaged erythrocytes in these tration of accurate therapy (Nydegger, 1985). diseases (Elkon et al., 1980; Kabbash et al., 1982; Swaak et al., 1984), indeed the value of IgG coated erythrocyte clearance as a measure of reticuloendoth- Animals Spontaneous immune-complex disease elial Fc receptor function has been questioned (Frank occurs in both animals and man as a result of both et al., 1983) and the mechanisms of clearance of heat foreign and autologous antigens. In animals, vasculitic http://pmj.bmj.com/ damaged erythrocytes are even less clear. Thus, at the disease may result from viral infection; for example present time, data on reticuloendothelial function in there is strong evidence for the participation of viral patients with vasculitis is conflicting and the situation antigen-host antibody complexes in the pathogenesis is far from clear. ofaleutian disease ofmink (Henson & Gorham, 1973). Deficiencies of the complement system are Animals, particularly NZB/NZW Fl hybrid mice, associated with an increased may develop autoimmune disease with DNA-anti- incidence of immune DNA complexes (Cochrane & Koffier, 1973). complex mediated disease. This association is stron- on September 27, 2021 by guest. Protected gest in patients with inherited defects of the classical pathway, particularly Cl subcomponents or C4 Vasculitis and specific infection in man In man, the (Schifferli & Peters, 1983), but the reasons for this best known example of a foreign antigen provoking association are not entirely clear. Since C2, C4 and immune complex mediated vasculitis is that associated Factor B are encoded within the MHC, it has been with hepatitis B (Gocke et al., 1970; Trepo et al., 1970). suggested that the association results from linkage The clinical features are often very similar to those of disequilibrium with other disease susceptibility genes. patients with necrotizing vasculitis of the polyarteritis However, genes for Clr, Cls, Clq and C3 are not nodosa type; there is no relationship between the linked to HLA, suggesting that it is loss ofcomplement development of vasculitis and the type of liver disease function that is important: the classical complement present. Circulating hepatitis B surface antigen pathway is involved in the inhibition of precipitation (HbsAg)-antibody complexes have been demon- of antigen-antibody complexes (Schifferli et al., 1982) strated (Gocke et al., 1970) and deposits of HbsAg, whereas solubilization of antigen-antibody immunoglobulins and complement components precipitates is mainly an alternative pathway function found in vascular lesions (Trepo et al., 1974). Hy- Postgrad Med J: first published as 10.1136/pgmj.62.729.627 on 1 July 1986. Downloaded from MAJOR SYSTEMIC VASCULITIDES 631

pocomplementaemia (Duffy et al., 1976) and Neoplasia and vasculitis Clinical vasculitis syndromes cryoglobulinaemia (Levo et al., 1977) may accompany have been associated with neoplasia, including hairy the vasculitis and the cryoprecipitate may contain cell leukaemia (Elkon et al., 1979; Goedert et al., both HbsAg and antibody, further supporting the 1981), chronic leukaemia (McCombs, 1965), Hodg- concept ofimmune complex mediated vascular injury. kin's disease (Sams et al., 1968), multiple myeloma However, despite such strong supportive evidence for (Williams et al., 1985) and the 'pre-leukaemic' stage of a causative role of HbsAg, not all investigators have monocyte leukaemia (Leung et al., 1986). The reasons been able to confirm this (Ewan et al., 1981). Passive for an association between arteritis and malignant trapping of the abundant circulating viral antigen has lymphoproliferative diseases are not clear. It has been not been rigorously excluded. Further, in most studies suggested that infiltration of the reticuloendothelial the sexual preferences of the patients were not given system by malignant cells may hatnper clearance of and a large number of homosexuals having other immune complexes (Elkon et al., 1979), but others concurrent infections was not ruled out. favour a common pathogenesis predisposing to the Vasculitis in man has been associated with a variety development of both disorders (Goedert et al., 1981). of other viral infections including herpes simplex (Phinney et al., 1982), cytomegalovirus infection Autoantigens and vasculitis in man Autoimmune (Doherty & Bradfield, 1981) and more recently, reactions are frequently associated with vasculitis. human serum parvovirus (Li Loong et al., 1986). Immunoglobulins may act as rheumatoid factors and Bacterial antigens from-several agents including strep- cryoglobulins in diseases such as SLE, rheumatoid tococci (Ingelfinger et al., 1977), staphylococci (Boul- arthritis and bacterial endocarditis (Nydegger, 1985; ton-Jones et al., 1974) and meningococci (Davis et al., Theofilopoulos & Dixon, 1979). In addition, the 1976) have also been implicated. Both antigen and participation of idiotype - anti-idiotype complexes in specific antibody have been found in lesions (Nydeg- immune complex mediated disease opens up new ger, 1985). In such infections, the immune response of possibilities (Kunkel, 1984). In one study of patients the host may play a major role in determining the with mixed essential cryoglobulinaemia, the IgM pathological manifestations: in subacute bacterial monoclonal component reacted with the F(ab)2 frag-

