sumario

Alergol Inmunol Clin 2000;15:5-12

F. Ortiz Masllorns
Royal Academy of Medicine of Asturias. Chief Consultant in Immunology. Jimnez Daz Foundation. Madrid. Spain

Review article Autoimmune diseases and physiological autoimmunity: recognition of self

EVOLUTION OF THE CONCEPT OF AUTOIMMUNITY
The term "autoimmunity" might perhaps be disquieting and to some extent contradictory: to the word "immunity", which we are used to correlate with defence because its etymological derivation is allusive to the exemption of some damage or some burdensome obligation, the prefix "auto-" is anteposed. This would appear to suggest a defence against oneself. It is therefore not surprising that autoimmunity be counted among the concepts of Medicine that have experienced the most profound and far-reaching changes in the course of the short history of Immunology as a science. Ehrlich, one of the pioneers of Immunology and its first great theorist, in 1901 used the expression horror autotoxicus to refer to the "extremely dysteleological"(sic) situation that might result from the formation of "autotoxins" noxious for the individual himself1. Ehrlich thought that, considering that some antibodies directed against tissue antigens are able to generate lesive actions ("toxic" actions, as they were termed at that time) in experimental animals, the organism should have available, under normal circumstances, control mechanisms preventing the formation of antibodies against its own components, or preventing their "toxic" action. Without entering into the discussion about whether "autoantibodies" might actually be formed, he restricted himself to reasoning that, in the affirmative case, their possible noxious effects would have to be controlled so that health did not become deranged. Since that time, the expression horror autotoxicus has been repeated ad nauseam, though not always in its original sense2. Throughout the 20th Century, the term proposed by Ehrlich has been often used to postulate the belief that the generation of autoantibodies against ones own components might somehow be forbidden. It is possible that the rotund sonority of the Latin words led to their being used to dress up ideas that were not precisely coincident with those of their author, and to forget that he himself had already suggested the need to conceive possible failures in the internal regulation of the immune response in order to be able to explain some pathological phenomena. Whatever the interpretation given to Ehrlichs words may be, the truth is that three years later, in 1904, Donath and Landsteiner3 described the antibody, which now carried their names, that was responsible for the crises of haemoglobinuria a frigore which were then frequently seen in syphilis patients. This, now, is a true autoantibody, as it is not only able to react with human red blood cells from any individual, but also with those of the patient himself, both in vitro and in vivo. The demonstration of the existence of the biphasic DonathLandsteiner antibody proved that, at least under pathological conditions, antibodies were actually produced that were directed against components of oneselfs

Correspondence address: Dr. Fernando Ortiz Masllorns Maximino Miyar, 12, 2 A 33300 Villaviciosa (Asturias)

