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Autoimmune disease re-examined in light of metagenomic concepts

Proal, Amy (2012) Autoimmune disease re-examined in light of metagenomic concepts. PhD thesis, Murdoch University.

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The concept of autoantibodies was developed at a time when, due to the limitations of culturebased techniques, the human body was considered to be largely sterile. However, over the past few years, researchers in the emerging field of metagenomics have developed molecular tools that instead allow microbes to be identified by their genomic fingerprints. These tools have opened a door to an era of tremendous discovery. Homo sapiens has been shown to harbor thousands of species of microbes in tissue and blood that were previously undetectable. Today it is estimated that around 90% of the cells in the human body are microbial, and that the genes of these microbes outnumber our own by a factor of at least 10:1. The genomes of intracellular microbes can directly interact with our own genomes, meaning that humans may be best described as superorganisms. When populations of these microbes interfere too much with the metabolism of Homo sapiens, the resulting changes in the proteome can lead to disease. This suggests that the inflammation observed in "autoimmune" disease may instead result from an effort by the innate immune system to target pathogens and restore microbial homeostasis. Many intracellular microbes survive by dysregulating the expression of genes and antimicrobials via key nuclear receptors. The VDR nuclear receptor plays a critical role by expressing cathelicidin and TLR2, the primary intracellular defenses. It appears that the pathogens that cause autoimmune disease accumulate during a lifetime, with individuals increasingly accumulating microbes as the innate immune response becomes incrementally compromised. One reason that autoimmune disease is more common in women may be that they have an additional site of VDR expression, in the cycling endometrium. Thus, they may more easily acquire microbial loads than their male counterparts. The interaction of many different microbes acting in concert is more likely to cause a particular autoimmune condition rather than, as Koch suggested, a single organism. This helps account for the high levels of comorbidity observed amongst patients with autoimmune conditions. Autoantibodies are increasingly being identified as the body's response to specific pathogens, with collateral damage from these antibodies exacerbating the disease process. The possibility that microbes drive the autoimmune disease state calls for a re-evaluation of how these diseases are routinely treated. While the standard of care for autoimmune disease remains the use of medications that slow the immune response, treatments aimed at eradicating pathogens would attempt instead to stimulate the body's antimicrobial defenses. We have collaborated with American and international clinicians to research a therapy designed to reactivate the innate immune response in patients with autoimmune disease. Our case series demonstrate that patients generally report symptomatic improvement, but only after experiencing temporary increases in inflammation and disease symptoms. This is likely due to immunopathology - a reaction in which the release of cytokines and cellular debris accompany microbial death. Thus we must reconsider the long-term consequences of using immunosuppressive substances. For example, the secosteroid vitamin D reduces inflammation, but may do so at the expense of slowing the innate immune response and its ability to target underlying pathogens. Furthermore, the concept of vitamin D "deficiency" may itself be flawed. The low levels of 25-D in many patients with inflammatory conditions may be a result rather than a cause of the disease process. Conventional interpretation of other out- of-range metabolites must be similarly re-examined. This work offers a novel framework with which to understand and treat inflammatory disease, with broad implications across many disciplines. Efforts to further validate this model are needed, taking researchers down entirely new avenues of exploration.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): School of Veterinary and Biomedical Sciences
Supervisor(s): Marshall, Trevor, Berry, Cassandra and Eagles, D.
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