endocarditis complexes were mainly found in patients ments of the IgG. The cryoglobulin contained copyright. with disease of longer duration and with marked antibodies to HbsAg which was found to inhibit systemic manifestations (Bayer et al., 1977). binding between the cryoglobulin IgM and the F(ab)2 In Kawasaki disease (mucocutaneous lymph node of IgG. HbsAg was not inhibitory for cryoglobulins syndrome) there is indirect evidence that an as yet lacking hepatitis antibodies (Geltner et al., 1980), unidentified infective organism may provoke the implying that some cryoglobulins contain idiotype - vasculitic illness; a feverish phase is followed in the anti-idiotype immune complexes. third week by thrombocytosis, increased platelet

aggregation, serotonin release and circulating immune (d) Summary ofthe role ofimmune complexes in the http://pmj.bmj.com/ complexes. The latter may be responsible for the pathogenesis ofvasculitis platelet aggregation (Levin et al., 1985). There are many similarities between the manifestations of this Animal models of vasculitis suggest that immune disease and serum sickness. complexes may play a central role in pathogenesis. Several human diseases associated with vasculitis Drugs and vasculitis Several drugs have been (particularly the secondary vasculitides) are accom- associated with the development of vasculitis, includ- panied by striking serological abnormalities which ing iodine (Rich & Gregory, 1943), sulphonamides support these concepts. The pathogenesis of the on September 27, 2021 by guest. Protected (Rose & Spender, 1957), penicillin (Waugh, 1952), primary vasculitides (e.g. polyarteritis and Wegener's and, more recently alclofenac (Billings et al., 1974). granulomatosis) are less easy to explain in this way Vasculitis has also followed vaccination with inac- since immunological abnormalities, whilst present, are tivated influenza virus (Blumberg et al., 1980) and less striking. The association between vasculitis, desensitizing injections for atopic respiratory disease hepatitis B and some bacterial antigens, suggests that (Phanuphak & Kohler, 1980). However, a major infectious agents could be implicated in the aetiology problem with these observations is determining of vasculitic syndromes. The reasons for the pattern whether a drug was given for early manifestations of and severity of tissue involvement in each particular the vasculitis or whether it played a truly causative disease remain unclear, and the target of immune role; similarly, a cause and effect relationship between injury within the vessel wall itself is unknown. vaccination, desensitizing injections and vasculitis has not been proven. Direct antibody attack There is evidence that cell specific autoantibodies may 632 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 contribute to pathogenesis of tissue injury in some (a) Cellular mechanisms in Iymphocyte-predominant vasculitic diseases. Such mechanisms may also be vasculitis considered as 'in situ' complex formation with antibody binding to autologous antigens, but they will Some types ofvasculitis are characterized by a perivas- be discussed separately from the previous section, cular lymphocyte and macrophage infiltrate (Soter & since they raise some interesting points. Austen, 1980) with few, if any, accompanying neutro- In SLE, IgG anti-endothelial antibodies have been phils which are so characteristic of the immune demonstrated (Cines et al., 1984) which can fix C3 and complex-induced serum sickness of vasculitis. The release PGI2 from endothelial cells with subsequent lymphocyte-predominant type of vasculitis is par- adherence of platelets. It has been suggested, but not ticularly associated with cutaneous vasculitides (Soter proven, that D/DR antigens are the target antigen & Austen, 1980) but may be observed in human since both B cells and monocytes can adsorb out the systemic vasculitis (McCluskey & Fienberg, 1983) and activity. Such surface-bound IgG could potentially it has been suggested by some investigators that non- attract leucocytes to the vessel wall allowing a variety immune complex mediated mechanisms ofinjury may of mediators of tissue injury to participate. be involved (Moyer & Reinisch, 1984). Thus the role of Autoantibodies have also been found in Wegener's endothelial and smooth muscle cells in promoting the granulomatosis (van der Woude et al., 1985; Jones & lymphocyte influx is under investigation. Lockwood, unpublished observations) which appear Endothelial cells have the potential to play an active to be directed towards extranuclear components of role in the induction of vasculitis since not only may granulocytes and monocytes. The significance of such they share surface determinants with various antibodies for the pathogenesis of the small vessel haemopoietic cell lines (see above) (Ryan et al., 1981; vasculitis and the granulomatous reaction found in Hirschberg et al., 1979), but they are also capable of Wegener's, is unclear at the present time. However, it behaving as antigen presenting cells (Hirschberg et al., is interesting that intravascular lysis of leucocytes has 1980). In one study BALB/c splenic lymphocytes were been described as an early event in the process oftissue activated by co-culturing in vitro and in vivo with an injury (Donald et al., 1976); the lysis was followed by endothelial mouse cell line (ME-2 cells); the lym- platelet aggregation and fibrin deposition in vessels phocytes underwent proliferation and were then injec- with intact endothelial cells. ted intravenously into syngeneic mice who developedcopyright. The detection of antibodies to granulocytes and vasculitis in the lungs, brain and other organs. It was monocytes is intriguing in view of the demonstration, suggested that endothelial cell antigens (cross-reactive using monoclonal antibodies, of shared antigens bet- between ME-2 cells and BALB/c endothelial cells) ween blood monocytes, granulocytes, tissue macro- were able to sensitize the splenic lymphocytes which, phages and some types ofendothelial cells (Hogg et al., following injection into the host, were able to by-pass 1984; Knowles et al., 1984). Endothelial cells and suppressor mechanisms and recruit host cells to