F. Ortiz Masllorns

own body and that were able to exert a "toxic" effect on the cellular elements involved, in this case the red blood cells. No particular importance was attached over the following decennia to the facts related to autoimmunity, despite the demonstration that in infectious diseases some of the antibodies generated were not directed against antigens of the microorganism, but against components of the host (the Wassermann reaction for the diagnosis of syphilis is a good example)4. This attitude changed but little when Rivers et al., in 1933, began publishing a series of experiments on the induction of neurological diseases in experimental animals through immunisation with nervous tissue broths or extracts. We now know this by the mane of experimental autoimmune encephalomyelitis (AEA), which has served as a model for the study of some human demyelinating diseases such as multiple sclerosis and postvaccination encephalitides. There are few episodes that are as demonstrative of the weight of prejudices as the attitude of Witebsky between 1953 and 1956. Witebsky, a disciple of Hans Sachs (who had himself been a predilect disciple of Ehrlich6), had by 1953 compiled sufficient data for demonstrating the experimental production of thyroiditis in rabbits injected with thyroid tissue. Out of fidelity to what he called the "law" of horror autotoxicus, Witebsky was unable to admit the validity of his own experiments, and spent three further years in searching for the errors he was convinced he had made, in which he expected to find an explanation for the results of his otherwise certainly brilliant investigations. When in that same years Dacie and Worlledge7, building on previous observations by Dameshek and Schwartz8 and applying the anti-immunoglobulin tests devised by my own teacher, Coombs9, achieved the demonstration of the autoinmmune nature of many human haemolytic anaemia, Witebsky again refused to accept this, as he firmly believed that the organism "was forbidden" to generate antibodies capable of reacting with its own structures. It was not until 1956 that Witebsky, surrendering to the irrefutable evidence of his own studies and of those of other investigators, finally decided to publish the data he had compiled on experimental autoimmune thyroiditis10. In that same year, and almost at the same time, Roitt et al.11 published their own work on Hashimotos thyroiditis demonstrating its autoimmune nature, and Adams and Purves12 reported the presence in the sera of hyperthyroid patients of a substance which they called LATS (for
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long-acting thyroid stimulator) and which was endowed with a potent and prolonged functional stimulatory effect on thyroid tissue in vitro. This opened the doors, in that year of 1956, to the modern age of the study of autoimmunity in its double clinical and experimental perspective. It is not happenstance that that same decade saw the inception of Burnets "clonal selection" theory13, which laid the foundations of the colossal edifice of modern Immunology. This is not the proper place and time to recount in detail the impassionating history of the knowledge of autoimmunity: what is pertinent is to find out what we now think about it. Jan Klein, a Czech immunologist transplanted into Germany, gave to one of his books, which was published in 1982 and soon achieved widespread diffusion, the title "Immunology: the science of self-nonself discrimination". With this he wanted to stress that one of the fundamental problems of Immunology, since a number of decades ago, resides in understanding the differences the immune system established between the recognition of components of ones own body and that of substances alien to it15. The recognition of the biologic "self" leads to its tolerance: there is no immune response, or at most a minimal, attenuated one, against what is one individuals own and peculiar self. The breakdown of that tolerance, the apparition of responses against self, the increase of already-existing responses to a quantitatively higher level or their qualitative modification are the manifestation of autoimmunity. In any case, its foreseeable pathogenetic consequences must be analysed in order to ascertain whether the autoimmune status necessarily causes disease, whether it is compatible with a healthy situation of the organs and tissues directly involved and of the organism as a whole, or even whether such a status is necessary in order to maintain a state of good health.

AUTOIMMUNITY AND DISEASE

In order to accept the existence of a state of autoimmunity it is sufficient to be able to demonstrate convincingly the presence of antibodies or of lymphocytes reacting specifically with components of the organism itself, even if the mechanism of their production and the ultimate reason for their presence remain unknown. The technical advances in immunologic diagnosis allow us to do this with increasing accuracy and sensitivity. As a consequence, the existence of states and situations of immunity directed

Autoimmune diseases and physiological autoimmunity: recognition of self

against a large number of components of our own organism in persons affected by the most variegate pathological processes, and even in individuals considered to be normal, becomes increasingly patent. When, as is quite often the case, the stigma of autoimmunity appears in a patient, we should ask ourselves: does he suffer a disease "because of" autoimmunity, or a disease "with" autoimmunity? Such doubts caused Witebsky, shortly after his "conversion" to autoimmunity and his abjuration from the "law of horror autotoxicus ", to lay down a body of criteria, which are reminiscent of Kochs postulates for the infectious diseases, in order to render it possible to state on an objective basis the supposedly autoimmune aetiology of some human diseases16. In summary, Witebskys postulates demanded, in order to establish the autoimmune nature of a disease, the demonstration of the existence of autoantibodies or autoreactive cells, the identification of the autoantigen involved, and the induction of a similar autoimmune response, accompanied by a disease similar to the human one, in some experimental animal. The advances achieved in Immunology since Witebskys original proposal led Rose (who had been one of his co-workers) in 1993 to revise, together with Bona, the criteria considered to be valid for the definition of autoimmune diseases. According to Rose and Bona17, the direct demonstrative test for the autoimmune nature of a disease is its passive transfer to a normal receptor. Such a procedure, which for ethical reasons is ruled out as an experimental one in the human species, had been however carried out in 1951 by Harrington et al.18 on himself and on a group of volunteers, using sera from patients with idiopathic thrombocytopenic purpura. As regards those autoimmune processes which are not mediated by antibodies but by autoreactive lymphocytes, patients having received an allogeneic bone marrow transplantation for the treatment of a leukaemia or an aplasia have sometimes suffered, as an unexpected and disagreeable complication, the development of an autoimmune disease (thrombocytopenic purpura, thyroiditis, myastenia, type 1 diabetes mellitus) which had been inadvertently present in the bone marrows donor19. There is furthermore one form of passive transfer occurring spontaneously as an "experiment of Nature": this is the passive transfer occurring between a mother with an autoimmune disease and the infant she bears in her bosom, and it is a highly instructive example for what we are presently discussing; I shall return to it later. On the other hand, it is possible to reproduce diseases similar to the human ones in experimental animals by transfusing to them antibodies ob-

