Auto-immunity Fact or Fiction

Read before the Society Wednesday 14th January 1970. The recognition that the mammalian organism is capable of developing an immune response against its own normal tissue components has aroused interest in the implication of auto-immune reactions in human disease. This interest may, however, be too widely applied, and the label “auto-immune” may be applied to a particular clinical entity with a complete disregard for the rather exacting criteria which this aetiology demands; indeed one might say that the word auto-immune is almost synonymous with the word idiopathic, in the clinician’s dictionary. Some definitions first. By auto-immune disease it is widely understood that there is a failure at some point for the body to differentiate between its own tissue components and those of a foreign material; it can no longer distinguish, if one likes to put it in more crude terms, between “self” and “non-self” . Consequently the host launches an immunological response towards its tissue components, with the resulting pathological changes and clinical manifestations. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, Spring 1971, 6(5): 34-37 doi:10.2218/resmedica.v6i5.876


AU TO -IM M UNITY F A C T OR FICTION
A l a s d a i r K. T

. C o n n
Read before the Society W ednesday 14th January 1970 T h e recognition that the mammalian organism is capable of developing an immune response against its own normal tissue com ponents has aroused interest in the implication of auto-immune reactions in human disease.This interest may, however, be too widely applied, and the label " auto-immune" may be applied to a particular clinical entity with a complete disregard for the rather exacting criteria which this aetiology demands; indeed one might say that the word auto-immune is almost synonymous with the word idiopathic, in the clinician's dictionary.Some definitions first.By auto-immune disease it is widely understood that there is a failure at some point for the body to differen tiate between its own tissue components and those of a foreign material; it can no longer distinguish, if one likes to put it in more crude terms, between " self" and " non-self" .Conse quently the host launches an immunological response towards its tissue components, with the resulting pathological changes and clinical manifestations.
T h e subject of auto-immunity has however, like so many other intensely investigated fields been clouded by vague and indeed, often confusing, terminology.
Th e term auto immunity at present enjoys the widest use, and under this rather nebulous heading are included many diseases resulting from the reactivity of antibodies directed toward the host tissues.These diseases range from Hashimoto's thy roiditis, and rare forms of haemolytic anaemia right through to disseminated lupus erythematosis, rheumatic fever and dermatomyositis.
Before we even begin to consider exactly what significance the immunological response has in these diseases, we can perhaps make a few pertinent points.
First, it can be shown, and this will be dis cussed in more detail later, that the auto immune process plays an intricate, and perhaps as yet incompletely revealed part in the process of cellular damage.It still remains to explain how the process came to be in existence; so that, when we use the term auto-immunity we are describing a particular pathogenic mechan ism; we are not forwarding an aetiology.Auto-immunity is a process, like degeneration is a process; it does not explain how this pro cess came about.
Second, auto-antibodies, and, presumably, auto-reactive delayed hypersensitivity, can occur as a result of tissue damage.Trauma to an organ may lead to cellular necrosis and death, with the liberation of tissue com ponents, and these tissue components may elicit an immune response; but this need not be an aggressive respanse.One example is that of the post myocardial infarc tion, or Dressier, syndrome.Following myo cardial infarction, antiheart antibodies, as de tected by both indirect immofluorescence and antibody consumption tests were present in the serum of recovering patients, but absent from that of controls.Following recovery, the levels of these antiheart antibodies fell to undetect able levels.Dressier suggested that cardiac necrosis may lead to this auto-immune response.In rabbits certainly, animals immunised against rabbit heart do not develop any histological changes in the myocardium, despite high levels of circulating antibody.Kaplan found tran sient antiheart antibodies were sometimes present after heart operations, especially com missurotomy.Antibodies to liver are found in rats following administration of hepatotoxic agents.Therefore the demonstration of an auto-immune response, i.e. the detection of antibodies towards the host's own tissues, does not seem, in itself, to provide good evidence that tissue damage in disease has an im m uno logical cause.
Unfortunately this concept is not so well instilled into many of our minds as it could be.Auto-immunity is not synonymous with auto-aggression.A nd yet, the im m une mech anism need not invariably benefit the hostthe anaphylactic response, with its often fatal outcome, is a dramatic example to the erring physician.
It may be seen that an auto-immune process can play a part in the perpetuation of a patho logical situation.A question that must be answered is that if, once initiated, the process is self-perpetuating, or whether the original perturbation is necessary for the continuation of the pathological state.In other words how important is the im m une process in the pro longation of the disease.This problem can be tackled from several angles.