macrophages were found to share unique non-HLA- amplify vascular injury (Hart et al., 1983). http://pmj.bmj.com/ DR antigens not expressed on B lymphocytes or other It has also been proposed that vascular smooth tissues which may have important implications for muscle cells (VSMC) may play an active role in lymphocyte-endothelial cell interaction (see below). In recruiting lymphocytes (Moyer & Reinisch, 1984). In other studies, the monoclonal antibody OKM5, showed vitro studies of VSMCs and splenocytes from the that antigenically distinct types ofendothelial cell were MRL/lpr mouse, which is particularly prone to present within one organ, namely the kidney; OKM5 develop arteritis, showed that the VSMCs were able to was reactive with renal medullary, but not cortical, stimulate a mononuclear inflammatory cell phlogistic small vessel endothelial cells, and was unreactive with response, culminating in VSMC autodestruction. The on September 27, 2021 by guest. Protected glomerular capillary endothelial cells (Knowles et al., VSMCs from these autoimmune mice spontaneously 1984). Such observations suggest tissue specificity of express Ia (which could promote T-cell sensitization to the vasculitic process may partly depend on the surface 'self' antigens) and released an interleukin-l-like factor molecules which endothelial cells carry, and that these (which could encourage a lymphoid influx into the may vary both between and within organs. vascular site). Preliminary studies in humans suggest lymphocytes Cellular mechanisms may play a role in certain types of vasculitis. Thus, increased lymphocyte mediated cytotoxicity to "'in- The role of particular cell types namely endothelial dium-labelled human endothelial cells was observed in cells, vascular smooth muscle cells, eosinophils and 7 patients with giant cell arteritis and Takayasu's lymphocytes will be discussed. It is likely that macro- disease, whilst serum mediated cytotoxicity (e.g. phages are also involved, particularly in the gran- mediated by oxidized lipoproteins) was increased in 7 ulomatous vasculitic disorders, but information on the patients with systemic necrotizing vasculitis (Scott et nature of their participation is scant. al., 1984). MAJOR SYSTEMIC VASCULITIDES 633 Postgrad Med J: first published as 10.1136/pgmj.62.729.627 on 1 July 1986. Downloaded from

(b) The role of eosinophils in vasculitis blood vessels (Sergent, 1980). Turkeys injected with mycoplasma gallisepticum develop cerebral arteritis The Churg-Strauss syndrome is characterized by which seems to be mediated by mycoplasma toxins hypereosinophilia and a granulomatous vasculitis (Thomas et al., 1966). Necrotizing arteritis may occur (Churg & Strauss, 1952). Activated and degranulated in rats with spontaneous hypertension and the vas- eosinophils have been seen migrating towards the cular lesions may contain immunoglobulin (Ohta et granulomatous lesions which have been found to al., 1959). contain large amounts of eosinophil cationic protein and eosinophil protein-X (which are toxic to many cells and tissues) (Tai et al., 1984). Raised IgE levels Conclusions are found in some patients with the syndrome which may trigger eosinophils to take part in cytotoxic The aetiology and pathogenesis ofvasculitis and ofthe reactions (Conn et al., 1976) via their recently demon- primary systemic vasculitides in particular, remain strated IgE receptors (Capron et al., 1981). Thus it is largely speculative - progress has been hampered by possible that eosinophils play a central role in the the considerable clinical and pathological overlap pathogenesis of this granulomatous vasculitis and the between many of the syndromes. The animal models severity of the disease may be partly related to the of serum sickness and the Arthus reaction have been extent of eosinophil degranulation in tissues. helpful in understanding certain aspects of the path- Wegener's granulomatosis is also a granulomatous ogenesis ofthese disorders but many gaps and incons- vasculitis in which elevated IgE levels have been istencies remain. It is likely that both humoral and reported (Conn et al., 1976) but a role for eosinophils, cellular mechanisms mediate tissue injury but if any, in this disease has not yet been substantiated. specificity must develop at some point to allow a patient with say, polyarteritis nodosa to be differen- tiated from one with Wegener's granulomatosis. Non-immuno-pathogenetic mechanisms. Non-immunological mechanisms may cause vas- Acknowledgements copyright. culitis, including necrotizing arteritis. Ence- phalomyocarditis ofmice is probably caused by direct COSS and YCN acknowledge the support of the Medical infection of vascular elements by virus, and viral Research Council, the critical comments of Professor D.K. particles have been demonstrated in and around the Peters and the secretarial assistance of Miss Sue Goodwin.

References

BAART DE LA FAILLE-KUYPER, E.H., KATER, L., KOOIKER, GUNNAR, S., JOHANSSON, 0. & PRIN, L. (1981). Fc http://pmj.bmj.com/ C.J. & MEES, E.J.D. (1973). IgA-deposits in cutaneous receptors for IgE on human and rat eosinophils. Journal of blood-vessel walls and mesangium in Henoch-Schonlein Immunology, 126, 2087. syndrome. Lancet, i, 479. CHUMBLEY, L.C., HARRISON, E.G., DEREMEE, R.A. (1977). BAYER, A.S., THEOFILOPOULOS, A.N., EISENBERG, R., Allergic granulomatosis and angiitis (Churg-Strauss syn- FRIEDMAN, S.G. & GUZE, L.B. (1977). Thrombotic throm- drome). Report and an analysis of 30 cases. Mayo Clinic bocytopenia purpura-like syndrome associated with infec- Proceedings, 52, 477. tive endocarditis. A possible immune complex disorder. CHURG, J. & STRAUSS, L. (1952). Allergic granulomatosis,