tained from the plasma of patients or (in the case of the cellular aspect of autoimmunity) through the administration of patients lymphocytes to mice from strains unable to reject the human cells because they have an immune deficiency. Further criteria proposed by Rose and Bona consist in indirect tests, which suggest the autoimmune character of a process but do not suffice to prove it, or in circumstantial data that would promote the search for more determinant criteria. In my own opinion, the revision proposed by Rose and Bona does not represent a real advance in relation to Witebskys original postulates, which even today represent a sound basis for establishing the autoimmune character of a disease. Whichever the adopted criteria may be, it does seem to be beyond any doubt that autoimmunity can cause disease, because the autoantibodies or the autoreactive T lymphocytes are able, at least on certain occasions, to anatomically or functionally damage the organs or tissues on which they act20. As for the autoantibodies, an obvious demonstration of their pathogenetic capabilities is given, as I have pointed out earlier, by the neonatal syndromes arising because of the active transport of immunoglobulins from the maternal circulation to the foetal one21. Maternal autoantibodies belonging to the IgG class (the only one to pass from the mother to the foetus through the placenta) may cause in the newborn a myastenic syndrome, a derangement of the atrioventricular conduction, an hyperfunction of the thyroid gland, an anaemia or a thrombocytopenia. Thus, they are able to reproduce in the neonate manifestations that are those of the mothers autoimmune disease. These syndromes are almost always benign and limited in their duration to the duration of the persistence of the received antibodies, which are metabolised at a rate laid down by the biologic half-life of IgG, that is about three weeks. The most striking exception is the atrioventricular block occurring in the foetus when the mother suffers systemic lupus erythematosus and has high titres of anti-Ro (anti-SS-A) antibodies; these, after passing into the foetal circulation, irretrievably damage the conduction tissue. It should be recognised, however, that in this one and in other neonatal syndromes associated to maternal autoantibodies the simple passive transfer not always suffices as an explanation, as the immune system of the foetus bay, despite its immaturity, contribute to the pathogenesis or modulate the effects of the transplacentally received antibody. On the other hand, there are immunological markers of autoimmune character that, because they are frequently
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F. Ortiz Masllorns

associated to certain diseases, are highly useful for diagnosis or for the assessment of the patients status, even though their participation in the genesis or in the development of the disease may not have been demonstrated. This is for instance the case of the rheumatoid factor, which is arguably involved in some of the extraarticular manifestations of rheumatoid disease but has an uncertain significance as to the production of synovitis. The heterogeneity of the autoantibodies that are collectively designated "rheumatoid factor"22 renders the assessment of their participation in the pathogenesis even more difficult. This is also the case in systemic lupus erythematosus, in which an extensive constellation of autoantibodies occurs for many of which we do not have any hint of participation in the pathogenesis of the process23,24. In some cases, the autoimmune response is not the cause but rather the consequence of a disease or lesion of different origin. Burns, traumatisms (including the surgical ones), ischaemia and other processes that course with tissue destruction permit the release of tissue antigens against which specific antibodies arise that may be detected two or three weeks after the event. The autoimmune response arising under such circumstances is not an unimportant phenomenon, a curiosity for the learned, but may act and behave as a secondary pathogenic factor. This occurs, for instance, in Dresslers syndrome: pericarditis associated with pleuritis, with pneumonitis or with both in patients recovering from an acute myocardial infarction25.

