AARDA Scientific Advisory Board members Betty Diamond, M.D., Chair of the SAB; M. Eric Gershwin, M.D.; Noel R. Rose, M.D., Ph.D., SAB Chairman Emeritus; and AARDA President/Executive Director Virginia T. Ladd organized the Cell Damage and Autoimmunity Colloquium, an international colloquium bridging scientific and clinical disciplines. Held in April 2007, this Colloquium was co-sponsored by the American Autoimmune Related Diseases Association, the Johns Hopkins Center for Autoimmune Disease Research, and the Sjögren's Syndrome Foundation, with financial support from the National Institutes of Health, Genentech, and Abbott. The purpose of the meeting was to discuss the role of cellular and tissue damage in the initiation, development, and persistence of autoimmune disease. One of the exciting aspects of this Colloquium is that it has opened the door for future collaborative opportunities.
The focus of the presentations and integrative discussions at the Colloquium were five potential etiologic and pathophysiologic processes fundamental to autoimmune disease, i.e., inflammation, infection, apoptosis, environmental exposure, and genetics. While the major focus of the Colloquium was on pathophysiologic mechanisms involved in the initiation phase of autoimmune disease, important information emerged on processes responsible for clinical expression of disease.
Inflammation has close clinico-pathologic associations with autoimmunity, but future analyses will require better definition and metrics of inflammation, particularly for the earliest cellular and molecular components dependent on recruitment of elements of innate immunity. Understanding the role of inflammation in the development of autoimmunity is still a subject of active investigation and debate.
A clear distinction needs to be made between initiating events, such as cell injury, "danger," and inflammation, on the one hand, and the host response, including innate immunity and adaptive autoimmunity, on the other. Doctors Betty Diamond (Feinstein Institute for Medical Research), Diane Mathis (Harvard University), and Polly Matzinger (National Institutes of Health) each called for better recognition that autoimmunity may follow tissue damage--but may not progress to autoimmune disease.
Accordingly, the need is to develop a more relevant definition of inflammation at the molecular and cellular levels rather than the clinico-pathological level. Regardless of how inflammation is defined, examples exist of autoimmune disease in the absence of overt inflammation and of inflammation in the absence of relevant autoimmunity. In human disease, it is often difficult to exclude entirely a role of inflammation. Even "non-inflammatory" diseases mediated by autoantibodies, like autoimmune hemolytic anemia and autoimmune thrombocytopenia, may be a consequence of some prior infection. Reducing inflammation in certain autoimmune diseases can restore immunologic balance and induce a remission that allows at least temporary withdrawal of immunomodulatory drugs.
Participants noted that the emergence of autoimmunity may be a corollary of the "hygiene hypothesis" stating that decreased baseline inflammatory (pathogen) burden explains increasing trends in the prevalence of most autoimmune diseases.
Infection has long been invoked as an underlying trigger for the induction of autoimmune disease. Usually infectious diseases are self-limited with full host recovery, with or without therapy. Uncommonly, infections induce autoimmune disease in humans; and although infection may be associated with increased levels of autoantibodies, most infections and virtually all vaccinations in humans lack well-established links to autoimmune diseases. Suspect infections requiring closer interrogation include the Epstein Barr virus (systemic lupus erythematosus and other diseases), hepatitis C virus (autoimmune hepatitis), beta hemolytic streptococci (rheumatic carditis), and Heliobacter pylori (autoimmune gastritis); but even if a microorganism were to be incriminated, mechanisms of initiation/perpetuation of autoimmunity continue to challenge investigators. Documented autoimmune diseases that occur as sequelae to infection include rheumatic fever and Guillain-Barre-type polyneuropathy--and, possibly, late-phase Lyme disease.
For certain diseases, the basic research question is whether the "trigger" of the autoimmune disease is the infection itself by providing, say, an antigen mimic, or a failure of normal immuno-regulation to limit the immune response to infection. Autoimmune disease may follow infection by many years, and/or the underlying infection may be subclinical or unrecognized. There appears to be a potential dual role of infection both as an inducer of autoimmunity and then as a promoter of progression from autoimmunity to autoimmune disease.