Journal of the American Medical Association, 238, 408. allergic angiitis and periarteritis nodosa. American Journal on September 27, 2021 by guest. Protected BILLINGS, S., BURRY, H.C., EMSLIE, F.S. & KERR, G.D. ofPathology, 27, 277. (1974). Vasculitis with alclofenac therapy. British Medical CINES, D.B., LYSS, A.P., BINA, M., CORKEY, R., KEFALIDES, Journal, 4, 263. N.A. & FRIEDMAN, H.M. (1982). Fc and C3 receptors BLUMBERG, S., BIENFANG, D. & KANTROWITZ, F.G. induced by herpes simplex virus on cultured human (1980). A possible association between influenza vaccina- endothelial cells. Journal ofClinical Investigation, 69, 123. tion and small-vessel vasculitis. Archives of Internal CINES, D.B., LYSS, A.P., REEBER, M. BINA, M., DE- Medicine, 140, 847. HORATIUS, R.J. (1984). Presence of complement-fixing BOULTON-JONES, J.M., SISSONS, J.G.P., EVANS, D.J. & anti-endothelium cell antibodies in systemic lupus eryth- PETERS, D.K. (1974). Renal lesions of subacute infective ematosus. Journal of Clinical Investigation, 73, 611. endocarditis. British Medical Journal, 2, 11. CLARK, E. & KAPLAN, B.J. (1937). Endocardial, arterial and BRAATHEN, L.R., FORRE, C.T., HUSBY, G. & WILLIAMS, other mesenchymal alterations associated with serum R.C. JR. (1979). Evidence for Fc IgG receptors and sickness disease in man. Archives of Pathology, 24, 458. complement factor C3b receptors in human choroid COCHRANE, C.G., WEIGLE, W.O. & DIXON, F.J. (1959). The plexus. Clinical Immunology and Immunopathology, 14, role ofpolymorphonuclear leukocytes in the initiation and 284. cessation of the Arthus reaction. Journal ofExperimental CAPRON, M., CAPRON, A., DESSAINT, J.-P., TORPIER, G., Medicine, 110, 481. 634 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

COCHRANE, C.G. (1985). In The Inflammatory Process, ofInternal Medicine, 98, 76. Zweifach, B.W., Grant, L., McCluskey, R.T. (eds). p. 613. FEARON, D.T. (1984). Cellular receptors for fragments ofthe Academic Press: New York. third component of complement. Immunology Today, 5, COCHRANE, C.G. & KOFFLER, D. (1973). Immune complex 105. disease in experimental animals and man. Advances in FLIGIEL, S.E.G., WARO, P.A., JOHNSON, K.J. & TILL, G.O. Immunology, 16, 185. (1984). Evidence for a role ofhydroxyl radical in immune- COHEN, R.D., CONN, D.L. & ILSTRUP, D.M. (1980). Clinical complex-induced vasculitis. American Journal of Path- features, prognosis and response to treatment in polyar- ology, 115, 375. teritis. Mayo Clinic Proceedings, 55, 146. FRANK, M.M., HAMBURGER, M.L., LAWLEY, T.J., KIM- CONN, D.L., McDUFFIE, F.C. & DYCK, P.J. (1972). Immun- BERLEY, R.P. & PLOTZ, R.H. (1979). Defective reticuloen- opathologic study of sural nerves in rheumatoid arthritis. dothelial system Fc-receptor function in systemic lupus Arthritis and Rhewnatism, 15, 135. erythematosus. New England Journal of Medicine, 300, CONN, L.C., McDUFFIE, F.C., HOLLEY, K.E. & SCHROETER, 518. A.L. (1976). Immunologic mechanisms in systemic vas- FRANK, M.M., LAWLEY, T.J., HAMBURGER, M.I. & BROWN, culitis. Mayo Clinic Proceedings, 51, 511. J. (1983). Immunoglobulin G Fc receptor-mediated CORNACOFF, J.B., HERBERT, L.A., SMERD, W.L., VAN- clearance in autoimmune diseases. Annals of Internal AMAN, M.E., BIRMINGHAM, D.J. &WAXMAN, F.J. (1983). Medicine, 98, 206. Primate erythrocyte-immune complex-clearing mechan- FRANKLIN, E.C. (1980). The role of cryoglobulins and ism. Journal of Clinical Investigation, 71, 236. immune complexes in vasculitis. Journal of Allergy and COUNAHAN, R., WINTERBORN, M.H., WHITE, R.H.R., Clinical Immunology, 66, 269. HEATON, J.M., MEADOW, S.R., BLUETT, N.H. & SWETS- FYE K.H., BECKER, M.J., THEOFILOPOULOS, A.N., MOUT- CHIN, H. (1977). Prognosis ofHenoch-Schonlein nephritis SOPOULOS, H., FELDMAN, J.-L., & TALAL, N. (1977). in children. British Medical Journal, 2, 11. Immune complexes in hepatitis B antigen-associated CUPPS, T.R. & FAUCI, A.S. (1982). The vasculitic syndromes. periarteritis nodosum. Detection by antibody-dependent Advances in Interrial Medicine, 27, 315. cell-mediated cytotoxicity and the Raji cell assay. CZOP, J. & NUSSENZWEIG, V. (1976). Studies on the American Journal ofMedicine, 62, 783. mechanism of solubilisation of immune precipitates by GELTNER, D., FRANKLIN, E.C. & FRANGISNE, B. (1980). serum. Journal ofExperimental Medicine, 143, 615. Antiidiotypic activity in the IgM fractions of mixed DAVIS, J.A.S., PETERS, N., MOHAMMED, I., MAJOR, G.A.C. & cryoglobulins. Journal ofImmunology, 125, 1530. HOLBOROW, E.J. (1976). Circulating immune complexes F.G. A GERMUTH, (1953). comparative histologic and copyright. in a patient with meningococcal disease. British Medical immrnunologic study in rabbits of induced hypersensitivity Journal, 1, 1445. of the serum sickness type. Journal of Experimental DIXON, F.J., VAZQUEZ, J.J., WEIGLE, W.O. & COCHRANE, Medicine, 97, 257. C.G. (1958). Pathogenesis of serum sickness. Archives of GOCKE, D.J., HSU, K., MORGAN, C., BOMBARDIERI, S., Pathology, 65, 18. LOCKSHIN, M. & CHRISTIAN, C.L. (1970). Association DOHERTY, M. & BRADFIELD, J.W.B. (1981). Polyarteritis between polyarteritis and Australia antigen. Lancet, H, nodosa associated with acute cytomegalovirus infection. 1149. Annals ofRheumatic Diseases, 40, 419. GOEDERT, J.J., NEEFE, J.R., SMITH, F.S., STAHL, N.I.,

