245LEADING ARTICLES

Autoimmunity and Disease

THE LANCETLONDON 29 JULY 1961

THE detection in the serum of autoantibodies directed

against body constituents of one sort or another hasbecome almost commonplace. At first observed incertain acquired haemolytic anaemias - and in apronal(’Sedormid’) and some other drug purpuras,2 theyhave since been noted in systemic lupus erythematosus,3Hashimoto’s disease and some other thyroid disorders,4rheumatoid arthritis,5 and Sjogren’s disease. 6 In

addition, progressive liver disease is known to providemany instances of autoantibody production, 7 andnumerous recent papers have described autoimmunereactions associated with such diverse conditions as (toname only a few) chronic pancreatitis, 8 perniciousanaemia,9 Addison’s disease,lo male infertility," andulcerative colitiS.12 This field gives every indication ofalmost logarithmic fertility; and the Medical ResearchCouncil’s latest annual report, published this week

(see p. 248), draws timely attention to its importance.While it can hardly be doubted that autoimmunisation

does occur in a not inconsiderable array of diseases, westill know little of whether, or how, this response isrelated to the causation of lesions; but experimentalevidence provide some pointers. It is well established 13that serum-autoantibodies against, for example, thyroidor brain can be readily elicited in rabbits or guineapigsby immunisation with the relevant homologous or,indeed autologous, tissue. The appearance of theseantibodies is often followed by characteristic lesions inthe appropriate organ of the animal immunised. But inexperiments of this type lesions may appear withoutdemonstrable circulating antibody, and in normalanimals into which large amounts of high-titre antibodyfrom affected animals are infused lesions do not develop.Experimental autoimmune disease has been transmittedonly by transfer of living lymph-node cells from immu-nised animals. This has suggested that the lesionsresulting from autoimmunisation arise in associationwith an immune response of the delayed-hypersensitivitytype mediated by cells of the lymphocyte series, and thatthis, rather than circulating antibody, is the mechanismof tissue injury.

In man, therefore, we must hesitate to attributelesions to the presence of autoantibodies in the serum.After acute myocardial infarction, specific serum-

autoantibodies against heart may develop 14; but theseclearly arise as a result of the lesion, and they apparentlyhave no causal role in the continuance of cardiac damage.On the other hand the destructive effect of antibodyagainst red cells or platelets seems obvious enough inhaemolytic autoimmune disorders. In these conditionsactual union of antigen and antibody can be shown, byanti-globulin tests, to have occurred in the body; thespecificity of the eluted antibody can also bedemonstrated. It is by no means certain, however, thatwhen fixed y-globulin is detected in affected tissues (forinstance, by the immunofluorescence technique on

glomeruli of lupus kidneys ’15 or on the myocardium inrheumatic fever 16) it is specificially bound to antigen;its adherence may well be due to non-specific causes.The cytotoxicity of serum of patients with autoimmunethyroiditis has been demonstrated by tissue-culture ofthyroid cells," and this method is being used to studyother autoimmune systems. Nevertheless, in manyinstances of autoantibody production in disease, auto-antibody has not yet been shown to be harmful to antigen-containing tissues in vivo, or even to have access toantigen. For instance, with the serum antinuclearfactors of lupus,18 and the antibodies which participatein the autoimmune complement-fixation test of Gaj-dusek the relevant antigens are presumably inacces-sible owing to their intracellular position. Whether theirrelease on cell death or injury can lead to immunologicalreactions in the tissue is an open question. The haema-toxylin bodies of lupus lesions may represent suchreactions, but other such instances are few. As STEINERand V OLPÉ 19 point out, the histological study of auto-immune disorders at present lacks criteria for dis-

tinguishing specific activities of "

immunologicallycompetent cells "-especially those involved in delayed-type hypersensitivity reactions. The immunofluorescentmethods which have revealed y-globulin production inthe cytoplasm of cells of the plasmacyte series have notrevealed the immunologically specific activity associatedwith cell-bound antibody. This is a major gap inresources for investigating cellular aspects of autoimmuneprocesses; for the information obtainable from skin-

testing is limited, and methods are needed for studyingdelayed hypersensitivity at a precise cellular level. Thetechnique of observing lymphocyte behaviour in mixedtissue-culture preparations, which PULVERTAFT has

described,17 may prove a basis for approaching thisproblem, especially as it provides opportunity for

studying the combined effects of antibody and sensitisedcells on the substrate tissue.

