J Clin Pathol: first published as 10.1136/jcp.s3-12.1.132 on 1 January 1978. Downloaded from

J. clin. Path., 31, Suppl. (Roy. Coll. Path.), 12, 132-143

Inflammation and fibrosis Rheumatoid arthritis a disease?

A. M. DENMAN From the Division ofImmunological Medicine, Clinical Research Centre, Harrow, Middlesex

We now understand many of the immunopatho- arteritis with perivascular infiltrates of chronic logical processes that damage joints and other inflammatory cells, and aberrant immune responses. structures in rheumatoid arthritis and diffuse con- Secondly, virus-infected cells initiate the whole nective tissue diseases. Unfortunately, our progress spectrum of inflammatory and immune reactions in this direction is matched by an equal failure to which characterise the human disorders. These identify the causes of all but a few of these disorders. include complement activation by the classical and Nevertheless, the stimuli which initiate these diseases alternative pathways, which in turn initiate such are probably commonly encountered and tissue processes as the immediate hypersensitivity reaction, damage results when these immunopathological platelet aggregation, and the chemotaxis of granulo- processes are abnormal in intensity and duration- cytes and mononuclear phagocytes. Furthermore, in other words, disease follows an unusual host virus-infected cells attract either through reaction to a variety of environmental factors. This virus-coded on the membrane or

principle is well illustrated by the degenerative because infected cells commonly carry receptors for copyright. disease of the central nervous system, subacute the Fc portion of the immunoglobulin molecule. sclerosing panencephalitis, which ensues in in- These cells also attract a cellular response in the dividuals who are unable to control the growth form of both specifically sensitised T lymphocytes and dissemination of measles virus. An equivalent and non-sensitised K cells (Allison, 1974). Thirdly, example in rheumatology is the onset of rheumatic there are various ways in which virus can evade fever and rheumatic carditis in susceptible individ- elimination by the host despite initiating an immune uals exposed to /3-haemolytic streptococci. The response and therebyprovokingimmunopathological central theme in the connective tissue diseases is the damage. There are several mechanisms by which failure of patients with these disorders to limit the virus infection could induce a persistent inflamma- http://jcp.bmj.com/ extent of their response to external insults. In non- tory response in the synovial membrane and these susceptible individuals these produce trivial injury are considered in turn (see Figure). In each case and a short-lived reaction. Conversely, chronic rheumatoid arthritis would result from continued disease ensues when these stimuli are not eliminated interaction between virus infection and the host or the host reaction is uncontrolled. response. Despite intensive efforts, there is no firm evidence that rheumatoid arthritis and other connective tissue to viral Reaction persistent (Fig. a) on October 1, 2021 by guest. Protected diseases result from virus infections (Wilkes et al., 1973; Marmion and Mackay, 1977). The association Arthritis commonly accompanies acute virus in- between virus and polyarteritis nodosa in fections. The simplest mechanism by which a tran- some patients with this disorder remains the only sient infection might be followed by rheumatoid established instance. Moreover, in these attempts arthritis would be when arthrotropic virus persists sophisticated techniques have been used for ident- in the joints of susceptible individuals and thereby ifying latent or defective virus. Nevertheless, reluc- provokes a continued immune response. Also virus tance to abandon this theory is justifiable, mainly might possibly reach the joint from the blood in the because it remains a plausible explanation of most of form of an immune complex formed between viral the clinical and laboratory findings. Firstly, the antigens and antibody. This process has been clearly immunopathological features of experimental viral demonstrated in arthritis after some bacterial in- infections closely resemble those of spontaneous fections. Chronic post-viral arthritis could result if connective tissue diseases in man. These include the host response was unable to eliminate the circulating immune complexes and autoantibodies, original infection. This susceptibility might be 132 J Clin Pathol: first published as 10.1136/jcp.s3-12.1.132 on 1 January 1978. Downloaded from Rheumatoid arthritis-a virus disease ? 133

a b C Fig. Putative mechanisms for the viral pathogenesis ofrheumatoid arthritis. (a) Reaction to viral antigen. (b) Allergic reaction to altered antigen. (c) Reaction to altered membrane. (d) Defective suppressor mechanism. (e) Infected B-lymphocytes. A = Synovial cell antigen. A = Viral antigen. T = T-lymphocyte. B = B-lympho- cyte. + = Immune reaction, T-B co-operation. + + + = Allergic