NATURAL ANTIBODIES AND AUTOANTIBODIES

Since the first half of the 20th century we know of the existence in many individuals, healthy or diseased, of antibodies of highly diverse specificities, which are considered to be "natural" because they arise spontaneously and with no precise relationship to any immunising event26. Among the natural antibodies there are for instance those directed against the blood group substances, which may give rise to accidents because of the transfusion of incompatible blood, or those directed against the galactosyl epitope, which have achieved relevance because of their participation in the hyperacute rejection of xenotransplants. The specificities of the natural antibodies encompass a very extensive spectrum, in which some dozens of substances may be found that are integrant components of the organism itself: intracellular components, membrane re8

ceptors, circulating proteins, cytokines, hormones and their precursors and even small-size molecules, including cholesterol! We must therefore admit that there are autoantibodies, which represent a part of the large panoply of the "natural" antibodies. Because of their possible relationship to well-known autoimmune diseases, it should be stressed that one can demonstrate in the sera of almost all healthy subjects, if tested with sufficiently sensitive techniques, the presence of low titres of rheumatoid factor, of antinuclear, antierythrocyte and antityroglobulin antibodies, and of a host of other autoantibodies. A large proportion of the natural antibodies and autoantibodies, which are usually polyspecific and low-affinity ones, are produced by CD5+ B lymphocytes (also known as B-1 lymphocytes) that represent only a small fraction of the B cells entrusted with immunoglobulin synthesis27-29. The B-1 subpopulation is usually increased in patients with autoimmune diseases and in animals subjected to experimental autoimmunity. On the other hand, it is not infrequent to detect autoantibodies in human lymphoproliferative processes involving the CD5+ B-lymphocytes; this occurs, for instance, in chronic lymphoid leukaemias or in B-cell lymphomata. It is also rather usual to find an increase of the B-1 lymphocytes in aged persons, in coincidence with the fact that the presence of autoantibodies, which is the revealing hallmark of a autoimmune response, becomes more evident with advanced age30. In such advanced ages of life, and in contrast to a lesser formation of antibodies against exogenous antigens, one can observe an increase in the production of autoantibodies with various specificities: antinuclear, antithyroid, rheumatoid factor, and many others, among them the anti-idiotype antibodies that, as we shall see later, are but another form of autoantibodies. The findings are similar in all cases: higher rates of positivity and higher titres in aged subjects than in younger ones. Curiously, the positivity rates again decrease, yet without returning to normality, in the very aged individuals (80 to 90 years), and return to normal in the centenarians. This is usually attributed to diminished survival of the seropositive individuals: one might think, although there is no positive proof for it, that a loss or a weakening of the tolerance to the components of ones own organism in advanced age favours or predicts the development of diseases that may ultimately be lethal. And yet, the presence of autoantibodies in the aged is not usually associated to suffering the corresponding diseases. With few exceptions, autoimmune diseases appear in the younger or middle ages of li-

Autoimmune diseases and physiological autoimmunity: recognition of self

fe, and not in old age. One might therefore surmise that the autoantibodies appearing in senectude do not have, by themselves, pathogenic capabilities; they might perhaps even play a physiological role in the conditions inherent to ageing, as we shall later see. The existence of these forms of "natural" autoimmunity forces us on the one hand to try to establish their limits and their relations to pathologic autoimmunity, and on the other hand to establish what their functional significance is within the whole of the organisms economy. As regards the former, to establish the limits of natural autoimmunity amounts to as much as establishing up to what point the immune system of each individual is tolerant toward the components of his own body. Undoubtedly, in many instances the state of self-tolerance is not an absolute one, and one may even ask if a complete tolerance, both to bodily components and to foreign antigens, exists at all. By their own nature, the studies on tolerance are based on negative data suggesting the absence of a response. However, as the sensitivity of the methods used to a great extent conditions the positivity or negativity of the results achieved, the progressive improvement of the immunologic techniques has rendered it possible to detect minimal degrees of response in situations where such a response had not even appeared to exist. Faced with the states of tolerance, including that to the biologic "self", one should not think of a complete suppression of the ability to respond to the "tolerogen", to the antigen inducing such tolerance, but rather of a regulation to extremely low levels.

