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Autoimmunity: limited progress for the patient, despite decades of research

2009; Wiley; Volume: 70; Issue: 5 Linguagem: Inglês

10.1111/j.1365-3083.2009.02318.x

1365-3083

Nicolas Delaleu, Ammon B. Peck,

Immunotherapy and Immune Responses

By definition, autoimmunity refers to the capacity of somatically generated antigen receptors to recognize self-molecules, and through this recognition event these self-molecules may become targeted antigens for inflammation. The concept that an inflammatory/immune response directed specifically against self-antigens can represent the basis for human illness entered mainstream medical thinking in the 1950s and 1960s. Viewed from this perspective autoimmunity was at first categorized as a principally harmful process [1]. However, strong evidence suggests that higher organisms are not, possibly cannot or even should not be free of autoimmunity [2, 3]. Immunological recognition of specific molecules is crucial in defining immunological responsiveness, immunological tolerance and maintaining tissue homeostasis. The presence of physiological autoimmunity also mandates the existence of regulatory networks both on a systemic and tissue-specific level [4]. Similar to evolutionary theory, which does not address the genesis of life per se, but rather life’s evolvement, research within the field of autoimmunity repositioned itself in recent years, not in studying the emergence of autoimmunity, but in investigating the progression from the recognition of ‘self’ and unperceived tissue pathology into overt clinically manifested disease. Whether specific inflammatory conditions should be classified as autoimmunity, according to Rose and Bona [5], can be established by direct, indirect or even circumstantial evidence. Nevertheless, experimental proof for assigning certain clinical conditions to specific families of defined autoimmune diseases is considerably more difficult than expected. For example, one might consider myasthenia gravis a well-established autoimmune disease based on the availability of direct evidence [6]. In contrast, classification of Sjögren’s syndrome is far more circumstantial [7], while serious argument could be invoked as to the classification of hepatitis-induced immunity against the liver. In order to understand autoimmunity, it is imperative to know how the inflammatory/immune response protects its host. During the relatively short life-span of cellular immunology, remarkable advances have occurred, highlighted by the many insights into the definition of immune cells, mechanisms of antigen-presentation and antigen recognition, molecular interactions and pathways for immune activation entwined with processes of immune regulation and tissue repair. Over this time, a series of published observations, quite often serendipitous findings, would spark a flurry of new research activity that would quickly die off as the next fascinating research area came en vogue. Such cyclic waves, which were often accompanied by the emergence of new technologies, can be observed throughout most areas of research, as well as our cultural lives, noting the clichés ‘TV Killed the Radio Star’, the Buggles and ‘Reality Killed the Video Star’, Robbie Williams. Most notable in this regard might be the recent appreciation of innate immunity [8] and how the once much maligned T-suppressor cell population has risen like a phoenix metamorphed into the much-coveted regulatory T cell [4]. Irrespective, or possibly just due to ever inflating numbers of immune-cell subsets and molecules associated with the immune system, less resources are dedicated to elaborating immunological theory. Indeed one might pose the question: ‘does immunology need ever emerging theories or can it even have basic theories given the evolutionary context under which the innate and adaptive immune systems were introduced into and evolved within a species [3, 9]? So, moving from theory to working hypotheses, the immune system is most often thought of as functioning through recognition of ‘self–non-self’ [1], ‘strangers’ [8] or ‘danger’ [10]. Today, a wave of intense fascination for studying autoimmune diseases has swept the field of immunology, sometimes uniting and other times dividing, efforts to better understand the bases for this large set of diseases afflicting an ever increasing number of individuals anxiously waiting for research to produce cures. A quick look at the number of publications that are referenced in MedLine using the term ‘autoimmunity’ shows a remarkable increase over the past 40 years that is currently being sustained (Fig. 1A) despite many reduced research budgets resulting from current economic pressures. Between 2000 and 2007, an average of 815 papers were published per year, while between 2007 and 2009, an average of 740 papers are estimated to be published (Fig. 1B). For purpose of comparison, data are also presented for the search terms ‘B cell receptors’ and ‘regulatory T cells’, two topics central in immunology. Not surprising, the number of autoimmunity papers for the past 5 years dealing with B cell receptors and regulatory T cells is averaging nearly 60 and 235 manuscripts per year, respectively. Numbers of references indexed by MedLine within different fields of immunology (A) 1970 – August 2009 (B) 2006 – August 2009. In the context of this editorial, we would be remiss not to comment on the contribution of the Scandinavian Journal of Immunology to the area of autoimmunity research. For example, a similar search in MedLine indicated that 40 papers on autoimmunity were published over the past two and one-half years [11–50]. While 19 of these deal primarily with general immunology [11–26] genetics [27] and technologies [28, 29], the remaining 21 papers [30–50] focus on specific autoimmune diseases. Not surprising, the more popular topics have been multiple sclerosis/experimental autoimmune encephalomyelitis (six manuscripts) [30–35] diabetes/Addison’s disease (four manuscripts) [36–39] and rheumatic diseases/collagen-induced arthritis (four manuscripts) [40–43]. Which of these manuscripts have or will make a difference for the autoimmune patient? There is little argument that basic and clinical research in the field of autoimmunity eventually must bring about effective interventions to stop the progression of pathogenic inflammation/immunity. Ideally, identification of individuals who are genetically predisposed to develop an autoimmune disease should make intervention strategies more effective, thereby slowing or reversing tissue and/or organ destruction. Unfortunately, due to the covert nature of autoimmunity, disease is usually not recognized until tissue