Trends in Immunology
ReviewAutoimmunity and the environmentInfections and autoimmunity – friends or foes?
Introduction
The immune system is an amazing collection of biological processes designed to defend the body against invasion by infectious pathogens and tumor cells. This system includes innate, adaptive and memory responses that are constantly activated, adapted and improved to meet the challenge of evading pathogens more efficiently. In addition, the immune system must be tolerant and distinguish between self and nonself, so that substances that are identified as nonself stimulate an immune response, while no harm is inflicted upon self. However, as in any complex system, malfunctions occur, leading to diseases of immune dysregulation. Autoimmunity is a consequence of the breakdown of self-tolerance; the result is an attack of the immune system on various organs and tissues as if they were foreign invaders. Autoimmune diseases (AD) are the third leading cause of morbidity and mortality, after heart disease and cancer, in the industrialized world. For autoimmune disorders to develop, a combination of genetic, immunologic, hormonal and environmental factors is required, comprising what is known as ‘the mosaic of autoimmunity’ 1, 2, 3. Among these key elements, the impact of infections on the development of autoimmunity is substantial, and various mechanisms have been suggested to explain this relationship. In recent years, the compound interplay between infections and autoimmunity has been studied extensively. Here, we summarize the current literature and preliminary results from our international study on this issue 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 (Figure 1). The versatile interactions of ADs with different infectious agents, the burden of infections from childhood to adulthood, immune and genetic mechanisms, and the possibility that infections also confer protection from autoimmunity are also discussed (Box 1).
Section snippets
The interplay between autoimmunity and infections
Clinicians have all witnessed autoimmune phenomena after an infectious disease. These clinical observations, involving various infectious agents and autoimmune diseases, have been reported extensively, and for some autoimmune diseases the mechanisms have been effectively elucidated.
The genetics–autoimmunity–infection triad
Genetics play an important part in susceptibility to developing autoimmunity and influence the response of an individual to environmental factors such as infections. The importance of genetics in the pathogenesis of AD is supported by their clustering in families, and by a high concordance rate in twin studies (i.e. 24% in SLE, 25% in multiple sclerosis [MS], 40% in type 1 diabetes [T1D] and 63% in primary biliary cirrhosis [PBC]) [26]. The major histocompatibility complex (MHC) genes and
Different infectious pathogens can induce autoimmunity
The infection side of this equation includes a wide spectrum of microorganisms (viruses, bacteria, parasites and fungi), all of which are able to induce autoimmunity in humans and in animals. An infectious agent can trigger different autoimmune disorders, whereas several agents can be involved in the pathogenesis of a single AD. Dealing with the entire spectrum of infections and autoimmunity is beyond the scope of this article, hence only a few examples are given for each type of microorganism.
Mechanisms by which infectious agents induce autoimmunity
Post-infection autoimmunity can be induced by multiple mechanisms, such as molecular mimicry, epitope spreading, bystander activation, viral persistence and polyclonal activation.
The burden of infections from childhood to autoimmunity
Triggering of autoimmunity is not always a hit and run event, but rather a cumulative process. The immune system is affected by repeated infections from childhood, and in immune-sensitive individuals, a breakthrough point might occur when the infection burden crosses a crucial level. This breakthrough point might be reached when a specific pathogen load, immune load (i.e. antibody titer) or a unique combination of pathogens is established. The ‘pathogen burden’ concept can be effectively
The protective dialogue between infections and autoimmunity
Despite the large body of evidence given earlier to support the contention that infections cause autoimmunity, in some cases infections can actually protect individuals from autoimmune and allergic diseases. This concept, termed the ‘hygiene hypothesis’ was first suggested in 1989 by Strachan [71], who assumed that the increase in ADs observed in Western countries was partly caused by a decline in infectious diseases and improved hygiene. This notion applies to most ADs, especially T1D [72], MS
Conclusions
Reviewing the multi-faceted interactions between infections and autoimmunity reveals many possibilities for pathogenic or protective relationships between different species of infectious pathogens and autoimmunity. Revealing the scope of these phenomena and their genetic codes might enable the use of preventive methods that will reduce the burden of infections and the burden of ADs.
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Both authors have equally contributed.