This Golden Anniversary of Burnet's landmark article in 1957 on antibody production 'using the concept of clonal selection'1 is a timely commemoration, particularly among those who 'were there when it happened.'. Immunology then was very different from what it is today, mostly comprising antibody production and specificity, allergies, cell-dependent processes including phagocytosis, and delayed-type cutaneous sensitivity and homograft rejection attributable to cell-bound antibodies. There were no B lymphocytes, no thymic production of T lymphocytes nor polarized subsets thereof nor regulatory cells, no major histocompatibility complex, no dendritic cells nor antigen presentation, no cytokines nor chemokines, no inbred nor congenic nor transgenic nor gene knockout mice: can this possibly be imagined? Yet clonal selection theory (CST) still remains the bedrock on which contemporary immunology squarely rests.
Burnet's spectacular research career has attracted many tributes of which the few here are selected from a supplement 'A Lifetime of Creativity' commemorating his 80th birthday in 1979, published in the 1978–1979 Annual Review of the Walter and Eliza Hall Institute.2 M Cohn (pp 9–13) chose lysogeny as his illustration of Burnet's creativity, a quality he associated with several characteristics including 'controlled or disciplined fantasy (imagination)' and 'being demonstrated repeatedly in the lifetime of an individual'. PB Medawar (pp 31–33) lauded Burnet's great gift of 'imaginative synthesis' illustrated specifically by the designation of self-tolerance as an acquired characteristic,3 the citation for Burnet's Nobel Award in 1960—'it is hard to think of two phenomena more disparate than on the one hand certain virus ailments that trouble mice, and on the other hand the unusual placental arrangements of dizygotic twin cattle which lead them to become red cell chimeras and mutually tolerant of each others grafts; yet both of them are comprehended within Burnet's conception of the biology of self-recognition, the cornerstone of his theory of the immune response'. NK Jerne whose natural selection theory of antibody production had been published 2 years earlier4 wrote as follows (pp 34–38): 'The enormous advances since 1957 in our knowledge of the immune system have proven Burnet's hypothesis to be basically correct, even in its very first formulation. No further comments are needed. I hit the nail, but Burnet hit the nail on its head'—this tribute followed a whimsical essay 10 years before in which Jerne had described the Clonal Selection Theory as 'the complete solution to immunology'.5 My own tribute in the WEHI Review is on 'Burnet and Autoimmunity' (pp 39–45) and opens with: 'Burnet's longest and most passionate concern in science—he refers to it as an obsession—was the enigma of non-self discrimination by the immune system. This concern makes Burnet's interest in autoimmunity readily understandable'. This 'obsession',6 which was influential for my research career, can be traced back to 1940.7 I noted that, initially, Burnet was in little sympathy with Jerne's idea, 'mainly because I could not see how this approach could cover the self-non-self differentiation which I shall always regard as crucial to all immunological theory'.8 Later, however, and perhaps influenced by ideas of Talmage (see the monograph of Podulsky and Tauber9 p41), Burnet was to consider it more satisfactory 'if the replicating elements essential to any such theory were cellular in character ab initio',1 rather than antibody as in Jerne's theory.4 Moreover Burnet came to realise that a selection theory provided a release from the need to postulate some form of positive recognition of self, noting that 'we have always recognized the clumsy character of the self-marker self recognition scheme'.1 And further 'it is a great virtue of the Jerne hypothesis that it provides an alternative method of recognizing self from non-self, since any clones of cells which carry reactive sites corresponding to body determinants will be eliminated'.1
While Burnet's 1957 article was adequately explicit, it was in the Flexner lectures delivered a year later at Vanderbilt University Medical School, and published as a monograph in 1959,10 that the implications of CST were fully explored in the context of most of what was then known about immunology. However, for the purposes of this review, attention will be particularly directed to Chapter VIII, 'The Pathology of the Immune Response', containing one of Burnet's neat aphorisms (p 122: 'it is a truism that the best test of a physiological concept is its application to pathological conditions'. Accordingly, then, Burnet examined the applicability of CST to disease states in which the essential pathogenesis seemed to depend on malfunction of the mechanisms of immunity. Among these he listed allergic diseases (adroitly bypassed in the