response. - = Suppressor T-cell copyright. action. (See text for detailed d explanation.) determined by the titre to which virus grew initially than similar cells from resistant mouse strains in the infected joint thereby determining the number (Yoon et al., 1976). In man ethnic variation in of cells carrying viral antigens. resistance to rubella virus is correlated with HLA Genetic factors undoubtedly determine the haplotypes (Honeyman and Mensor, 1974). Similarly immunopathological consequences of virus infection there is an association between certain HLA antigens http://jcp.bmj.com/ in a number of species by regulating the extent and of the B series and the risk of developing hepatitis B distribution of virus replication. This point is well antigenaemia after exposure to this virus (Hillis illustrated by cytomegalovirus infection in different et al., 1977). Moreover, cellular resistance to infec- inbred mouse strains (Olding et al., 1976). In many tion with influenza A virus is influenced by HLA strains this results in an acute infection with wide- type (Spencer et al., 1978). spread tissue injury and death within four weeks of The distribution of infected cells as well as the exposure. Other strains survive the initial infection extent of virus growth also influences the outcome but remain chronically infected and continue to shed of the infection. Thus B lymphocytes have usually on October 1, 2021 by guest. Protected readily detectable virus. The most interesting strains been considered to be the principal if not the are those that remain latently infected with circu- exclusive site of Epstein-Barr (EB) virus persistence. lating immune complexes, causing immune complex However, this virus also grows in epithelial cells in glomerulonephritis, and, occasionally, autoantibodies tissue culture, suggesting that an unusual distri- to DNA. In these strains virus can be detected only bution of it in some individuals could predispose to with difficulty by cocultivating spleen cells with allo- the later development of geneic feeder cells. (Leman et al., 1977). In addition to the well-known In some instances the extent to which virus grows associations between some forms of postinfective in different hosts is governed by histocompatibility arthritis and HLA B27 antigens of the D series have . Thus the pancreatic islet cells of mouse been linked with susceptibility to both rheumatoid strains that are genetically susceptible to the dia- arthritis (Stastny, 1976) and Sjogren's syndrome betogenic effect of encephalo-myocarditis virus (Chused et al., 1977). Thus it is tempting to speculate support the growth of this virus to far greater titres that connective tissue diseases may be related to J Clin Pathol: first published as 10.1136/jcp.s3-12.1.132 on 1 January 1978. Downloaded from