One prominent inquiry raised in general discussion was whether the progression to autoimmune disease is direct, or indirect by occurring as a bystander effect from a hyper-response to a pathogen. One theory raised in discussion was that infection may switch the class of a protective immune response and divert the immune system to a pathogenic mode, leading to autoimmune disease.
Apoptosis is the disintegration of cells into membrane-bound particles that are then ingested and digested by other cells. Despite considerable interest and research in this area, the role of apoptosis in the origin and development of autoimmunity has yet to be established. This role remains elusive and controversial.
Apoptosis has been identified as a unique form of cell death, different from necrosis which results from an insufficient blood supply. The distinction is of importance as necrotic cells are more pro-inflammatory than apoptotic cells. Effective apoptosis rids the host of damaged cells, usually without causing inflammation. Despite the identification of apoptosis as a distinct type of cell death, there may be overlap with other forms of cell death.
Infection or environmental exposures may raise the apoptotic burden to initiate autoimmune disease or even explain exacerbation and remissions.
Participants agreed that, while apoptosis is important in certain diseases, more evidence is needed to establish its role in the development of autoimmune disease, particularly in organ-specific autoimmune diseases. Insights into the role of apoptosis may lead to strategies to prevent or modulate autoimmune type 1 diabetes, for example, including the development of agents to limit apoptosis. However, it was considered doubtful whether apoptosis itself would be sufficient to explain entirely the occurrence of autoimmune type 1 diabetes, or other expressions of autoimmunity.
Environmental exposure is highly likely, though unproved in most instances, to contribute to the immunopathogenesis of autoimmune disease. Although environmental agents are widely believed to serve as necessary "triggers" of autoimmune disease in genetically predisposed individuals, only a few such agents (mainly drugs and some nutrients) have been clearly identified. Celiac disease stands out as an autoimmune disorder where the environmental precipitant, gluten, is known. In addition, there are a relatively limited number of fully validated examples of medically induced autoimmune diseases. In most instances, the autoimmune disorders induced by these agents are self-limited and resolve with discontinuation of the offending agent. In other instances, nonspecific or crossreactive mechanisms may result in chronic disease. The mechanisms of the environmental effect on the induction of autoimmunity and the development of autoimmune disease could be as varied as the environmental antigens themselves.
Genetic susceptibility is strongly implicated in every model of the study of the cause of autoimmune disease. An essential genetic foundation underlies all these hazards for autoimmunity in the form of risk-associated polymorphisms in immunoregulatory genes. The transformation from susceptibility (which includes polyclonality and cellular vulnerability) to autoimmunity (and a larger immune repertoire) to an autoimmune disease is defined as a stochastic experience.
Individuals with identical genomes may not necessarily develop a particular autoimmune disorder, and the genetic influence varies greatly in different situations. From a simple probability standpoint, the higher prevalence of autoimmune diseases among women might be explained by the presence of two X chromosomes, presuming the existence of an immune response gene on the X chromosome; but currently hormonal influences are seen as the more important. Moreover, the relative contribution of each of these different genetic contributors varies over time, such that the occurrence of autoimmune disease is in part related to age and its impact on the immune system.
In conclusion, the Colloquium emphasized the two-way relationship between cell injury and autoimmune disease; injury may be the consequence of the autoimmune response. The quantity and quality of the autoimmune response, the setting of its induction, and the genetics of the host determine a possible pathologic outcome. A robust discussion and dialogue raised a number of important topics for future scientific exploration. The participants identified several key goals and recommendations to facilitate the development of improved disease prevention and treatment strategies for autoimmune disease.
It was generally agreed that, whereas the ultimate goal is to develop cures for autoimmune disease, it was acknowledged that the development of safer and more clinically effective/efficacious treatment regimens would be a more realistic and still an extremely challenging endeavor.