monograph), some candidate autoimmune diseases and congenital agammaglobulinaemia. However Burnet was not at that time entirely comfortable with the categorization of autoimmune disease, since he cites Hashimoto-type thyroiditis as the only 'fully established entity' in representing an immunological attack on a normally inaccessible antigen and, among others, haemolytic anaemia and 'collagen diseases proper' were distinguished as resulting from 'a dysfunction of some of the cells producing antibody globulin' (p 132). Curiously, Burnet did not mention experimental autoimmune encephalomyelitis despite this being at that time the most widely available model of autoimmune disease, and one which Burnet had discussed earlier on in 1948 in speculations on autoimmunity.11 Chapter VIII developed some 'corollaries' that became integral to his thinking: 'If the clonal selection hypothesis is correct, antibody-producing clones must, from their nature, be subject to a high level of random somatic mutation in regard to the pattern of gamma globulin produced'. Some of these mutant patterns would be 'forbidden, that is, capable of reaction with self-components', and this would call for 'some means by which minor somatic mutations giving rise to forbidden patterns ......are rendered ineffective', by what was termed 'homeostatic mechanisms'. One such mechanism could be the antigen concentration to which an antibody-producing cell might be exposed (p 65). Somatic mutation in the context of autoimmune disease is reconsidered again later (see below), but we can note that Burnet (an avowed Darwinian) remarks (p 140): 'It is a legitimate objection to somatic mutation wherever it is used that it makes it too easy to explain anything. This should not, however, inhibit us from using the concept where it is needed'.
An engagement with autoimmunity
As it happened, the publication of Burnet's 1957 article1 coincided rather closely with my return to Melbourne from abroad, bent upon a career in gastroenterology, which then was the major interest of the Clinical Research Unit associated with the Hall Institute and the adjacent Royal Melbourne Hospital. Burnet's ideas mesmerized me, and more so following our fortuitous discovery of positivity with an 'Autoimmune Complement Fixation Test' (developed for other purposes) using sera from patients with a hitherto obscure form of chronic active hepatitis.12 Notably, such patients had already been ascertained by positivity in tests on clotted blood for lupus erythematosus cells, as a suggestive indicator for autoimmunity.13 This evidence , plus published data on the antiglobulin test in 'acquired' haemolytic anaemia, and on a red cell agglutination test for rheumatoid factor (anti-Fc of IgG), together with the clear insufficiency of the 'collagen vascular disease' hypothesis for systemic lupus erythematosus (SLE) and analogous multisystem rheumatic diseases, led to my entry into a life-long career in autoimmunity. In the event, this suited Burnet quite well and drew him into close and fruitful associations in the clinical arena.
Shortly after publication of his monograph on CST,10 Burnet received an invitation from a North American publisher to write a text on autoimmune disease. He referred this to me with a wily comment that academic progression can be enhanced by the authorship of a book, by which time (1960–61) my enthusiasm had become more aroused by further developments, notably the discovery in Dunedin, New Zealand, of spontaneously occurring autoimmune disease in the New Zealand Black strain of mice (with Burnet losing no time in acquiring these for the Hall Institute), and by the introduction of Coons' procedure of indirect immunofluorescence as a versatile procedure for detection of an autoantibody in serum. During 1961, as my writing proceeded, it was amazing to realize how many diseases hitherto described in medical texts as 'of unknown aetiology' fitted readily into the autoimmune category.14 The theoretical section of the monograph was constructed around the principles of CST, with autoimmune reactivity being ascribed to emergence of 'forbidden clones' that had arisen via somatic mutations in the genetic machinery for production of antibody and its antigen recognition site, together with failure of regulatory homeostasis to eliminate such clones. Comment was directed to the characteristic clustering of autoimmune diseases within individual patients and among their family members, foreshadowing the major interest today in the multiple genetic contributions to autoimmune disorders (see below). Soon after publication of 'Autoimmune Diseases' in 1963,14 a prevailing scepticism over the concept of autoimmunity slowly began to abate, and finally subsided following a widely attended international meeting on autoimmune disease sponsored by the New York Academy of Sciences, published in two volumes in 1965.15