134 A. M. Denman unusual patterns of viral persistence determined by because the immune response may be subverted histocompatibility antigens. However, this is unlikely (Mims, 1974). to be the full explanation. For example, although Thus certain spread from cell to cell antibody titres after rubella immunisation are in part despite the presence of antiviral antibody. The related to HLA antigens, a similar association is not infected cells are not lysed by antiviral antibody and found with joint symptoms in subjects immunised complement and these same viruses induce interferon with this virus (Griffiths, et al., 1977; Spencer et al., poorly and are resistant to the antiviral action of 1977). interferon (Hook et al., 1976). The antibody response The character of the immune response also deter- may itself be rendered ineffective. For example, the mines the outcome of viral infections. The rheuma- interaction of antibody to measles virus with viral toid synovial membrane is densely infiltrated with antigens expressed on the surface of measles- chronic inflammatory cells, mostly T lymphocytes infected cells may lead to these antigens being (Van Boxel and Paget, 1975). An important function deleted. As a result the infected cells are no longer of at least a subpopulation of T lymphocytes is to lysed by antibody and complement acting in com- recognise antigens, and particularly bination (Joseph and Oldstone, 1975). Furthermore, histocompatibility antigens, that have been altered in prolonged virus infections antigenic drift can by virus infection (Doherty and Zinkernagel, 1975). occur so that the initial antibody response against This recognition in turn generates a cytotoxic infected cells becomes progressively ineffective. This reaction which, in several animal models, is extremely change in viral antigenicity has been observed in efficient in limiting virus growth and dissemination Iceland sheep infected with visna in which immuno- although often at the expense of initiating an allergic logical responses were followed for a prolonged reaction that damages the infected cells. Such re- period (Petursson et al., 1976). sponses in man may also be under genetic control The antibody response may not invariably func- since the cell-mediated immune response to vaccinia tion to the advantage of the infected host. It has been virus is related to HLA-Cw3 (de Vries et al., 1977). suggested that by binding to viral antigens antibody It is pertinent to ask why, if the cellular response in prevents sensitised T lymphocytes from making con- rheumatoid arthritis is indeed directed at cells bear- tact with these antigens, thereby blocking their copyright. ing viral antigens at their surface, this response cytotoxic action. This possibility has been extensively should fail to eradicate or control the infectious discussed in relation to the survival of tumour cells. process. Furthermore, other forms of immune In addition, immunoglobulin has been shown to response potentially directed against virus-infected inhibit the growth of by binding cells are also operating in theaffectedtissue(Marmion to Fc receptors on the surface of cells infected with and Mackay, 1977). A variety offactors are known to this virus (Costa et al., 1977). This kind of inter- perpetuate viral infections. Some of these are purely action may limit the expression of viral antigens on in that the cells are the surface of cells and anatomical affected totally latently infected thereby http://jcp.bmj.com/ inaccessible to host responses. This situation clearly reduce the efficiency of a cell-mediated reaction. In obtains in the pathogenesis of virus infections of the addition, antibody may stimulate the growth of virus central nervous system. Even when the responsible in lymphoreticular cells as in dengue virus in- agents are able to elicit an immune response there fections (Halstead et al., 1976; Halstead and may be no local response to the infected cells O'Rourke, 1977). (Oldstone et al., 1977). Other factors are immuno- Other factors may operate to impair the efficiency logical in nature. Severe immunodeficiency dramati- of antiviral reactions mediated by T lymphocytes. It cally predisposes to persistent virus infections and is firmly established that cytotoxic T lymphocytes on October 1, 2021 by guest. Protected patients with agammaglobulinaemia are prone to generated during the course of viral diseases of develop ECHO virus infections of the central nervous mice kill only virus-infected target cells that bear system often accompanied by an inflammatory H2 antigenic specificities common to both the condition resembling dermatomyositis (Wilfert et al., cytotoxic cells and the infected cells (Doherty and 1977). Although it has been suggested that patients Zinkernagel, 1975). There is still some debate about with connective tissue diseases have defective cell- the reason for this restriction. It has been postulated mediated immune responses to viruses (Wolf and that cytotoxic T lymphocytes recognise not specific Ziff, 1976), defects of comparable severity to those viral antigens but histo-compatibility antigens that seen in patients with unequivocal primary immuno- have been modified by virus infection. Considerable deficiency have not been detected. However, this evidence has accrued to support this view. Cells that possibility has not been extensively analysed. More- express viral antigens but lack histocompatibility over, even when virus infection provokes an appar- determinants are not attacked by cytotoxic T ently normal response the infection may persist lymphocytes even though such cells are still sus- J Clin Pathol: first published as 10.1136/jcp.s3-12.1.132 on 1 January 1978. Downloaded from Rheumatoid arthritis-a virus disease ? 135 ceptible to lysis by antibody and complement host to mount an effective immune response against (Zinkernagel and Oldstone, 1976). Similarly only the invading virus is impaired. This principle is those cell lines infected with lymphocytic- illustrated by the results of experiments with street choriomeningitis virus that express H-2 genes are rabies virus (Wiktor et al., 1977). Lethally infected lysed by sensitised T lymphocytes (Doherty et al., mice fail to develop cytotoxic T lymphocytes 1977). The lysis of infected cells by specifically specific for target cells infected with rabies virus, sensitised T lymphocytes seems to be of critical whereas strong reactions ofthis nature are induced in importance during the early stages of at least some mice surviving challenge with attenuated strains of virus infections. T lymphocytes sensitised against rabies virus. The effects on the specific antiviral vaccinia virus appear only in the course of in-vivo response may be long lasting. T lymphocytes speci- infections by this virus and indeed seem to destroy fically cytotoxic for infected cells are not generated infected target cells before infectious virus particles in mice infected with lymphocytic choriomeningitis have been assembled (Zinkernagel and Althage, virus when the potentially responding cells are 1977). exposed to a high level of syngeneic cells infected The requirement for histocompatibility between with this virus (Dunlop and Blanden, 1977). target and effector cells has not been examined as A similarly specific suppression can be demon- systematically in man. However, similar restrictions strated by in-vitro experiments. These findings have been shown with respect to the lysis of human suggest that some viruses that grow in lymphoid cells infected with influenza virus (McMichael, tissues may delete all lymphocytes with the potential et al., 1977) and, albeit less conclusively, by EB ability to generate a cytotoxic response against host virus (Tursz et al., 1977). There is no detailed in- cells infected by this virus, a state equivalent to formation about the pattern of histocompatibility 'clonal deletion' of the responding cells. Induced and other antigens expressed on different cell types defects of this nature could perpetuate virus in- in the rheumatoid synovial membrane. Modulation fections in man. In addition, such defects would make of these antigens by virus or the immune response to it difficult to interpret the results of clinical studies virus could affect the sensitivity of infected cells to designed to incriminate certain viruses in the patho-