According to ideas on acquired immunity, the

presence of autoantibodies in the serum (whether or notthey are agents of tissue injury) is but one expression of

1. See Dacie, J. V. The Hæmolytic Anaemias; Congenital and Acquired.London, 1954.

2. Ackroyd, J. F. Brit. med. Bull. 1955, 11, 28.3. Dameshek, W. Ann. intern. Med. 1958, 48, 707.4. Roitt, I. M., Doniach, D., Campbell, P. N., Hudson, R. V. Lancet, 1956,

ii, 820.5. See Glynn, L. E., Holborow, E. J. Ann. rheum. Dis. 1960, 19, 197.6. Jones, B. R. Lancet, 1958, ii, 773. Bunim, J. J. Ann. rheum. Dis. 1961,

20, 1.7. Gajdusek, D. C. Nature, Lond. 1957, 179, 666.8. Thal, A. P., Murray, M. J., Egner, W. Lancet, 1959, i, 1128.9. Schwartz, M. ibid. 1960, ii, 1263.

10. Anderson, J. R., Goudie, R. B., Gray, K. G., Timbury, G. C. ibid. 1957,i, 1123.

11. Rumke, P. Vox sanguinis, 1954, 4, 135.12. Broberger, O., Perlmann, P. J. exp. Med. 1959, 110, 657. Asherson,

G. L., Broberger, O. Brit. med. J. 1961, i, 1429.13. Waksman, B. H. Int. Arch. Allergy, 1959, 14, suppl.

14. Ehrenfeld, E. N., Gery, I., Davies, A. M. Lancet, 1961, i, 1138.15. Mellors, R. C., Ortega, L. G., Holman, H. R. J. exp. Med. 1957, 106, 191.16. Kaplan, M. H., Dallenbach, F. D. ibid. 1961, 113, 1.17. Pulvertaft, R. J. V., Doniach, D., Roitt, I. M., Hudson, R. V. Lancet,

1959, ii, 216.18. Holborow, E. J., Weir, D. M., Johnson, G. D. Brit. med. J. 1957, ii, 2,

732.19. Steiner, J. W., Volpé, R. Canad. med. Ass. J. 1961, 84, 1165, 1227, 1297.

246

20. Good, R. A., Rotstein, J. Bull. rheum. Dis. 1960, 10, 203.21. Leonhardt, T. Lancet, 1957, ii, 1200.22. See Ziff, M. Amer. J. Med. 1961, 20, 1.23. Weir, D. M., Holborow, E. J., Johnson, G. D. Brit. med. J. 1961, i, 933.

Buchanan, W. W., Crooks, J., Alexander, W. D., Koutras, D. A.,Wayne, E. J., Gray, K. G. Lancet, 1961, i, 245. White, R. G., Bass,B. H., Williams, E. ibid. p. 368.

24. Hughes, R. P., Carpenter, C. H. Amer. J. Syph. 1948, 32, 265.

abnormal functional activity of the body’s system ofimmunologically competent cells. The relation of thismalfunction to genetic changes in these cells has beenstressed by BURNET and others, and developments infield studies of autoimmunity certainly point to an

important genetic factor in some of these conditions. Incongenital agammaglobulinxmia, where the incidence ofa rheumatoid-like condition is high, family studies haverevealed a hereditary factory and a striking prevalenceof hypergammaglobulinsemia in the siblings of a patientwith systemic lupus has been reported.21 The familialoccurrence of both rheumatoid arthritis and systemiclupus is now well documented, and the Rose-Waalerrheumatoid factor has been found with some frequencyin the symptom-free relatives of patients with rheuma-toid arthritis.22 Transitional clinical syndromes withserological features of more than one disease in the auto-immune group are being increasingly recognised-so farin various combinations involving rheumatoid arthritis,lupus, Sjogren’s disease, and thyroiditis.6 23 Analysis ofthe patterns of autoantibody production in man has stilla long way to go, but it is already providing informationwhich may lead to an understanding of the fundamentaldisturbances which underlie autoimmunity and theirrelation to disease.