PHYSIOLOGICAL AUTOIMMUNITY
What may the functional significance of the autoimmunity states we detect in normal individuals now be? In 1975, and working on ideas previously put forward by Boyden, Pierre Grabar31 coined the concept of "physiologic autoimmunity". Wigzell, in 1977, proposed for it the term "positive autoimmunity"32. According to this concept, the presence of antibodies directed against normal substances or against tissue components of the body would help in the normal functioning of the organism, acting through various mechanisms. Among those mechanisms one might point out the elimination of metabolites and of cells or cell remainders that have become aged or altered through the passage of time or as a consequence of fulfilling their function. A few examples will illustrate what we understand as physiologic or positive autoimmunity.

Natural antibodies directed against cholesterol may contribute to the elimination of lipoproteins containing "bad" cholesterol, through a mechanism involving binding of the lipoprotein-antibody complexes to complement component receptors (mainly C3 fragment receptors) present in the cell membranes of a number of cells and especially in the red blood cells. The action of the anti-cholesterol antibodies is selective for the low-density lipoproteins, or LDL (and also for the very-low-density and intermediate-density lipoproteins, respectively VLDL and IDL), because what the antibody recognises is the 3-hydroxy group of the cholesterol molecule. This epitope, however, is not exposed on the surface of the highdensity lipoprotein (HDL) molecules because of their high protein-cholesterol ratio. In this way, the natural antibody discriminates between the "good" and "bad" varieties of plasma cholesterol33. The rheumatoid factor, an autoantibody directed against antigenic determinants in the constant regions of IgG, is present at high titres in a high proportion of the patients with rheumatoid arthritis and with some other connective tissue diseases, but it is also present in small quantities in almost all normal subjects. In the latter, its titre and affinity transiently increase under the action of immunogenic stimuli such as infections or vaccinations34,35. Besides its eventual pathogenic role in a number of diseases, under normal conditions the rheumatoid factor co-operates in the elimination of the antigen-antibody complexes that are formed in very small quantities (and in slightly higher quantities in the situations pointed out) as a result of the normal functioning of the immune system. In a similar way, antibodies directed against the red blood cells, which react better with the aged cells than with the newly-formed ones, help in selectively eliminating the deteriorated erythrocytes which gradually become less efficient in their oxygen-transport function. Other physiologic autoantibodies participate in the rapid elimination of nuclear or cytoplasmic components that are occasionally released, and thus prevent them from triggering more significant autoimmune responses. Paradoxically, the "physiologic" autoimmunity protects against the development of a "pathogenic" one. These examples, and further ones that might be proposed, refer to minimal manifestations of an autoimmune response that is regulated down to infinitesimal levels and may only be perceived when it is given much attention and when highly sensitive procedures are used for detecting it. Many of the diseases that are classed as "autoim9

F. Ortiz Masllorns

mune" might be considered to represent the result of an exaggeration of the corresponding physiologic phenomena, which would turn into pathogenicity factors when the titre or the affinity of the normal autoantibody increase, or when its isotype changes, or when the activity or the subpopulation of the physiological reactive lymphocytes change. Thus considered, the fundamental core of the autoimmune diseases often resides in a qualitative change, and sometimes also in a quantitative one, in the regulation of the response to antigenic components of ones own body. According to this point of view, autoimmunity is not a sporadic, disease-causing event: when it remains within the adequate levels, it is a further one among the physiologic mechanisms that, continually and inapparently, act to preserve the composition and functioning of our organism within their normal limits. The breakdown of the tolerance to self that gives rise to a pathological state of autoimmunity would then be nothing else than a more or less far-reaching derangement in the regulation of the immune recognition that is constantly occurring within and regarding ones own body.