cytotoxic mechanisms. genesis of chronic inflammatory diseases. copyright. Virus infections also interfere directly with immune Such studies usually rely on evidence of increased responses and produce a variety of immuno- rather than decreased immune responses to candi- suppressive effects. These are not accounted for by date viruses. Even relatively trivial virus infections the obvious assumption that virus has a simple produce disturbances in circulating lymphocyte cytopathic effect on those lymphocytes whose populations. For example, in normal human sub- function is impaired (Woodruffand Woodruff, 1975). jects infected with wild-type influenza A virus or live, Indeed, even under highly artefactual conditions in attenuated influenza vaccine the numbers of circu- which lymphoreticular cells are exposed to high lating T lymphocytes are greatly depressed (Schein- titres of virus in vitro only a small proportion of berg et al., 1976). The effects of persistent virus http://jcp.bmj.com/ these cells become infected. Thus measles virus infection on functions mediated by T lymphocytes inhibits the reactivity of cultured human lympho- are not confined simply to those involving cytotoxic cytes to several stimuli including plant mitogens, reactions against infected cells. Interferon is secreted tuberculin purified derivate (PPD), and by most populations of lymphoreticular cells, allogeneic lymphocytes. This inhibitory effect is including T lymphocytes, and these populations exerted only in the early stages of culture and the interact synergistically to increase interferon pro-

immunosuppression clearly does not result from a duction (Tsukui, 1977). The capacity of mice to on October 1, 2021 by guest. Protected cytopathic effect of the virus (Lucus et al., 1977). produce interferon in response to interferon in- In-vivo experiments also show a discrepancy be- ducers becomes progressively impaired during the tween the immunosuppressive effects of virus in- course of persistent infections with several viruses fection and obvious depletion of a functionally such as encephalomyocarditis virus and influenza important lymphocyte population. Lactic dehydro- A2 virus (Stringfellow, et al., 1977). genase virus inhibits contact sensitivity to dinitro- Thus there are numerous ways in which viruses fluorobenzene in mice, an immune response evade elimination by the immune response of the mediated by circulating T lymphocytes. Nevertheless, host. This problem is compounded when one con- there is no obvious depletion of T lymphocytes siders the potential survival of defective viruses that during acute infection with this virus (Michaelides infect host cells without producing fully infectious and Simms, 1977). progeny. Cells that are non-productively infected The immuno-suppressive effects of acute virus commonly fail to express surface antigens able to n fection are obviously important if the ability of the elicit an immune response. Defective particles may J Clin Pathol: first published as 10.1136/jcp.s3-12.1.132 on 1 January 1978. Downloaded from 136 A. M. Denman also produce atypical effects in infected cells, phocytes still produce interferon when infected with including the stimulation of host DNA synthesis, lymphocytic choriomeningitis virus (Merigan et al., with resulting growth disorder (de Marchi and 1977). Furthermore, the in-vivorelevanceofinterferon Kaplan, 1977). Mutant viruses with unusual growth to host resistance has been shown by experiments in characteristics often produce atypical immuno- which the virulence of encephalomyocarditis virus pathological sequelae in infected hosts. Thus was greatly increased in mice treated with anti- temperature-sensitive mutants of measles virus interferon serum (Gresser et al., 1976). There are produce a pattern of central nervous system in- other antiviral mechanisms that do not necessarily fection which is atypical in its distribution and long- involve T-lymphocyte cytotoxicity. Lymphoid cells term pathological consequences (Woyceichowska from normal human donors lyse human fibroblasts et al., 1977). Cyclical changes in rheumatoid arthritis infected with cytomegalovirus (Diamond et al., could be accounted for by the irregular appearance of 1977). Again, blood lymphocytes from human viral antigens on infected cells which only inter- volunteers inoculated with vaccinia virus specifically mittently provoke an immune response. kill target cells infected with vaccinia virus. However, Apparently therefore the host humoral and cell- this cytotoxicity shows no restriction to genetically mediated immunity response to virus may fail to related target cells and is mediated by lymphocytes eliminate the infection. Moreover, an ineffective other than T cells. The reaction seems to be mediated immune response may still be responsible for in- by non-sensitised cytotoxic cells (K cells) acting in flicting tissue damage. Nevertheless, it should not be combination with specific antibody (Perrin et al., assumed that the lymphocytes and monocytes that 1977). continue to infiltrate the sites of persistent infection There are also 'natural killer' cells in mice which are exclusively engaged in cytotoxic responses to inactivate cells transformed by that also infected cells. Various lymphocyte populations also do not require to be histocompatible with the target mediate a direct antiviral effect in certain situations. cells (Becker et al., 1976). In addition, some lympho- This applies particularly to EB virus infections. cyte populations limit the growth of some viruses T lymphocytes from the blood of patients with such as myxoviruses by allowing virus to enter the