or organ function is impaired; thus, cures are most likely to be the future work of cell biologists focused on regenerative medicine and transplant physicians. Such research efforts will most probably also attribute more importance to tissue in the context where the autoimmune reaction will or has taken place, e.g. matrix, cellular and neuronal interactions together with mechanisms maintaining homeostasis. Discussion of autoimmunity generally centres around three issues: an individual’s genetic predisposition, the environmental trigger initiating the immune response against self-molecules, and the subsequent lack of immune regulation that results in chronic inflammation. Considering the complexity of each of these topics, together with the presumed diversity of autoimmune diseases, reaching the final goals of prevention, intervention and/or cure must be viewed as a difficult task. At increasing frequency, the scientific community has advanced the notion of being on the brink of major breakthroughs in treatments that would have significantly improved the lives of individuals suffering from an autoimmune disease. Unfortunately, in reality, this moment constantly slips into future years. Whether or not this seemingly limited progress with respect to therapies and cures lies in the possibility that our animal models of autoimmunity remain inappropriate for human disease, despite considerable research effort remaining tied to animal models, is a much discussed topic, but clearly must be considered [51]. However, limitations in design of clinical studies harbour immense opportunities for research relating to animal models. The development of more appropriate, and eventually to some extent humanized animal models, might increase predictability of clinical trials, which often relate to drug candidates identified in murine and other animal studies [51]. While there is a wide range in the relative degree for established genetic predisposition among autoimmune diseases, it should not come as a surprise that strong associations exist between the major histocompatibility complex (MHC) and autoimmune diseases, since an individual’s immune system develops around the MHC genetic phenotype. However, there is increasing evidence for a major role of the non-MHC genetic phenotype, a fact that is supported by genome-wide association studies. It now seems obvious that both the MHC and non-MHC gene products need to be distinguished as having either immune-associated or non-immune-associated functions, since the target tissue must be considered a potential participant in the pathological processes. But how a target tissue actively participates remains a mystery that must be well-defined. Perhaps one of the most intriguing aspects of autoimmune research is the attempt to identify if and specifically what environmental trigger is capable of initiating an autoimmune process. Although such research efforts in the past led to the attractive antigen-mimicry model [52], this issue is often under-represented in the literature. Unfortunately, and despite serious attempts to identify exogenous triggers contributing to the aetiology of specific autoimmune diseases, its basis remains in large parts conceptual. However, one must note that evidence for antigenic mimicry in any specific pathology is particularly difficult to obtain considering the potentially significant spatial distance between an initial priming site and the eventual target tissues, which will, only after years, be functionally affected. Nevertheless, discussions surrounding microbial triggers are of crucial importance in defining autoimmune diseases, especially as the term autoimmune disease usually implies the absence of immune responses to exogenous factors as a significant contributor in its pathogenesis. Despite the general acceptance that autoimmune diseases result from an immune dysregulation, i.e., the inability of the immune system to downregulate an on-going inflammatory response against ‘self’, several lines of evidence suggest that this concept represents an oversimplification and cannot account for all ‘anomalies’ observed in autoimmune contexts. Notably, if the stimulating environmental antigen is not cleared in the initial inflammatory response and subsequent adaptive immunity phase, downregulating the response could easily become detrimental to the host. In setting up a chronic response, the immune system would be doing what it has been programmed to do, hold in check and, if possible, clear eventually the stimulating antigen. The fact that the antigenic epitope(s) may be self-molecules, activated endogenous viral antigens, and/or aberrant self-proteins should remain irrelevant to the host’s immune system. It is also important to note that in several autoimmune conditions, not only inappropriate destruction, but also inappropriate healing may contribute significantly to the pathogenesis [53]. Both processes are closely connected to the immune response and the state of inflammation. Despite the fact that many fundamental questions remain unanswered, there is currently a sense of optimism that we are close to defining a variety of heretofore problematic and controversial aspects of autoimmunity. The expectations we put into new technologies, which presumably allow less biased study design, hopefully will live up to the promise of generating extensive (even ‘global’) datasets of exceptionally high quality. The information technology (IT) revolution has undoubtedly begun to revolutionize immunology and, thereby, autoimmune research. This arena is expected to continue to impact how we do future research. However, with respect to the patients’ overall quality of life, to date, a harsh reality tends to confront the researcher. Life with an autoimmune disease, irrespective of the enormous amount of acquired knowledge about specific autoimmune conditions, is still accompanied by great suffering, often shorted life expectancy and a substantial financial burden for the individual and society. While we slowly push the frontiers of science forward, for most patients, current treatments, e.g., hormone replacement therapy (for type 1 diabetes and thyroiditis), anti-inflammatory and chemotherapeutic drugs (for rheumatic and Crohn’s disease), and artificial tears or saliva (for autoimmune sicca syndromes), generally offer the patient only limited temporary relief from symptoms. With each unsuccessful or only minimally successful clinical trial based on seemingly promising research, the concept of ‘bench to bedside’ drug/reagent discovery is being challenged. Nevertheless, it will be of utmost interest to see if the next break-through results from a serendipitous finding or a superbly planned experiment.