IMMUNOLOGIC RECOGNITION OF ONES OWN SELF

There are a number of facts that demonstrate that recognition of the biologic "self" is a necessary mechanism for the good functioning of the organism. In the ontogenetic development of the T lymphocytes, occurring mainly in the thymus, the recognition of histocompatibility antigens and of other molecules of the individual himself ensures the double selection of the precursors: a negative selection leading to the elimination of the lymphocyte clones that would respond in excess against "self", and a positive one promoting the maturation of those clones that are able to recognise the histocompatibility proteins, necessary for antigen presentation36. We know in fact that most T lymphocytes, endowed with the ab receptor, cannot recognise antigenic peptides unless they are offered to them on the surface of antigen-presenting cells in association with the latters own histocompatibility molecules2,37. But there is still more: the antibody molecule produced under the stimulus of one antigen has, because it is specific for that antigen, a unique antigenic peculiarity (the idiotype), which renders it different from antibodies with other specificities, and against which a second antibody (anti-idiotype) is formed that recognises it 38,39. The
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anti-idiotype response, when cunningly manipulated, gives rise to surprising phenomena that are none the less true because they are striking, such as prophylactic immunisations against infectious diseases without the need for microbial antigens, or the imitation of hormone effects in vitro and in vivo in the absence of the true hormone. Above all, however, the idiotype-anti-idiotype interactions intervene in the regulation of the immune response, limiting its duration and its intensity. It is not difficult to become aware that the idiotypic regulation of the immune response is a form of recognition of "self" structures by other structures that are equally "self" and of similar nature. The antiidiotypes an individual forms against his own antibodies at all events merit being considered as autoantibodies. The natural killer (NK) cells represent the third lymphocyte population, distinct from those of the T and B cells. Through their mainly cytotoxic or cytolytic action they participate in the antimicrobial defence and in the "immunologic surveillance" against tumoural growth that helps maintain the homeostasis of the organism. In order to act against their target cells they use a strategy that might be termed one of "negative recognition". Whereas a T or B lymphocyte becomes activated when it positively recognises the presence of the antigen, the NK lymphocyte becomes activated when it is unable to recognise histocompatibility antigens on the surface of the cell with which it has made contact. The receptors on NK cells are "inhibition receptors"40, as they maintain the lytic activity of the cell in a state of inhibition as long as they are recognising the presence of histocompatibility antigens. Because of this, their targets are infected cells or those in the process of malignant transformation, in which the expression of such antigens is abolished, reduced or altered. The human placenta is, on its motherly side, rich in a form of large granular cells that evidence morphologic and functional similarity to the NK lymphocytes. These cells are a part of a complex mechanism that demands, for the success of the reproductive process, the immunologic recognition of foetal antigens by the mother in order to guarantee the presence of cell populations and the production of cytokines required in these circumstances41,42. However, if the syncytiotrophoblast, as the foetal surface exposed to the maternal circulation, should express histocompatibility antigens of paternal origin that are foreign to the mother, the foetus would be immunologically attacked and the pregnancy would be unable to progress. In the opposite situation, if the syncytiotrophoblast should be completely devoid of histocompatibility antigens it

Autoimmune diseases and physiological autoimmunity: recognition of self

would be an easy and ready target for the NK cells and for the granular cells of the placenta. This double difficulty is obviated through the expression by the syncytiotrophoblast of a particular protein, HLA-G43, which is coded for by genes of the major histocompatibility complex (MHC). The HLA-G antigen is not polymorphic and thus does not create materno-foetal incompatibility problems, but it does have the basic structures required for recognition by the "inhibition receptors" of the NK cells and their equivalents, which in this way remain in their inactive status and do not attack the foetal membranes.

cessary ally which may sometimes turn against ourselves. In Ehrlich, close to a century ago, invented the expression "horror autotoxicus" to refer to the risk that might be derived from the response against ones own antigens, we must now return, as Avrameas proposed in 1991 26, to a renewed version of the classical dictum "know thyself!", convinced as we are that the homeostasis of the organism and its defence against what is alien to it are based in the continuing inspection of our own identity by our own immune system.