infectious mononucleosis inhibit the transformation cell but not to complete a full growth cycle: in- copyright. of susceptible cord blood lymphocytes by EB virus fectious progeny are not released (Zisman and (Rickinson et al., 1977) while T lymphocytes from Denman, 1973). normal adults also inhibit the transformation of Little attention has been paid to the possibility mature B lymphocytes by this same virus (Thorley- that the lymphocyte populations that infiltrate the Lawson et al., 1977). It has been suggested that T rheumatoid synovial membrane form part of the lymphocytes from individuals previously exposed to elaborate host response to continued infection and EB virus normally limit the growth of B lympho- that these cells are not exclusively committed to cytes in which the viral has been incorpor- cytotoxic reactions. Attempts at demonstrating that ated (Moss et al., 1977). Although the mechanism by the infiltrating cells are cytotoxic in vitro for fibro- http://jcp.bmj.com/ which T lymphocytes restrict the transforming blasts derived from the rheumatoid synovial mem- activity of EB virus is uncertain, interferon may be brane of the same or other patients have been in- responsible: lymphocytes from subjects sensitised conclusive (Griffiths et al., 1976). Defects in this to the virus by natural infection release material with range of antiviral effects could contribute to viral the characteristics of interferon which inhibits the persistence. ability of EB virus to transform cells (Lai et al.,

