Annals of the Rheumatic Diseases 1993; 52: S1-S2 Si

Annals ofthe RHEUMATIC Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S1 on 1 March 1993. Downloaded from DISEASES

Foreword

Investigators pondering the cause of inflammatory as agent provocateurs and it is vital that their evolutionary rheumatic diseases have been largely preoccupied with patience is matched by those who bestow research immunology since the discovery of autoantibodies over 30 grants. years ago. The ability to initiate organ specific autoimmune These seemingly contrasting interpretations are not diseases by the experimental presentation of organ specific mutually exclusive. 'Some infectious diseases are autoantigens to the immune system gave a further dangerous to us not because the body fails to defend itself incentive to pursue this theme. An analysis of the major against them but-paradoxically-because it does defend rheumatological journals shows that on average some itself: in a sense, the remedy is the disease'.' As a cogent 10-1 5% ofall articles published over the past 20 years have example, immunodeficiency predisposes to rheumatic a major immunological component, and this takes no disorders, through atypical infections in common variable account of immunological investigations into the hypogammaglobulinaemia and putatively from infections rheumatic diseases appearing in other scienti& journals. in complement deficiency associated with connective tissue Much of this massive body of data has informed us about diseases. Severe forms of immunodeficiency, such as immunopathological mechanisms. For example, it is highly defects in HLA molecule assembly, may well prove to be probable that cytokines synthesised in the rheumatoid gross examples of commoner defects predisposing to synovial membrane make a major contribution to cartilage persistent infections with immunological abnormalities. In degradation. Similarly, it is likely, though less securely these subjects immune mediated disease may be the price established, that HLA associations with rheumatic diseases of host defence. Furthermore, postinfectious reactive operate through T cell recognition of genetically disease, including arthritis, is one of the few situations in determined, variations of which there is some intellectual about the topographical oligopeptides security validity http://ard.bmj.com/ presented in the -presenting grooves. However, not of immunological reasoning. unreasonably, rheumatologists and their patients ask This Heberden issue is a selection of contributions from relatively simple questions about cause, effect, and scientists who have approached these problems in very interdiction, and it is in this context that the contribution different ways. The diversity of these studies illustrates the of immunology to rheumatological understanding has also justifiably broad spectrum of immunological studies in the to be assessed. rheumatic diseases. Indeed there are few areas of scientific

There are two fundamentally different approaches to enterprise in which dogmatism about research strategy is on September 25, 2021 by guest. Protected copyright. interpreting immunological aberrations in the rheumatic so misplaced; a moment of youthful insight may have the diseases. The first argues that these aberrations are primary same investigative potential as the efforts of a respected events. Persistent inflammation in the rheumatoid synovial team working on a well defined project. membrane and autoantibody production in systemic Avrion Mitchison examines the problem from the disorders like systemic lupus erythematosus result from a standpoint of tolerance and its breakdown. As a scientist breakdown in tolerance. A rigorous analysis of events such who played a major part in the classical debate on the as peptide processing in antigen-presenting cells, the genes nature of tolerance, his interest in this field has been encoding T cell antigen receptors, and the genes sustained in the current era when transgenic technology determining variable sequences in autoantibody synthesis has allowed earlier theories to be subjected to rigorous can eventually be expected to disclose abnormalities experimental scrutiny. The study of to collagen predisposing to immunoproliferative disorders and and its control is a plausible model for probing the link immune mediated tissue damage. The strongest argument between immunological reasoning and an autoimmune favouring this view is the contribution of genetic factors to aetiology for rheumatoid arthritis. human rheumatic diseases and animal models of Complementing Avrion Mitchison's paper, Hans Acha- rheumatic diseases. Orbea shows how microbial infections may trigger From an alternative viewpoint, the immunological polyclonal T and B cell reactivity by acting as abnormalities in the rheumatic diseases are mainly "superantigens", rather than conventional . This epiphenomena which may on occasion inflict damage process could abrogate tolerance and thereby initiate on tissues or circulating cells but do not initiate autoimmune diseases. The technical elegance of the these diseases. The wealth of microbial disorders experiments he describes holds the promises of reviving accompanied by similar abnormalities is the most decades of speculation about the link between common cogent reason for adopting this stance. Rational research infectious agents and the rheumatic diseases. His paper in a disease such as rheumatoid arthritis should be also illustrates the complex manner in which retroviruses directed at seeking the ghost in the immunopatho- subvert the control of immune response. However, logical machine. Many microbes are adept at acting ironically, the extent to which the abrogation of classical S2 Foreword