REFERENCES FINAL CONSIDERATIONS

After considering all the foregoing, we must ask ourselves one question: if a recognition of our own structures is constantly going on, and if autoimmune responses are continuously occurring at a rate excluding abnormality, shall we have to abandon the idea that the immune system discriminates between what is our own and what is alien to us, between the biologic "self" and the "non-self"? Shall we have to forget the definition of Immunology put forward by Klein14? Not at all! What happens is that the discrimination between self and nonself cannot be postulated in a clear-cut manner, as an allor-nothing phenomenon, but must be depicted with subtler nuances. It is not a matter of presence or absence of response, but one in which in the immune response, and depending on the origin of the antigen among other factors, there may be changes in the quantity, the affinity or the isotype of the antibodies formed, or in the degree of proliferation of each of the lymphocyte populations, or in the amount of each cytokine that is secreted, or in the expression of the latters receptors; in summary, there may be changes in the complex interplay of so many regulating factors. When it becomes impossible to carry out a fine regulation of all the variables is when the normal, physiological autoimmune response turns into a pathogenic event. Autoimmunity, insofar as it is a cause of disease, reveals a derangement in the regulation of the recognition or of the response to the components of ones own body. We must yet once again review and revise our mental schemes about autoimmunity, and modify them in the light of what new discoveries are continuously teaching us. Autoimmunity can no longer be viewed simply as a menacing enemy, but it must be considered to be a ne1. Ehrlich P , Morgenroth J. Zytotoxine als Antikrper. Berl Klin Wochenschr 1901; 38: 251-260. 2. Adams D. How the immune system works and why it causes autoimmune diseases. Immunol Today 1996; 17: 300-302. 3. Donath J, Landsteiner K. ber paroxysmale Hmoglobinurie. Mnch Med Wochenschr 1904; 51: 1590-1601. 4. Weil E, Wien BH. Antikrper in den Infektionskrankheiten. Klin Wochenschr 1909; 22: 372-379. 5. Rivers TN, Sprunt DH, Berry GP . Experimental allergic encephalomyelitis. J Exp Med 1933; 58: 39-54. 6. Silverstein AM. A History of Immunology. San Diego: Academic Press, 1989. 7. Dacie JV, Worlledge S. Autoimmune haemolytic anaemias. Prog Hematol 1969; 6: 82-120. 8. Dameshek W, Schwartz SO. On the pathogenesis of hemolytic anemia. N Engl J Med 1938; 218: 75-82. 9. Coombs RRA, Mourant AE, Race RR. A new test for the detection of weak and "incomplete" Rh agglutinins. Br J Exp Pathol 1945; 26: 255-266. 10. Rose NR, Witebsky E. Studies on organ specificity. V. Changes in the thyroid glands of rabbits following active immunization with rabbit thyroid extracts. J Immunol 1956; 76: 417-427. 11. Roitt IM, Doniach D, Campbell PN, Vaughan Hudson R. Autoantibodies in Hashimoto's disease (lymphadenoid goitre). Lancet 1956; 2: 820-821. 12. Adams DD, Purves HD. Abnormal responses in the assay of thyrotropin. Proc Univ Ontago Med School 1956; 34: 11-12. 13. Burnet FM. The clonal selection theory of acquired immunity. Londres: Cambridge University Press, 1957. 14. Klein J. Immunology: the science of self-nonself discrimination. Nueva York: John Wiley & Sons, 1982. 15. Schwartz RS. Mechanisms of autoimmunity. En Rich RR, ed. Clinical Immunology. Principles and practice. San Luis: Mosby, 1996; 1053-1061. 16. Witebsky E, Rose NR, Terplan K, Paine JR, Egan RW. JAMA 1957; 164: 1439-1447. 17. Rose NR, Bona C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunol Today 1993; 14: 426-430.