An intention to compile a second edition of the 1963 monograph to accommodate the rapidly expanding knowledge on autoimmunity became diverted by more immediate research needs and the evident lack of any wholly satisfying experimentally based explanation for natural immune tolerance. However, Burnet in 1972 did publish a largely theoretical monograph, Autoimmunity and Autoimmune Disease,16 in which he retained earlier concepts10, 14 including forbidden or rogue clones of lymphocytes consequent on somatic mutagenesis as agents of autoimmune attack. He was encouraged particularly by Burch's mathematically-based interpretations of data on age-specific occurrence applied to some typical autoimmune disorders, notably SLE,17 and some less well-validated chronic disorders including Dupuytren's fibrotic contracture of the fingers,18 psoriasis, dental caries and others. Burch emphasized the stochastic nature of the occurrence of these diseases, and theorized that the age-specific incidence rates reflected the occurrence of a limited number of sequential somatic gene mutations involving recognition of autoantigen by forbidden clones of lymphocytes.19
However, during the 1970s, there developed many other preoccupations for autoimmunity, as indeed for immunology in general, including an ever-widening range of laboratory technologies and increasingly diverse experimental animal models. Moreover the rise of molecular immunology was then about to begin—the ensuing seminal discoveries and heated controversies have been analyzed in the context of immunological self and clonal selection theory by Podulsky and Tauber.9 So, by the 1980s, autoimmunity had acquired such multiple layers of complexity, and expanded inventories of candidate diseases, that a multi-authored text seemed the only solution to presenting collective knowledge. This was accomplished in collaboration with NR Rose of the John Hopkins Medical School, Baltimore, MD, USA with four editions called for between 198520 and 2006,21 and with the latter accommodating some 80 different autoimmune disorders.
Autoimmunity: 50 years after clonal selection theory
Presently, 50 years after CST, there remain many pressing problems, relevant to both the clinical and experimental arenas.
Attaining a definition of an autoimmune disease
Despite assignments since the 1950s of 'postulates' or 'markers' of an autoimmune process, most recently in 1993,22 the border remains porous. In fact, there are unfulfilled needs for definition criteria even for many individual diseases in the autoimmune category, resulting in two schools of thought on definition, 'nominalist' and 'essentialist'.23, 24 And further, authorities on autoimmunity regularly include questionable disease entities, celiac disease and ulcerative colitis among others despite the likely provocative agents, dietary gluten and colonic microflora respectively, not being self constituents in the strict sense. And still further, there is now recognized a diverse group of diseases, referred to by some as autoinflammatory, that appear to depend more on activation of processes of innate immunity; prevalent examples are the inflammatory components of atherosclerosis affecting the arterial wall,25 and steatohepatitis affecting the liver.26 In these examples, 'unphysiological' cellular accumulations of lipid provoke release by phagocytic cells of proinflammatory cytokines that cause tissue injury and fibrosis. Further distinctions between innate and adaptive autoimmunity were discussed in relation to induced genetic deficiency in mice of the enzyme 
-mannoside II that is prejudicial to the innate immune functions of mannose-binding lectins in serum.27
Recognition of the community burden of autoimmune disease is insufficiently appreciated
An estimate was made in 1997, for the first time, using published data on known prevalences of autoimmune diseases, of the overall population prevalence of such diseases: from this emanated the often cited figure of approximately 5%.28 More recently the population prevalence for 31 possible or probable autoimmune diseases was ascertained from the National Patient Register of Denmark to yield a similar population prevalence figure of 5%29 and, as well, there was revealed an extensive comorbidity across the 31 diseases within individuals, and aggregation within families. However, the burden is not merely numerical, since many autoimmune diseases confer life-long disability and create heavy demands for therapeutic resources. It can be noted that 'autoimmunity' is finally becoming as much a household word as many of the major diseases (rheumatoid arthritis, lupus, type 1 diabetes, multiple sclerosis) that it encompasses, and a call could be made on medical school curricula to encourage a greater awareness among practising doctors of the role of the immune system in health and disease to enable earlier diagnosis and better management.