O ne must be immediately put on one's guard by the observation that many auto im m une antibodies can be present without overt pathological damage.The Wasserman reaction, for example, demonstrates antibody to cardiolipid -a phospholipid which occurs in mitochondria of mammalian cells.This auto-antibody develops after several types of virus infection, including vaccination and glandular fever; diseases in which there may be m inim al observed tissue damage.It is per haps worthwhile first to consider that perhaps if the spirochaete had not been observed and isolated in cases of syphilis, this disease too, in the light of a positive antibody reaction to heart tissue, may have been found in the ranks of the auto-immune disorders.
One method of determining the relationship of the genesis of the sensitised state to the prolongation of the clinical disease is to see if damage to the corresponding organ follows injection of extracts of various tissues, and if, once initiated in this way, the process is self perpetuating.
Field and Laspary attempted this with testis and brain and found that the lesions produced in the target organs tended to decrease in intensity once the course of in fection was terminated.However, the organ that has received the greatest amount of attention concerning this aspect of research has undoubtedly been the thyroid gland.It was early discovered that the serum of patients with H ashimoto's thyroiditis contain auto antibodies against thyroglobulin, that this antibody is organ specific and that it does not cross react with extracts of thyroid glands from the six other mammalian species studied.Since then, antibodies toward microsomal thyroid antigen have been discovered.
Ex perimental im m unization of animals with homologous or autologous thyroid extracts should, and indeed does, lead to the produc tion of circulating thyroid antibodies and to lesions within the gland virtually indistinguish able from the pathological appearance of Hashimoto's disease.There is, however, no consistent relationship between the level of circulating antibodies and the severity of thy roid lesions, at least in neither rats nor rabbits.However, the injected extract has an im port ant bearing on the results -aqueous prepar ations of thyroglobulin are rapidly catabolised and do not persist as a sustained stimulus.In the case of injections of thyroglobulin in corporated with complete Freund's adjuvant the stimulus is sustained.Homologous thy roid extracts without adjuvant do not produce a rise in antibodies or a thyroiditis, it is only when thyroglobuln plus adjuvant, or thyro globulin that has been altered chemically by coupling onto a diazonium derivative is used that any measurable response is obtained.
Once the hypersensitive state is attained, using altered thyroglobulin, subsequent injec tions of unaltered thyroglobulin do not per petuate the response indefinitely.An interest ing result since recent work has demonstrated that thyroglobulin is physiologically secreted into the lymphatics.
W e saw that in the case of Hashimoto's thyroiditis which has been experimentally in duced, the level of antibodies does not correlate well with the degree of pathological damage within the gland, and so we need to consider the relative importance of de layed hypersensitivity and antibody, or h u m oral factors in auto-immune disease.In cer tain cases, for example the haemoloytic anaemias, the antibody is almost certainly more important.In the experimental field a transient allergic glomerulonephritis can be in duced by the transfer of large amounts of serum from an auto-immunized host develop ing antibodies towards its own kidney.
In other auto-immune disorders however, delayed hypersensitivity m ay be im portant.E vid en ce that both delayed hypersensitivity and antibody production was im portant in the pathological response was forwarded b y Brown et al, working on experim ental orchitis in guinea pigs.T h e y defined a system , using differently prepared tissue extracts, w hereby in som e anim als only antibody toward the testes developed, and others in w hich on ly a delayed hypersensitivity phenom enon developed.In neither case was there a characteristic orchitis.O nly when antibody was transferred to ani mals of the delayed hypersensitivity type, or cells transferred to the anim als in whom anti bodies had developed was the characteristic testicular dam age obtained.So in this experi m ental situation both and cell m ediated factors m ay be im portant.
W h ilst we k now that auto-antibodies m ay be present in a large num ber of diseases, w hat do we know o f the aetiology o f these so called auto-im m une diseases.T h e re m ay be several ways in which the auto-im m une process m ay be initiated and the aetiological factor m ight have to be present for the auto-im m une pro cess to be continued.O ne needs to consider the several types o f auto-im m une disorder.
First, there is the group o f diseases in which the auto-im m une disease follow s infection; and the obvious syndrom e illustrating this is rheum atic fever, follow ing a streptococcal infection o f the throat.
Kaplan has shown th at auto-antibodies to heart occur in acute rheum atic fever and that som e, b u t not all, of these react with streptococci.
R abbits im m unized w ith streptococci develop auto antibodies, and antibodies toward hum an heart.It m ay be that the antigens of strepto cocci and heart tissue are sim ilar or it m ay be that streptococcal antigens react as haptens.