1977). Allergic responses to viral antigens (Fig. b) on October 1, 2021 by guest. Protected Lymphocytes sensitised to other viruses such as cytomegalovirus in mice (Rytel and Hooks, 1977) Arthritis often complicates virus infections (Smith and rubella in humans (Buimovici-Klein et al., 1977) and Sanford, 1967; Rahai et al., 1976). Rubella is a also release interferon after in-vitro exposure to notable example. What is usually an ephemeral virus specific antigen. The amount of interferon joint infection could become a persistent arthritis released commonly indicates the degree of virus- if the infected individual mounted an allergic specific immunity better than more traditional tests response to viral antigen (Fig. b). An allergic that measure lymphocyte proliferation in response response would be analagous to allergic reactions in to viral antigen. Probably, therefore, interferon the respiratory tract and need not necessarily be secreted by T lymphocytes contributes to the antiviral marked by any increase in reaginic (IgE) antibody. activity mediated by this population. There are indications that reaginic responses are Other mononuclear cell populations probably enhanced in patients with rheumatic disorders share this property since nude mice lacking T lym- (Goldman et al., 1976) but this needs further syste- J Clin Pathol: first published as 10.1136/jcp.s3-12.1.132 on 1 January 1978. Downloaded from Rheumatoid arthritis-a virus disease ? 137 matic investigation. At present there is little direct has been much speculation about the mechanisms evidence bearing on this point but hypersensitivity which suppress immune responses and the diseases reactions such as transient urticaria are noted not that a defect in these mechanisms might provoke infrequently in virus infections in which acute (Waksman, 1977). Although an elaborate series of self-limited polyarthiitis is also a clinical feature. feed-back mechanisms operates at all stages in the immune response suppressor T lymphocytes have Persistent abnormalties in cells transiently infected received particular attention in the rheumatic by virus (Fig. c) diseases. There are claims that these cells are defective in patients with systemic lupus erythema- It has been assumed that if rheumatoid arthritis has tosus (Bresnihan and Jasin, 1977), but the techniques a viral aetiology the agent must persist in the synovial for assaying 'suppressor' functions in man are still membrane in order to provoke a continuous immune unsatisfactory and need critical evaluation (De la response. However, it is possible to postulate forms Concha et al., 1977). of viral pathogenesis where this need not be the case. Two principal kinds of defect can be proposed in One mechanism would be the 'hit-and-run' effect of relation to rheumatoid arthritis. The first postulates an agent (Fig. c). Viruses commonly alter the mem- that the antibody response is appropriate in its branes of infected cells (Stohlman et al., 1975). It initial specificity but the failure of normal suppressor is quite plausible that these changes would persist not mechanisms allows its prolongation long after the only in cells that no longer produced infective initial infection has subsided. Similar considerations particles but also in the progeny of the cells that were apply to the regulation of cell-mediated immunity. originally infected. In these circumstances the asso- The second kind of defect is an inappropriate ciation between rheumatoid arthritis and infection stimulation of an immune response to tissue antigens by a particular virus could not be made directly but or residual viral antigens in the affected joints which might be inferred from epidemiological or immuno- might involve either humoral or cell-mediated logical evidence. immune responses. Target cells infected with type A influenza virus, for example, display a common There are interesting examples of persistent copyright. alterations in the biological behaviour of infected protein antigen with which antisera to different type cells in which it may be difficult or impossible to A strains will react (Biddison et al., 1977). Accord- detect other features of continued infection. Thus ingly sequential infections with different influenza A murine neuroblastoma cells infected with lympho- strains could reactivate a reaction to residual mem- cytic choriomeningitis virus contain reduced con- brane antigens of any strain. centrations of the enzymes that make or degrade There are also several examples of cross-reactions acetylcholine (Oldstone et al., 1977). These abnorma- mediated by T lymphocytes. Cytotoxic T lympho- in cytes that kill target cells infected with influenza lities persist even cells that are no longer pro- virus also fail to between ducing infectious virus. Related abnormalities are distinguish serologically http://jcp.bmj.com/ noted in mice inoculated with the same virus at birth. distinct type A viruses (Zweerink et al., 1977; Conceivably, multiplying virus can alter the functions Effros et al., 1977). Moreover, T lymphocytes display of host cells and thereby produce membrane changes a wider range of cross-reactivity. Mouse T which would attract an immune response. Such in- lymphocytes sensitised to allogeneic stimulator cells fections would not produce cell death and for pro- are cytotoxic for trinitrophenyl-coupled target longed periods might not release cells of the same strain as the cytotoxic lymphocytes infectious particles. (Lemonnier et al., 1977). These results indicate that