Treatment of GonorrhoeaEVIDENCE from many countries indicates that the

incidence of gonorrhoea is increasing and that remedieswhich have proved effective in the recent past are losingsome of their efficacy. But sometimes this diminished

efficacy may be more apparent than real. Methods oftreatment have been simplified to the point where somecases are managed by those who have no special interest-in the disease and whose methods of diagnosis are lessthan adequate. HUGHES and CARPENTER 24 studied 216cases of allegedly penicillin-resistant gonorrhoea inmembers of the United States Armed Forces who hadbeen in hospital for from two to six months and had beentreated with large doses of penicillin for supposed gono-coccal urethritis, without response. They concludedthat, with few exceptions, the initial diagnosis of gonor-rhoea was mistaken because of unsatisfactory gram stainsfrom urethral exudates. Judging by some of the casesreferred to venereal-disease clinics after ineffective treat-

ment, failure to ensure proper diagnosis is a commonsource of error in this country. Another likely source ofapparent failure is prompt reinfection. The ease ofmodern treatment and the rapidity with which symptomsare relieved encourages some patients to continue

promiscuous contacts. Sometimes they even return atonce to consorts who have been sources of the infectionor whom they themselves have infected; for, unhappily,the tracing and treatment of infected contacts is often nomore than an aspiration. There is no means of dis-

25. Reyn, A., Korner, B., Bentzon, M. W. Brit. J. vener. Dis. 1958, 34, 227.26. Rees, E. ibid. 1952, 28, 115.27. Gisslen, H., Hellgren, L., Starck, V. Bull. Wld Hlth Org. 1961, 24, 367.28. Gentele, M., Lagerholm, B., Lodin, A. Acta Derm.-venereol., Stockh.

1960, 40, 256.29. Brown, W. J. Bull. Wld Hlth Org. 1961, 24, 386.30. Preston, J. M., Dunsworth, W. P. J. S.C. med. Ass. 1957, 53, 41.31. Thayer, J. D., Perry, M. I., Field, F. W., Garson, W. Antibiot. Annu.

1957, p. 513.32. Thayer, J. D., Perry, M. I., Magnuson, H. J., Garson, W. Antibiot.

Chemother. 1957, 7, 311.

tinguishing between relapse and reinfection unless

perhaps the organisms isolated in the two attacks ofurethritis differ widely in sensitivity 25; and histories arenot always helpful. Therefore many workers ascribe

reappearance of gonococcal discharge a week or moreafter apparent cure to reinfection. IAs regards possible causes of true relapse, REES 2s e

suggested that the presence of the gonococcus in a closedor intermittently draining focus might enable it to

escape the action of penicillin, and it would then remainas a potential source of reinfection if the focus reopened.Complications which might produce foci of this kindhave been thought to be unusual since the introductionof antibiotics; but an investigation by GISSLEN et a1.2’ inSweden showed that the incidence of salpingitis amongwomen with gonorrhoea admitted to hospital in Gothen.burg had risen to approximately 10% in recent years.They attributed the disparity between their own figuresand those reported by others to the fact that their studywas not limited to patients known to have venerealdisease but included others admitted to non-venereo-

logical departments. It has been suggested, also, thatpenicillin at the site of infection may be destroyed bypenicillinase, perhaps produced by other organismsinvading the urethra at the same time as the gonococcus.28Other possible factors are inadequate dosage of anti-biotics or maintenance of adequate levels in the blood fortoo short a time owing to the use of an unsuitable

preparation or perhaps to low renal threshold. Dosagemay be particularly important in women. Brown 29 !pointed out that estimates of the required dosage havebeen based almost exclusively on studies of the disease inthe male. PRESTON and DUNSWORTH,30 in South Carolina,found that 16-8% of women patients with gonorrhoeahad. positive cultures within one month after treatmentwith 600,000 units of procaine penicillin in oil with 2%aluminium monostearate (P.A.M.). When the dosage wasincreased to 1,800,000 units, the percentage of positivecultures dropped to 3-8. For this reason the UnitedStates Public Health Service recommends a minimum of1,800,000 units of P.A.M. for the treatment of females,and that males be treated with equally high dosage.Another possible cause of relapse was suggested byTHAYER et al.,31 32 who found that gonococci which hadundergone phagocytosis in tissue-cultures were not

killed by penicillin or other antibiotics even whensubmitted for as long as forty-eight hours to concentra-tions considerably above the minimal in-vitro inhibitinglevel. This led to the suggestion that gonococci under-going phagocytosis by fixed tissue cells in subepithelialconnective tissues might be protected from the action ofantibiotics and later cause reinfection of the mucousmembranes.The aspect which has attracted most interest is