L e t us now consider som e auto-im m une diseases such as thyroiditis.C u rren t thinking about aetiology o f this condition m ust surely change, for although the label auto-im m une is applied, it is, as I have endeavoured to ex plain, m erely describing the process, not the aetiology.
C urrent thought revolves around the discovery that often a fam ily history is obtained in these patients, and that m any people w ho are clinically norm al have high levels o f thyroid antibodies, w ithin these fam ily groups.
Indeed H all and Stanbury having recently exam ined a num ber o f fam ilies affected by th e condition have shown that the incidence approached 50% in siblings and that there is alm ost invariably an abnorm ality in one or other parent o f an affected patient.T h is is com patible w ith dom inant inheritance, and in the fam ilies they exam ined figures approaching theoretical were obtained.
In other fam ilies, both other genetic factors and indeed environm ental pressures such as iodine deficiency, puberty, pregnancy and viral in fections, m ay need to be suitable before the disease m anifests itself does not seem to be involved.
H ow m ight -and I assum e for the process of hypothesis -this genetic abnorm ality of the thyroid m anifest itself in physical terms?
It could of course be a lesion leading to faulty protein structure w ithin the thyroid follicular cell.T h is m ight lead to abnorm al release of norm al constituents and this con tinuing cellular damage m igh t elecit the " auto im m une" response.I f this is so, one m ight w onder w hy the clinical presentation is so late in life.Environ m en tal reasons have already been proffered bu t it is w orthw hile rem em ber ing that diseases such as H u ntingdon's chorea, w idely recognised by clinicians as an auto som al dom inant inherited disorder, does not norm ally present until the m iddle thirties in those affected and it m ay be even later.
T h is is an attractive hypothesis, fo r it m ay also lead to an understanding o f the assoc iation o f auto-im m une thyroiditis and o f A d d i sonian pernicious anaem ia, the latter being a disease in which over 8 0 % of patients have antibodies to gastric parietal cells.T h e thyroid and the gastric mucosa have a com m on em bryological precursor -nam ely the endoderm -and furtherm ore several sim ilar bio chem ical functions -for exam ple, the ability to concentrate iodine.I t m igh t be considered that if a biochem ical defect existed in the thyroid cell, and there are a vast number of possible defects, some of them might not only affect thyroid biochemistry, but gastric m eta bolism as well, the two cells sharing com mon pathways.
A nother defect m ight be that instead of the thyroid being abnormal there is defective con trol in antibody production.I find this less satisfying; why is the "control" always lost to certain specified organs -thyroid, gastric mucosa, adrenal glands.O n the tissue defect hypothesis it m ight be said that if the defect were in a more vital tissue -muscle, liverthis would be incom patible with life and the conception would never go to term.
T h e aetiology of auto-immune diseases may also be infection.Subacute sclerosing panen cephalitis is a degenerative disorder of the brain, the exact aetiology obscure.Antibodies to brain were discovered in these patients and the label auto-immune attached to the syn drome.It is only recently that antibodies to measles virus have been isolated in these patients, and it may be that the virus is slowly causing brain cell damage and subsequent im m une response.
T his syndrome may be elevated from auto-immune status to delayed infection status, a m uch more clearly com pre hended pathology.
And so, the course is clear.Research must now be directed towards distinguishing auto immunity as an epiphenomenon after tissue injury, from that which is more intim ately concerned with the pathogenesis of specific disease.T h a t the body can produce antibodies to its own cells is fact, but this does not imply disease, indeed the increase of lymphosarcoma in patients with intensive immusuppressive therapy, and the increase in incidence of bowel tumours in patients with m ultiple myeloma m ight suggest that immune processes play an im portant part in th e clearing of cellular debris and the prevention of abnormal or neo plastic cells arising.A full answer must await the elucidation of the control of the immune response, its magnitude and direction, and a fuller understanding of what is so vaguely termed immunological response.
. E xperim ents in the N ew Z ealan d Black M ouse strain and its hybrids are also of interest here.M ic e of this strain appear norm al at birth, b u t between four and nine m onths of age develop a h aem olytic anaem ia analogous to hum an auto-im m une h aem olytic anaem ia.T h e first abnorm ality detectable is that their circulating red cells begin to give positive direct antiglobulin tests and eventually the test becom es positive in virtually 10 0 % of the m ice.T h e results of crossing of this type with other strains show that the auto-im m une char acter of N Z B m ice is expressed in different ways, but is present in its F 1 hybrids.It is not influenced by the sex of the N Z B parent and this indicates the transmission of disease to the offspring is n o t sex linked, and the m ilk factor