DONALD, K.J., EDWARDS, R.L. & McEVOY, J.D.S. (1976). An JAFFE, E.S. & FAUCI, A.S. (1981). Polyarteritis nodosa, http://pmj.bmj.com/ ultrastructural study ofthe pathogenesis oftissue injury in hairy cell leukaemia and splenosis. American Journal of limited Wegener's granulomatosis. Pathology, 8, 161. Medicine, 71, 323. DUFFY, J., LIDSKY, M.D., SHARP, J.T., DAVIS, J.S., PERSON, GOREVIC, P.D., KASSAB, H.J., LEVO, Y., KOHN, R., MELT- D.A., HOLLINGER, F.B. & MIN, K.W. (1976). Polyarthritis, ZER, M., PROSE, P. & FRANKLIN, E.C. (1980). Mixed polyarteritis and hepatitis B. Medicine (Baltimore), 55, essential cryoglobulinaemia: clinical aspects and long-term 19-37. follow-up of40 patients. American JournalofMedicine, 69, ELKON, K.B., HUGHES, G.R.V., CATOVSKY, D., CLAUVEL, 287. J.P., DUMONT, J., SELIGMAN, M. & TANNENBAUM, H. HAMBURGER, M.I., LAWLEY, T.J., KIMBERLY, R.P., PLOTZ, (1979). Hairy-cell leukaemia with polyarteritis nodosa. P.H. & FRANK, M.M. (1982). A serial study of splenic on September 27, 2021 by guest. Protected Lancet, ii, 280. reticuloendothelial system Fc receptor functional activity ELKON, K.B., SEWELL, J.R., RAYAN, P.F.J. & HUGHES, in systemic lupus erythematosus. Arthritis and Rheumat- G.R.V. (1980). Splenic function in non-renal systemic lupus ism, 25, 48. erythematosus. American Journal ofMedicine, 69, 80. HART, M.N., SADEWASSER, K.L., CANCILLA, P.A., DE- EWAN, P.W., WATERSON, A.P. & PETERS, D.K. (1981). An 8 BAULT, L.E. (1983). Experimental autoimmune type of year survey ofhepatitis B antigen in a hospital population. vasculitis resulting from activation of mouse lymphocytes In Systemic Effects ofHBsAg Immune Complexes, Bartol, to cultured endothelium. Laboratory Investigation, 48,419. E., Chiandussi, L. & Sherlock, S. (eds). p. 1. Piccin Medical HENSON, J.B. & GORHAM, J.R. (1973). Animal model of Books: Padova. human disease: persistent viral infections, immunological- FAUCI, A.S., HAYNES, B.F. & KATZ, P. (1978). The spectrum ly mediated glomerulonephritis and arteritis, dysgam- of vasculitis, clinical, pathologic, immunologic and mopathies. American Journal ofPathology, 71, 345. therapeutic considerations. Annals of Internal Medicine, HENSON, P.M. (1982). Antibody and immune-complex- 89, 660. mediated allergic and inflammatory reactions. In Clinical FAUCI, A.S., HAYNES, B.F., KATZ, P. & WOLFF, S.M. (1983). Aspects of Immunology, Lachmann, P.J., Peters, D.K. Wegener's granulomatosis: prospective clinical and (eds). p. 687, 4th Edition. Blackwell Scientific Publica- therapeutic experience with 85 patients for 21 years. Annals tions: Oxford. MAJOR SYSTEMIC VASCULITIDES 635 Postgrad Med J: first published as 10.1136/pgmj.62.729.627 on 1 July 1986. Downloaded from

