Volume 66
Number 1 part 2
The Journal of P E D I A T R I C S
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"Autoimmune" disease--possible mechanisms DR. LAWRENCE. One of the current conjectures is that eczema may be an expression of an altered immune response to one's own tissues-an autoimmune disease. With this assumption in mind it may prove useful to consider briefly selective examples of immunologic phenomena which may mimic "autoimmune" disease and thereby be mistaken for it. There are three prototypes of such altered responsiveness I would like to discuss--one of which is known and two only suspected on the basis of current information. Each has as its basis the acceptance of the immunologic reality that we learn to recognize our own tissues and their products in embryonic life and all materials encountered thereafter are foreign and capable of eliciting an immune response. This state of affairs was postulated in the "self-recoguition '~
precept of Burnett and Fenner 169 and experimentally proved in the laboratory by Billingham, Brent, and Medawar. 17~ 1. Cross-reacting antigens. There exist in nature microbes which happen to possess chemical configurations in their structure which are also common to certain mammalian tissues. 1~ The host infected by these microbes may produce antibody(ies) which although induced by the microbe may also interact with certain of his own tissues. Although no disease has been clearIy ascribed to this mechanism some curious immunologic phenomena have been observed. One example occurred when patients with pneumococcal infections were treated with antipneumococcaI horse serum. Finland 1T2 discovered that horse serum containing antibodies to Type X I V pneumococcus caused agglutination of hu-
A
B
D
C Fig. 69. Delayed reactions transferred by means of leucocyte extracts compared to those achieved with dialysates of leukocyte extracts. A, Tuberculin reaction (35 by 40 ram.) at 24 hours in negative recipient 3 weeks after transfer with frozen and thawed white blood cell extract. B, Tuberculin reaction (35 by 20 ram.) at 24 hours in negative recipient 3 months after transfer with dialysate of frozen and thawed DNase-treated white blood cell extract. C, Coccidioidin reaction (45 by 25 ram.) at 24 hours in negative recipient 1 week after transfer with frozen and thawed DNase-treated white blood cell extract. D, Coccldioidin reaction (35 by 45 ram.) at 24 hours in negative recipient 3 months after transfer with dialysate of frozen and thawed DNase-treated white blood cell extract.
24 6
Holt: Con[erence on in[antile eczema
Fig. 70. Transfer of skin homograft sensitivity (accelerated rejection) by means of transfer factor sensitized to individual A's skin. Photoshows skin grafts on fourth day of residence 12 days after transfer, A's graft having undergone accelerated rejection while graft from unrelated donor (control) is unaffected and survived 11 days.
man erythrocytes. This mysterious occurrence became understandable when it was demonstrated that the polysaccharide of Type X I V pneumococcus and blood group A substance possessed similar antigenic configurations. 17a A more recent example of this phenomenon has been elucidated by Kaplan and Meyers e r i a n ~ in relation to a mechanism for the pathogenesis of rheumatic fever. These authors found that group A streptococci share an antigen with muscle fibers of cardiac and vascular smooth muscle of h u m a n subjects. The possibility of streptococcal infection inducing the production of an antibody which cross-reacts with the patient's cardiac muscle has great import in relation to mechanisrds of tissue damage in rheumatic fever. I n each example cited, if the cross-reactivity had not been established, the phenomena observed could have been considered "autoimmune." 2. Alteration of the individual specificity of tissues. We have proposed elsewherC~S, 176 a concept that views delayed allergy and homograft sensitivity as variants of a similar response which may mimic "autoimmune" states. Here it is postulated that extraneous envh'onmental agents (X), as a consequence of preferential (tubercle bacillus), obligatory (virus), or accidental (simple chemical) intracellular residence, alter the genetic individuality (self) of the host's tissues. This altered self-component upon phagocytosis by retieuloendothelial elements is recog-
January 1965
nized as foreign to the extent that the extraneous material has aItered the self-component with the elaboration of a transfer factor against the (self + X) complex. I n this context the delayed type of allergic inflammatory response may be viewed as a local type of homograft reaction, and the sensitized individual as one inadvertently misled into reacting against his own tissues as foreign (e.g., lung, skin) in the presence of the specific antigen (e.g., tubercle bacilli, tuberculin). This viewpoint is supported by the demonstration that transfer factor is a highly specific mediator of the tissue damage encountered in delayed allergy induced by bacteria, 177, 1~8 by fungi, 179 (Fig. 69) and by skin homografts is~ (Fig. 70). The properties and behavior of transfer factor in leukocyte extracts of human subjects have been summarized elsewhere 176, 181 and need not be detailed here. Of interest perhaps is our more recent finding that transfer factor is a dialyzable material of low molecular weight (40,000) which is not a protein or a globulin fragment and therefore not an antibody in the conventional sense. 182 3. Central failure of cells engaged in selfrecognition. There is not much to be said about this third possible mechanism of autoimmune disease except to acknowledge the possibility that it exists. However, it is a fact that our cells are dead and dying continuously and have in turn to be phagocytized and digested. This would suggest that despite the preservation of the genetic (i.e., antigenic) individuality of the self-components it is possible that the ceils engaged in self-recognition may malfunction and become inefficient or disabled. This could result in an aberrant recognition of "self" as foreign and the launching of an inappropriate immune response. There is as yet no disease or state to express this condition exactly. However, the laboratory model of "runt disease" produced in embryonic recipients of immunologically competent cells (i.e., the graft verses host reaction) may represent a close facsimile. 18a In any event, this last possibility wouId truly qualify for the adjective "autoimmune" if by this term one means a central failure of self-recognltion homeostasis with resultant damage to one's own tissues via immune factors. This sort of classification of possible mechanisms underlying autoimmune disease is in the nature of our current knowledge liable to be neither entirely accurate nor complete. It is hoped that its value may Iie in functioning as a
Volume 66
Number 1 part 2
"Autoimmune"
scaffold u p o n w h i c h to build, where it is understood that alterations are continually in progress. T h e unsettled role of the serum antibodies detected in experimental and clinical a u t o i m m u n e states as instruments of the tissue damage encountered has been c o m m e n t e d upon elsewhere.iS4, 185 W h a t I have said, it is quite apparent, is somewhat far afield from the problem of eczema which I have not studied. I t may, however, be of interest to this group in that it m i g h t offer leads for the future study of eczema. DR. SULZBEROEm One question, Dr. Lawrence. Have you ever tested the skin of sensitive individuals with your dialysate? DR. LAWRENCE. Yes. I t has no skin r e a c t i o n inducing properties. W e studied two individuals exquisitely sensitive to tuberculin; to one we gave the dialysate repeatedly, but we got no skin reaction. DR. SULZBERGER, I have no disagreement with anything Dr. Lawrence has said; it was beautiful
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work and has a deep significance for m a n y types of immunologic phenomena. I believe I advanced a similar hypothesis in 1940 lss regarding the interaction of antigen with the body cell forming a new effective antigen. I dislike the t e r m " a u t o i m m u n e disease" because we are almost all really a u t o i m m u n e almost all the time. N o r m a l l y in health we are i m m u n e to our own body material w h i c h produces no sensitivity in us. T h e happenings t h a t we call " a u t o i m m u n e disease" rest upon the fact that the individual becomes sensitized to substances in his body in a pathologic w a y - - o r at least in an unusual w a y - - i n contrast to the normal individual who remains i m m u n e to his own tissue. These are really "autosensitive diseases." You diametrically, violently change tile m e a n i n g of the words " i m m u n e " a n d " i m m u n i t y " if you call these reactions " a u t o i m m u n e . " I a m autoimmune, I believe, and I hope you all are and stay so.