The evolution of autoimmunity follows that of a normal immune response
A normal immune response begins in a peripheral tissue wherein an 'offending' antigen is endocytosed by a dendritic cell and thence transferred to the regional lymph node. Here an immune response proceeds via the germinal centre reaction in lymphoid follicles wherein there occurs activation of T and B lymphocytes with return to the affected tissue of activated T cells and specific antibody to dispose of the inciting antigen, so terminating the response. Very likely, autoimmune responses proceed in the same way,30 but with important provisos. Thus, for an autoimmune response to proceed, there needs to be coexisting inflammation such that antigen-presenting cells (APCs) are appropriately activated, natural immune tolerance must be in some way compromised and, finally, the response does not terminate because auto-antigen cannot be eliminated. Of course, there are many uncertainties in this scenario including the source and degree of the coexisting inflammation, the range of stimuli that activate Toll-like receptors (TLR) on a APC, and whether the initial stimulus is provided by spillage of native auto-antigen, by an apoptotic fragment, or by an auto-antigenic mimic.31 Maintenance of the reaction in the regional lymph node is the next step. This depends on whether low-prevalence auto-antigen-responsive T cells, as escapees of central tolerance in the thymus, happen to be en passage through the node, whether various cytokine–chemokine signalling pathways are conducive, whether processes of apoptosis are intact and, overall, the nature of the deficits in immune tolerance. Although tolerance was predicted by Medawar32 in 1960 as likely to be comprehended 'within a few years', this extraordinarily complex process comprises as many as 24 'overrides' or 'checkpoints' that stand in the way before a potentially auto-reactive immunocyte attains pathogenic reactivity.33 Finally, the direct effector processes aimed towards eliminating a foreign antigen or, in the case of autoimmunity, an auto-antigen, comprise activated CD4+ cytokine- releasing T cells, CD8+ cytolytic T cells (CTLs) and autoantibody-producing B cells, with down-stream recruitment of many effector elements including invariant NKT or NK cells, macrophages, mast cells, Fc receptors, complement and others. Evidence is accruing particularly for effector activity of CD8+ CTLs in autoimmune injury, for example in type 1 diabetes,34 and in primary biliary cirrhosis (PBC),35 which would be consistent with the capacity for display on the cell surface by MHC Class I molecules of peptides derived from intracellular autoantigens.
Until recently, autoimmunity was usually considered essentially as a pathology of the adaptive immune response. However, it is now recognized that some autologous molecules are capable per se of activating elements including TLR of the innate immune system. While in these situations T cells usually participate, even these are dispensable according to a mouse model of lupus driven by the B-cell stimulatory cytokine BAFF and elements of innate immunity.36
Auto-antigen and auto-epitope selection
Given the existence of deficits in natural immune tolerance, there obviously would be a highly diverse array of autologous antigens potentially capable of stimulation via the antigen receptor of relentless growth of self-reactive T- and B-lymphocytes. However, it is evident that not all such antigens are equal in this capacity, raising the challenging problem why only particular autologous molecules (often intracellular enzymes and sometimes cell surface receptors) become selected for auto-antigenic activity and, further, why only particular epitopes (auto-epitopes) of such antigens are selected. The long-popular hypotheses of molecular mimicry and epitope spreading have provided an attractive explanation except that there are relatively few situations, clinical or experimental wherein these mechanisms are convincingly demonstrable.31
Auto-antigen selection and epitope preference are currently being investigated in the context of autoimmune diabetic insulitis in which there is a high frequency of B- and T-lymphocyte reactivity to three islet 
-cell-autoantigens, pro-insulin, the 65 kDa isoform of glutamic acid decarboxylase (GAD65) and insulinoma antigen-2 (IA-2). Among these, GAD65 is of particular interest, for several reasons: (i) there is an alternative molecularly similar, although functionally different, isoform GAD67 that of itself is non-autoantigenic; (ii) recently, a solved crystal structure37 for both isoforms has shown that these exist in brain and islets as obligate dimers and has allowed for 'molecular positioning' of epitope sites; (iii) there is available a panel of human monoclonal antibodies (mAb) to GAD65; (iv) there are published data on reactivities of these mAbs with mutant GAD65 molecules derived by point mutagenesis and GAD67 
GAD65 sequence exchanges; and (v) there are known T-cell epitope sequences. All this has revealed that the C-terminal domain of GAD65 contains a 'super hotspot' of immune reactivity in which is clustered most of the epitope sites for anti-GAD65 antibody and for DRB1*0401-restricted T cells and this epitope site corresponds to a region of high molecular flexibility at the C-terminal of GAD65.38 This is encouraging for concepts that antigenicity (and autoantigenicity) depends on particular structural features of autoantigenic molecules including flexibility.38, 39
The 'cause' of autoimmune disease
We can at this point make a return to clonal selection theory of 50 years ago by citing Burnet's final sentence of his 1959 monograph.10 'And it is an article of my scientific faith that there is an intrinsic virtue in simplicity, if it aids understanding without doing violence to the facts of observation and experiment'. Unfortunately autoimmunity results in notoriously 'complex diseases', by reason of many interacting and incompletely defined environmental and genetic components that defy description in simple terms.
