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 virus 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 antibody either through reaction to a variety of environmental factors. This virus-coded antigens on the cell 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 antigen (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 hepatitis B 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 nasopharyngeal carcinoma 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 genes. 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 viruses 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 cell membrane 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