tolerance is relevant to the cause of a disease such as own strategy for confusing immune defences. This paper Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S1 on 1 March 1993. Downloaded from rheumatoid arthritis remains debatable; indeed this is still draws the important conclusion that the issues can be a disease in search of a universally accepted autoantigen. resolved by the techniques now available and are unlikely The T cell infiltration characteristic of rheumatoid to run unresolved into the next century. synovitis has been a fertile source of material for Retroviruses cause neoplastic, immunodeficiency, and immunological experiments; these cells serve as the nearest immune mediated degenerative diseases in many animal approach to an intelligent, dolphin-like probe, able to relay species. With the exception of the last category, analogous aetiological information to the investigator.2 Many theories diseases have been discovered in man. Faith in a retroviral about the immunopathogenesis of the disease presuppose cause for rheumatoid arthritis, systemic lupus that there are dominant clones, inducing disease because erythematosus, and other connective tissue diseases is at they react with relevant autoantigens or microbial antigens. least as rational as any other belief based on theory rather Hill Gaston examines the evidence for this belief and than incontrovertible evidence. There is the additional rightly stresses the practical difficulties in identifying, twist that the distinction between many exogenous isolating, and characterising such clones, even granted that retroviral sequences and some endogenous retroviral they do exist. sequences in the human genome is almost semantic. Many immunorheumatologists have been preoccupied Steffen Gay, Renate Gay, and William Koopman review with assessing the pathological significance of rheumatoid the mechanisms by which retroviral infection could factors and some observers have considered the generation account for the immunopathological features of of these self reactive antibodies to be the major rheumatoid arthritis and the evidence supporting this autoimmune mechanism responsible for the disease. The hypothesis. discovery of seemingly defective IgG glycosylation in Finally, Shozo Izui, Thierry Berney, Takanori Shibata, rheumatoid arthritis has prompted speculation that this and Thierry Fulpius show how immunochemical structural anomaly may make some immunoglobulin definition can account for the distinctive pattem of disease sequences abnormally antigenic. Protein glycosylation is in a murine model of systemic lupus erythematosus and, involved in many forms of protein interaction, immune by inference, in the human disease. Their contribution regulation, and control of endothelial cells in the emphasises the potential of analytical immunochemistry microvasculature. The paper by Elizabeth Hounsell and for explaining disease phenomena. Moreover, their studies Michael Davies examines these complexities and show how genetically determined selection of the antibody underlines the danger of oversimplification in this field. repertoire could interact with environmental factors such The passing years and scientific sophistication have not as infections to. produce many late manifestations of dispelled the suspicion that rheumatoid arthritis, and even human connective tissue diseases. multisystem connective tissue diseases, are really forms of reactive arthritis initiated and maintained by bacterial Clinical Research Centre, A M DENMAN infection. The dilemma is obvious; many decades of Division ofImmunological Medicine, intensive effort have not revealed agents with the Watford Road, credentials to satisfy an increasingly cynical Harrow, rheumatological community yet theories based on 'hit and Middlesex HAI 3U7,

run' mechanisms are more likely to convince theoretical http://ard.bmj.com/ physicists than hard nosed microbiologists. The paper by Graham Rook, Peter Lydyard, and J L Stanford reminds 1 Medawar P B. The threat and the glory. Oxford: , 1990: 175-6. us that bacteria, and particularly mycobacteria, are also 2 Denman A M. Lymphocytes: dolphins for enlightening rheumatological accomplished survivors in the human host and have their investigators? J Rheumatol 1986; 13: 9-12. on September 25, 2021 by guest. Protected copyright.