HIRSCHBERG, H., MOEN, T. & THORSBY, T. (1979). Specific graduate Medical Journal, 62, 35. destruction ofhuman endothelial cell monolayers by anti- LEVIN, M., HOLLAND, P.C., NOKES, T.J.C., NOVELLI, V., DRW antisera. Transplantation, 28, 116. MOLA, M., LEVINSKY, R.J., DILLON, M.J. & BARRATT, HIRSCHBERG, H., BERGH, O.J. & THORSBY, E. (1980). T.M. (1985). Platelet immune complex interaction in Antigen presenting properties of human vascular endoth- pathogenesis of Kawasaki disease and childhood polyar- elial cells. Journal ofExperimental Medicine, 152, 249S. teritis. British Medical Journal, 290, 1456. HOGG, N., MACDONALD, S., SLUSARENKO, M. & BE- LEVO, Y., GOREVIC, P.D., KASSAT, H.J., ZUCKER-FRANK- VERLEY, P.C.L. (1984). Monoclonal antibodies specific for LIN, D. & FRANKLIN, E.C. (1977). Association between human monocytes. Granulocytes and endothelium. Im- hepatitis B virus and essential mixed cryoglobulinaemia. munology, 53, 753. New England Journal ofMedicine, 298, 126. HORGAN, C., BURGE, J., CRAWFORD, L. & TAYLOR, R.P. LOCKWOOD, C.M., WORLLEDGE, S., NICHOLAS, A., COT- (1984). The kinetics of 3H-DSDNA/anti-DNA immune TON, C. & PETERS, D.K. (1979). Reversal of impaired complex formation. Binding by red cells and release into splenic function in patients with nephritis or vasculitis (or serum: Effect ofDNA molecular weight and conditions of both) by plasma exchange. New England Journal of antibody excess. Journal ofImmunology, 133, 2079. Medicine, 300, 524. IIDA, K., MORNAGHI, R. & NUSSENZWEIG, V. (1982). CR1 LI LOONG, T.C., COYLE, P.V., ANDERSON, M.J., ALLEN, G.E. deficiency in red cells from patients with systemic lupus & CONNOLLY, J.H. (1986). Human serum parvovirus erythematosus. Journal of Experimental Medicine, 155, associated vasculitis. Postgraduate Medical Journal, 62, 1427. 493. INGELFINGER, J.R., McCLUSKEY, R.T., SCHNEEBERGER, MATSUO, S., CALDWELL, P.R.B., BRENTJENS, J.R. & E.E. & GRUPE, W.E. (1977). Necrotizing arteritis in acute ANDREAS, G. (1985). In vivo interaction ofantibodies with poststreptococcal glomerulonephritis. Pediatrics, 91, 228. cell surface antigens. A mechanism responsible for in situ INMAN, R.D., FUNG, J.K.K., PUSSELL, B.A., RYAN, P.J. & formation of immune deposits in the zona pellucida of HUGHES, G.R.V. (1980). The Clq binding assay in sys- rabbit oocytes. Journal of Clinical Investigation, 75, 1369. temic lupus erythematosus. Discordance with disease McCLUSKEY, R.T. & FIENBERG, R. (1983). Vasculitis in activity. Arthritis and Rheumatism, 23, 1282. primary vasculitides, granulomatoses, and connective tis- IZUI, S., LAMBERT, P.-H. & MIESCHER, A. (1976). In vitro sue diseases. Human Pathology, 14, 305. demonstration of a particular affinity of glomerular McCOMBS, R.P. (1985). Systemic "allergic" vasculitis. Clin- basement membrane and collagen for DNA. A possible ical and pathological relationships. Journal of the a basis for local formation of DNA-anti-DNA complexes American Medical Association, 194, 1059. copyright. in systemic lupus erythematosus. Journal ofExperinental MEDOF, M.E., PRINCE, G.M. & MOLD, C. (1982). Release of Medicine, 144, 428. soluble immune complexes from immune adherence recep- KABBASH, L., BRANDWEIN, S., ESDAILE, J., DANOFF, D., tors on human red blood cells is mediated by C3b FUKS, A. & SHUSTER, J. (1982). Reticuloendothelial inactivator independent of BIH and accompanied by system Fc receptor function in systemic lupus eryth- generation ofC3c. Proceedings ofthe National Academy of ematosus. Journal ofRheumatology, 9, 374. Sciences of the USA, 79, 5047. KIMBERLEY, R.P., GIBOVSKY, A., SALMON, J.E. & FOTINO, MIYAKAWA, Y., YAMEDA, A. & KOSAKA, K. (1981). M. (1983). Impaired Fc-mediated mononuclear phagocyte Defective immune adherence (C3b) receptor on red cells