Recently we attempted to specify the 'total' cause of a highly studied autoimmune disease of the liver, primary biliary cirrhosis.35 We enquired how well-ascertained environmental provocations could generate a sufficiently potent autoimmunogenic stimulus, and proposed that this would require collusion with multiple pre-existing deficits in immune tolerance to maintain the relentless destruction by the immune system of the target tissue (biliary epithelial cells in the case of PBC) by deployment of all of the mechanisms normally mobilized to rid the organism of unwanted pathogens. For PBC we identified 'convenient truths' that sustained contemporary beliefs and, as well, we analyzed a number of 'inconvenient truths' that were less well accommodated on current knowledge and theory. We drew on the very high concordance (relative to other autoimmune diseases) in monozygotic twins for the occurrence of PBC, and the high risk for disease conferred by having a first-degree relative with PBC as a lead–in to the likely multiple anomalies in 'tolerance/autoimmunity' genes that collectively create the tolerance deficits postulated as critical to the occurrence of autoimmunity.33 Some recently described risk-associated polymorphisms of 'tolerance/autoimmunity' genes include the following: CTLA-4 that encodes a downregulatory molecule on T cells;40 PTPN22 (protein tyrosine phosphatase nonreceptor 22) that encodes a T-cell signalling molecule;41 NALP1 that encodes a protein involved in innate inflammatory processes;42 genes that encode receptors for interleukins 2 and 7 involved in risk for multiple sclerosis;43 FCRL3 described as a 'general autoimmunity gene;44 STAT4 that encodes a T-cell transcription factor for expression of interleukins with risk alleles for SLE and rheumatoid arthritis;45 and Bim which in mice encodes a protein that influences apoptosis.46
As a finale on the 'cause' of autoimmune disease, mention needs to be made of the occurrence of latency and the role of chance. The characteristic latency of autoimmune disease is well illustrated by demonstrability in long-archived sera of relevant serum auto-antibodies in subjects destined to succumb to autoimmune diseases including type 1 diabetes, SLE and PBC,30 suggestive of a multi-hit mode of pathogenesis, and the intervention of stochastic factors. This is amply illustrated by much less than 100% concordance for autoimmune disease in monozygotic twins35 and the widely differing times of incidence of diabetes in as shown inbred NOD mice housed under identical conditions.47 Chance could operate at a 'macro' level for example differing environmental/toxic exposures or psychological stresses, at a micro (cellular) level by the randomness of necessary interactions between collaborating cells in the generation of immune responses and, of course, at a genetic level at which it could be most susceptible to investigation.
We revert here to the role of somatic mutation in autoimmunity, as discussed by Burnet in the 1957 article,1 and 1959 monograph10 on CST, developed further in the 1972 monograph16 on autoimmunity that drew on the mathematical models of Burch,17 and redeveloped later in Burnet 1974 monograph on Intrinsic Mutagenesis.48 In the context of contemporary immunology, Goodnow33 estimated that the likely frequency of germline gene mutation, multiplied over the large number of known 'tolerance/autoimmunity' genes, would result in virtually all individuals bearing deleterious mutations in a heterozygous state. An autoimmune-prone phenotype could ensue either in the event of homozygosity of one or another such genes as a result of a 'disadvantageous' mating, or if a somatic mutation were to occur, as has been demonstrated, in a precursor cell of haemopoietic lineage, with inactivation of a single copy of an intact germline 'tolerance/autoimmunity' gene. Disease latency suggests that successive mutations may need to occur in a stepwise stochastic manner for the autoimmune phenotype to become apparent.
Concluding comment
Some contemporary 'molecular', 'structural', 'developmental' or 'regulatory' immunologists, concerned with the intricacies of the activation or deactivation of innate or adaptive constituents of the immune system, might see the 1957 clonal selection theory in an historical context perhaps as remote as the Battle of Hastings. For others, Burnet's writings will continue to have a contemporary flavour, as they do on this particular Golden Anniversary of the short report that introduced Clonal Selection Theory to the scientific community.
References
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