Also pertinent is the observation that the membranes on October 1, 2021 by guest. Protected of virus-infected cells injected into mice can provoke T lymphocytes sensitised to exogenous antigens inflammatory disorders resembling autoimmune could cross-react with modified histocompatibility disease and antigens. It is noteworthy that cytotoxic cells with a (Eaton Almquist, 1977). wide range of specificity are generated in mice during the early stages of acute lymphocytic chorio- Defective regulation of immune response to viral meningitis virus infection (Welsh and Zinkernagel, infections (Fig. d) 1977). These examples illustrate the general principle that The hypotheses so far considered postulate that a wide range of transient viral infections could in- virus alters the host cells in a manner that attracts itiate immune reactions that might interact with a continued immune response. Equally possibly the structural components of host cells such as histo- response is triggered initially by a transient virus compatibility antigens or viral incorporated infection in the joints but perpetuated by defective in cell membranes. Moreover, T lymphocyte regulation of the immune response (Fig. d). There reactions against histocompatibility antigens altered J Clin Pathol: first published as 10.1136/jcp.s3-12.1.132 on 1 January 1978. Downloaded from 138 A. M. Denman by virus infection could lead to true autoimmune pathological features of these disorders? The sim- reactions (Gleichmann and Gleichmann, 1976). plest view would be that these cells constitute a reservoir for the continued release of virus or virus Viral persistence in lymphoreticular cells (Fig. e) products. Persistent infection of lymphocyte, however, could have more profound effects on the Possibly virus grows in selected lymphoid cell immune response itself. Virus infections can increase populations as well as in the affected joints. In- the antibody response to exogenous antigens, as is activating these populations might both initiate and illustrated by experiments involving acute lactate perpetuate the immune response and its immuno- dehydrogenase elevating virus in mice (Riley et al., pathological consequences. Replication in lympho- 1976). But the more important issue concerns the reticular cells is an obligatorystage inthepathogenesis possibility that viruses can infect potentially auto- of many virus infections. Measles virus, for example, reactive lymphocytes of the T or B series and that grows readily in lymphocytes infected in vitro and the resulting uncontrolled proliferation of these cells cord blood mononuclear cells are particularly sus- would lead to autoimmune disease. This might ceptible (Sullivan et al., 1975). In severe natural follow the derepression of V genes coding for anti- infections measles virus antigen may be detected body synthesis or, alternatively, virus might alter the in a high percentage of blood monuclear cells receptor for self-recognition on lymphocyte surfaces (Osunkoya et al., 1974). Moreover, lymphocytes (Doherty et al., 1976). seem to acquire viral antigens even in the course of There is already experimental evidence to suggest banal infections by influenza virus (Wilson et al., that the foregoing is not entirely speculative. 1976). Thymocytes from preleukaemic mice persistently It is noteworthy that different viruses infect infected with Moloney murine leukaemia virus are lymphocyte sub-populations in a selective manner. cytotoxic for syngeneic target cells but not for Thus EB virus absorbs preferentially to B lympho- xenogeneic cells or virus-infected syngeneic cells cytes with complement receptors (Yefenof et al., (Proffitt et al,, 1976). These observations indicate 1976) while in human cells the growth of herpes that it is the subversion of lymphocyte recognition simplex type I virus is restricted to T lymphocytes that initiates the autoaggressive behaviour. However, copyright. (Kirchner et al., 1977). Precise analysis allows the the most telling observations concern the interactions populations at risk to be defined more accurately. of EB virus with different lymphocyte populations. Thus by selectively infecting human tonsil cell EB virus infects a minority of B lymphocytes in the cultures engaged in specific antibody synthesis it blood of patients with infectious mononucleosis can be shown that helper T lymphocytes are par- (Klein et al., 1975; Rocchi et al., 1977). Furthermore, ticularly susceptible to infection by herpes simplex there is some evidence that only a small population virus (Pelton et al., 1977). of B lymphocytes which have already begun to It is well known that certain viruses persist in synthesise Ig are vulnerable to viral transformation lymphoreticular cells indefinitely. Adenovirus can (Steel et al., 1977). http://jcp.bmj.com/ be cultured from tonsil cells long after the primary This process, as already discussed, may be abetted infection and the genome of EB virus is carried by the temporary depression of T lymphocyte permanently in B lymphocytes. Indeed, the most immunity at the height of the disease (Mangi et al., striking examples of viral persistence in many 1974) and which, if extreme, may produce a galaxy species concern the DNA herpes viruses. A lympho- of lymphoproliferative disorders in susceptible tropic herpes virus related to EB virus has been families (Purtilo et al., 1977). EB virus induces