system clearance in HLA-DR2 and MTI-positive healthy from patients with systemic lupus erythematosus. Lancet, http://pmj.bmj.com/ young adults. Journal ofExperimental Medicine, 157,1698. i, 493. KNOWLES, D.M., TOLIDJIAN, B., MARBOE, C., D'AGATI, V., MOYER, C.F. & REINISCH, C.L. (1984). The role of vascular GRIMES, M. & CHESS, L. (1984). Monoclonal anti-human smooth muscle cells in experimental autoimmune vas- monocyte antibodies OKM1 and OKM5 possess distinc- culitis. I. The initiation of delayed type hypersensitivity tive tissue distributions including differential reactivity angiitis. American Journal ofPathology, 117, 380. with vascular endothelium. Journal of Immunology, 132, NYDEGGER, U.E. & LAMBERG, P.H. (1980). The role of 2170. immune complexes in the pathogenesis of necrotizing KUNKEL, H.G. (1984). In Idiotypy in Biology and Medicine, vasculitides. Clinics in Rhewnatic Diseases, 6, 255. on September 27, 2021 by guest. Protected 1st Edition, Kohler, H., Urbain, H. & Cazenave, P.-A. NYDEGGER, U.E. (1985). A place for soluble immune (eds). p.429. Academic Press: London. complexes in clinical immunology. Immunology Today, 6, LAMBERT, P.H., DIXON, F.J., ZUBLER, R.H. AND MEMBERS 80. OF THE STUDY GROUP (1978). WHO collaborative study OHTA, G., COHEN, S., SINGER, E.J., ROSENFIELD, R. & for the evaluation of eighteen methods for detecting STRAUSS, L. (1959). Demonstration ofgamma globulin in immune complexes in serum. Journal of Clinical and vascular lesions ofexperimental necrotizing arteritis in the Laboratory Immunology, 1, 1. rat. Proceedings of the Society for Experimental Biology LAWLEY, T.J., HALL, R.P., FAUCI, A.S., KATZ, S.I., HAM- and Medicine, 102, 187. BURGER, M.L. & FRANK, M.M. (1981). Defective Fc PERESS, N.S., ROXBURGH, V.A. & GELFAND, M.C. (1981). receptor functions associated with the HLA-B8 DRW3 Binding sites for immune components in human choroid haplotype. New England Journal of Medicine, 304, 185. plexus. Arthritis and Rheumatism, 24, 520. LAWLEY, T.J., BIELORY, L., GASCON, P., YANCEY, K.B., PHANUPHAK, P. & KOHLER, P.F. (1980). Onset of polyar- YOUNG, N. & FRANK, M.M. (1984). A prospective clinical teritis nodosa during allergic hyposensitization treatment. and immunologic analysis ofpatients with serum sickness. American Journal of Medicine, 68, 479. New England Journal of Medicine, 311, 1407. PHINNEY, P.R., FLIGIEL, S., BRYSON, Y.J. & PORTER, D.D. LEUNG, A.T.C., McLAY, A. & BOULTON-JONES, J.M. (1986). (1982). Necrotizing vasculitis in a case of disseminated Polyarteritis nodosa and monocytic leukaemia. Post- neonatal herpes simplex. Archives of Pathology and Postgrad Med J: first published as 10.1136/pgmj.62.729.627 on 1 July 1986. Downloaded from 636 C.O.S. SAVAGE & Y.C. NG

Laboratory Medicine, 106, 64. (1984). Vasculitis affecting the kidney: presentation, his- PINCHING, A.J., LOCKWOOD, C.M., PUSSELL, B.A., REES, topathology and long-term outcome. Quarterly Journal of A.J., SWENY, P., EVANS, D.J. & BOWLEY, N. (1983). Medicine, 53, 181. Wegener's granulomatosis: observations on 18 patients SOTER, N.A. & AUSTEN, K.F. (1980). Pathogenetic mechan- with severe renal disease. Quarterly Journal of Medicine, isms in the necrotizing vasculitides. Clinics in Rheumatic 52, 435. Diseases, 6, 233. PUSSELL, B.A., LOCKWOOD, C.M., SCOTT, D.M., PINCHING, SWAAK, A.J.G., VAN DER KORST, J.K., HOEFNAGEL, C.A., A.J. & PETERS, D.K. (1978). Value of immune-complex BOOM, F.A. & MARCUSE, H.R. (1984). The clearance of assays in diagnosis and management. Lancet, ii, 359. heat-damaged erythrocytes by the reticulo-endothelial RAPOPORT, R.J., KOZIN, F., MACKEL, S.E. & JORDON, R.E. system in systemic lupus erythematosus and rheumatoid (1980). Cutaneous vascular immunofluorescence in arthritis. Rheumatology International, 4, 177. rheumatoid arthritis: correlation with circulating immune TAI, P.-C., HOLT, M.E., DENNY, P., GIBBS, A.R., WILLIAMS, complexes and vasculitis. American Journal of Medicine, B.D. & SPRY, C.J.F. (1984). Deposition of eosinophil 68, 325. cationic protein in granulomas in allergic granulomatosis RICH, A.R. & GREGORY, J.E. (1943). The experimental and vasculitis: The Churg-Strauss syndrome. British demonstration that periarteritis nodosa is a manifestation Medical Journal, 289, 400. ofhypersensitivity. Bulletin ofthe Johns Hopkins Hospital, TAN, E.M. & KUNKEL, J.G. (1966). An immunofluorescent 72, 65. study of the skin lesions in systemic lupus erythematosus. RONCO, P., VERROUST, P., MIGNON, F., KOURILSKY, O., Arthritis and Rheumatism, 9, 37. VANHILLE, P., MEYRIER, A., MERY, J.P. & MOREL- THEOFILOPOULOS, A. & DIXON, F.J. (1979). The biology MAROGER, L. (1983). Immunopathological studies of and detection of immune complexes. Advances in Immun- polyarteritis nodosa and Wegener's granulomatosis: A ology, 28, 89. report of 43 patients and 51 renal biopsies. Quarterly THOMAS, L., DAVIDSON, M. McCLUSKEY, R.T. (1966). Journal ofMedicine, 52, 212. Studies of PPLO infection. I. The production of cerebral ROSE, G.A. & SPENCER, H. (1957). Polyarteritis nodosa. polyarteritis by mycoplasma gallisepticum in turkeys: the Quarterly Journal ofMedicine, 26, 43. neurotoxic property of the mycoplasma. Journal of Ex- ROTHBERGER, H., ZIMMERMAN, T.S., SPIEGELBERG, H.L. perimental Medicine, 123, 897. & VAUGHAN, J.H. (1977). Leucocyte procoagulant TREPO, C.G. & THIVOLET, J. (1970). Hepatitis associated activity. Enhancement of production in vitro by IgG and antigen and periarteritis nodosa (PAN). Vox Sanguinis, 19,