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18. Harrington WJ, Minnich V, Hollingsworth JW, Moore CV. Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura. J Lab Clin Med 1951; 38: 1-12. 19. Marmont AM. Defining criteria for autoimmune diseases. Immunol Today 1994; 15: 388. 20. Naparstek Y. The role of autoantibodies in autoimmune disease. Annu Rev Immunol 1993; 11: 79-104. 21. Lefvert AK. Maternal antibodies. En Roitt IM, Delves PJ, ed. Encyclopedia of Immunology. Londres: Academic Press 1992; 10381042. 22. Ortiz Masllorns F. El factor reumatoide como ejemplo de la heterogeneidad funcional de las inmunoglobulinas. Inflamacin-93 1992; 3: 487-496. 23. Reichlin M. Systemic lupus erythematosus. En: Rose NR, Mackay IR, ed. The autoimmune diseases. San Diego: Academic Press, 1998; 283-298. 24. Eilat D, Naparstek Y. Anti-DNA antibodies: a puzzle of autoimmune phenomena. Immunol Today 1999; 20: 339-342. 25. Dressler W. A postmyocardial infarction syndrome. Preliminary report of a complication resembling idiopathic recurrent benign pericarditis. JAMA 1956; 160: 1379-1382. 26. Avrameas S. Natural antibodies: from 'horror autotoxicus' to 'gnothi seauton'. Immunol Today 1991; 12: 154-159. 27. Burastero SE, Casaoli P . Characterization of human CD5 (Leu-1, OKT1)+ B lymphocytes and the antibodies they produce. En Del Guercio P , Cruse JM, ed. B lymphocytes: function and regulation. Basilea: Karger, 1989; 231-262. 28. Kipps TJ. The CD5 B cell. Adv Immunol 1989; 47: 117-185. 29. Murakami M, Honjo T. Involvement of B-1 cells in mucosal immunity and autoimmunity. Immunol Today 1995; 16: 534-539. 30. Ortiz Masllorns F. Inmunidad y envejecimiento. En Segovia de Arana JM, ed. Biosociologa del envejecimiento. Madrid: Farmaindustria Serie Cientfica, 1997; 69-81. 31. Grabar P . The historical background of Immunology. En Stites DP ,

Stobo JD, Fudenberg HH, Wells JV, ed. Basic & clinical Immunology. Los Altos: Lange Medical Publications, 1982; 1-12. 32. Wigzell H. Positive autoimmunity. En: Talal N, ed. Autoimmunity: Genetic, immunologic, virologic, and clinical aspects. Nueva York: Academic Press, 1977; 693-707. 33. Alving CR, Wassef NM. Naturally occurring antibodies to cholesterol: a new theory of LDL cholesterol metabolism. Immunol Today 1999; 20: 362-366. 34. Evered D, Whelan J. Autoimmunity and autoimmune disease. Chichester: John Wiley & Sons, 1987. 35. Levinson AI. Nature of the stimulus for rheumatoid factor production. En: Shakib F, ed. Autoantibodies to immunoglobulins. Basilea: Karger, 1989; 135-150. 36. Punt JA, Singer A. T cell development. En Rich RR, ed. Clinical Immunology. Principles and practice. Sant Luis: Mosby, 1996: 157-175. 37. Ortiz Masllorns F. Iniciacin a la Inmunologa. Madrid: Fondo Bibliogrfico Fundacin Jimnez Daz, 1997. 38. Bona CA. Idiotype: internal image and network. En Roitt IM, Delves PJ, ed. Encyclopedia of Immunology. Londres: Academic Presss, 1992; 723-732. 39. Carson DA, Chen PP , Kipps TJ. Idiotypes in Biology and Medicine. Karger. Basilea: Karger, 1990. 40. Moretta A, Bottino C, Vitale M, et al. Receptors for HLA class-I molecules in human natural killer cells. Annu Rev Immunol 1996; 14: 619-648. 41. Scott JR, Rote NS, Branch DW. Immunologic aspects of recurrent abortion and fetal death. Obstet Gynecol 1987; 70: 645-653. 42. Snchez-Cuenca J, Martn JC, Pellicer A, Simn C. Cytokine pleiotropy and redundancy - gp130 cytokines. Immunol Today 1999; 20: 57-59. 43. Carosella ED, Rouas-Freiss N, Paul P , Dausset J. HLA-G: a tolerance molecule from the major histocompatibility complex. Immunol Today 1999; 20: 60-62.

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