identified in baboons, while in squirrel monkeys polyclonal Ig production by human B cells in vitro on October 1, 2021 by guest. Protected herpes virus saimiri is carried persistently in T (Rosen et al., 1977) and also potentiates antibody lymphocytes (Wright et al., 1976). production against other antigens (Luzzati et al., Additional manoeuvres may be needed to demon- 1977). Thus it is logical to conclude that the wide strate virus. Thus cytomegalovirus in B lymphocytes spectrum of autoantibodies that accompany this is recoverable only after the infected cells have been disease are stimulated by the same mechanism. cultured together with allogeneic cells (Olding et al., Indeed, self-reactive B lymphocytes are induced by 1975). It is also noteworthy that cytomegalovirus other stimuli which induce polyclonal activation of infection of human lymphocytes leads to a more this population such as pokeweed mitogen (Primi persistent infection than is observed with permissive et al., 1977). fibroblasts (St Jeor and Weisser, 1977). Such observations merely point to lympho- Should lymphoreticular cells prove to be the site reticular cells as plausible sites of virus persistence of virus persistence in the connective tissue diseases in the connective tissue diseases. Unfortunately no how would this explain the characteristic immuno- positive isolations have yet been achieved. For J Clin Pathol: first published as 10.1136/jcp.s3-12.1.132 on 1 January 1978. Downloaded from Rheumatoid arthritis-a virus disease ? 139 example, efforts to isolate virus from the lympho- lymphocyte populations or their products. This cytes of patients with connective tissue diseases by could indicate that the blood mononuclear cells and cocultivating or fusing lymphocytes with indicator the infiltrating lymphocytes in these disease are cells have failed. Nevertheless, there is indirect producing an antiviral substance which is not evidence that such cells could be persistently in- classical interferon. These cells could thereby be fected. Using herpes simplex virus type I as an contributing to the host defence against persistent example of a virus that invariably grows in stimu- infection. lated lymphocytes from normal human subjects, we have observed that this virus commonly fails to Table Fate ofherpes simplex virus in blood lympho- grow in lymphocytes from patients with a variety of cyte cultures from patients with different diseases (principal categories) connective tissue diseases (Table) (Denman et al., 1976). The blood lymphocytes from most patients Permissive* Non-permissive with rheumatoid arthritis support the growth of Normal controls (all ages) Severe herpes simplex lesions herpes simplex virus in a normal manner, with the Degenerative disorder Acute viral arthritis exception of patients with early, acute disease. In Neoplasiat Infectious mononucleosis contrast, cultured monuclear Acute infections (including Behget's disease cells isolated from septicaemias) Polyarteritis nodosa rheumatoid synovial effusions also fail to support Chronic infections (including Systemic lupus erythematosus the growth of this virus (Appleford and Denman, tuberculosis) Dermatomyositis Sarcoidosis Crohn's 1978). Presumably the abnormal behaviour of Hypersensitivity diseases (eg circulating lymphocytes reflects systemic changes erythema multiforme) induced by disease whereas, in rheumatoid arthritis Most drug reactions the abnormality is mostly localised in the affected Rheumatoid arthritis tissue. *At least 2-0 logs of infectious virus synthesised/0-25 x 106 cultured lymphocytes in 3 days (see Denham et al. (1976) for details). These findings are open to several interpretations. tExcluding lymphoproliferative disorders. Firstly, the underlying disease could induce an abnormality in the T lymphocyte population which Finally, there is the possibility that true interfer-

normally supports the growth of herpes simplex ence by defective viral particles prevents the growth copyright. virus and thereby render these cells refactory to this of herpes simplex virus in these cells. This notion is virus. Conventional assays for T lymphocyte strengthened by the observation that other viruses function in these patients do not reveal defects of such as measles virus and vesicular stomatitis virus sufficient severity to account for the non-permissive- grow normally in cultures that do not permit the ness. Moreover, even when the proportions of T growth of herpes simplex virus. But the occurrence lymphocytes in cultures of normal blood mono- of non-permissiveness to the same virus in several nuclear cells are artificially reduced to those found unrelated diseases makes it unlikely that failure of spontaneously in disease such cultures still allow herpes simplex virus to grow gives more than a herpes simplex virus to grow. However, only a small general indication that viral interference may be http://jcp.bmj.com/ percentage of the T lymphocytes in normal blood or operating (Denman et al., 1977). tonsils normally permit virus growth (Pelton et al., 1977), and it is uncertain that the immunological Conclusion competence of this population would be measured by standard tests. Secondly, non-permissiveness in Conventional methods have failed to elucidate the disease could be attributed to interferon production. pathogenesis of rheumatoid and connective tissue we not disease. A viral is worth because However, have detected increased amounts aetiology pursuing on October 1, 2021 by guest. Protected of interferon in these cultures using standard assays. there are no features of the disease which are in- Nevertheless, populations of T lymphocytes can compatible with this hypothesis. No agents have been often be isolated from the blood mononuclear cells reproducibly isolated from patients with these dis- of such patients on the basis of size or surface orders, but there are several ways in which virus markers which allow herpes simplex virus to grow infection could initiate or perpetuate a persistent in a normal fashion. Viral growth is abolished when immune reaction in the affected joints or other those populations which are permissive in isolation structures without the causative agentbeing amenable are re-exposed to the other lymphocyte populations to isolation or detection by even the most sophis- and cultured together with them. No such effects are ticated techniques currently available. Lympho- observed when lymphocytes from normal donors are reticular cells are a logical site for virus persistence similarly manipulated. 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