antigen-antibody complexes. Journal ofClinical Investiga- 410. copyright. tion, 59, 549. TREPO, C.G., ZUCKERMAN, A.J., BIRD, R.C. & PRINCE, A.M. RYAN, U.S., SCHULTZ, D.R. & RYAN, J.W. (1981). Fc and (1974). The role ofcirculating hepatitis B antigen/antibody C3b receptors on pulmonary endothelial cells: induction immune complexes in the pathogenesis of vascular and by injury. Science, 214, 557. hepatic manifestations in polyarteritis nodosa. Journal of SAMS, W.M., HARVILLE, D.D. & WINKELMAN, R.K. (1968). Clinical Pathology, 27, 863. Necrotising vasculitis associated with lethal reticuloen- VAN DER WOUDE, F.J., RASMUSSEN, N., LOBATTO, S., WIIK, dothelial diseases. British Journal ofDermatology, 80, 555. A., PERMIN, H., VAN ES, L.A. & VAN DER GIESSEN, M. SAVAGE, C.O.S., WINEARLS, C.G., EVANS, D.J., REES, A.J. & (1985). Autoantibodies against neutrophils and mon-

LOCKWOOD, C.M. (1985). Microscopic polyarteritis: ocytes: tool for diagnosis and marker ofdisease activity in http://pmj.bmj.com/ presentation, pathology and prognosis. Quarterly Journal Wegener's granulomatosis. Lancet, i, 425. ofMedicine, 56, 467. WALPORT, M.J., ROSS, G.D., MACKWORTH-YOUNG, C., SCHIFFERLI, J.A., WOO, P. & PETERS, D.K. (1982). Com- WATSON, J., HOGG, N. & LACHMANN, P.J. (1985). Family plement-mediated inhibition of immune precipitation. I. studies of erythrocyte complement receptor Type I levels: Role of classical and alternative pathways. Clinical and reduced levels in patients with SLE are acquired, not Experimental Immunology, 47, 555. inherited. Clinical and Experimental Immunology, 59, 547. SCHIFFERLI, J.A. & PETERS, D.K. (1983). Complement. The WAUGH, D. (1952). Myocarditis, arteritis and focal hepatic, immune complex lattice and the pathophysiology of splenic and renal granulomas apparently due to penicillin on September 27, 2021 by guest. Protected complement-deficiency syndromes. Lancet, ii, 957. sensitivity. American Journal of Pathology, 28, 437. SCOTT, D.G.I., BACON, P.A., ELLIOTT, P.J., TRIBE, C.R. & WILLIAMS, A.J., NEWLAND, A.C. & MARCH, F.P. (1985). WALLINGTON, T.B. (1982). Systemic vasculitis in a district Acute renal failure with polyarteritis nodosa and multiple general hospital 1972-1980: Clinical and laboratory myeloma. Postgraduate Medical Journal, 62, 445 features. Classification and prognosis of80 cases. Quarter- WILLIAMS, B.D., PUSSELL, B.A., LOCKWOOD, C.M. & COT- ly Journal ofMedicine, 51 292. TON, C. (1979). Defective reticuloendothelial system func- SCOTT, D.G.I., BLAKE, D.R., BLANN, A., SALMON, M., tion in rheumatoid arthritis. Lancet, i, 131 1. BRAILSFORD, S., WINYARD, P. & BACON, P.A. (1984). The ZUBLER, R.H., BYDEGGER, U., PERRIN, L.H., McCORMICK, role of lymphocytes and serum factors in vasculitic dis- J., LAMBERT, P.H. & MIESCHER, P.A. (1976). Circulating eases. (Abst). Annals of Rheumatic Disease, 43, 116. and intraarticular immune complexes in patients with SERGENT, J.A. (1980). Vasculitides associated with viral rheumatoid arthritis. Correlation of '251-Clq binding infections. Clinics in Rhewnatic Diseases, 6, 339. activity with clinical and biological features ofthe diseases. SERRA, A., CAMERON, J.S., TURNER, D.R., HARTLEY, B., Journal of Clinical Investigation, 57, 1308. OGG, C.S., NEILD, G.H., WILLIAMS, D.G. & TAUBE, D.B.