How autoimmune disease is initiated

Summary

There are very few, if any, “acquired” autoimmune diseases for which the proximal cause(s) is known. Lupus, multiple sclerosis, juvenile diabetes and psoriasis are no exception; although these diseases progress as a consequence of the autoimmune reaction, what sets off the reaction in the first place remains a mystery. We hypothesize that in some autoimmune diseases, nucleic acids and/or proteins of endogenous retroele­ments are etiological agents. If so, basic and clinical research on the disease may be complemented by the extensive knowledge of retrovirology that has been accumulated, and the retroelements may be new therapeutic targets.

It is reasonable to assume that, in the complicated balance between self and non-self reactivity of the adaptive immune system, any wrong step in the sequence of lymphocyte development, selection and activation may result in auto-aggression. But what causes these missteps, and which ones are important for which autoimmune disease? Our working hypothesis postulates that the highly variable antigens of endogenous retroelements provide mimetopes to the adaptive immune system, and that the RNA and cDNA of replicating retroelements trigger pathways of the innate immune system. An indication that this may be the case is provided by a deficiency in Trex1, a cellular DNase that digests retroelement cDNA. Trex1-deficient humans and mice suffer from various inflammatory diseases. Our lab investigates ways to inhibit retroelement expression and its effect on autoimmune disease in mice that are prone to lupus erythematosus, hemolytic anemia, or autoimmune diabetes.

Although it is not an accepted fact, many observations made by several investigators over the years have strengthened a retroelement-related hypothesis of autoimmune disease. Exogenous and endogenous retroviruses and retrotransposons are classified as retroelements. The retroelements establish additional copies in host cell genomes at new insertion sites via an RNA transcript that is copied into double-stranded DNA by reverse transcription. They are present in the genomes of all eukaryotes and are thus also ancient companions of the human genome, making up almost half of our genomic sequence.

There are several reasons why Koch’s postulates for the definitive proof of “infectious disease” etiology are difficult to fulfill for endogenous retroelements. These postulates have been important in defining our understanding of acute infectious disease caused by exogenous pathogens, but a broader framework is required for assessing the importance of a candidate pathogen in a complex multifactorial disease such as autoimmune disease. Thus, differences in MHC complex, for example, clearly play an important role, but one of the biggest obstacles to obtaining proof in this case is the nature of the pathogen—the endogenous retroelement. First, the large number and variety of retroelements, together with their high rates of mutation and recombination, make it difficult to identify the causative one(s). Second, its being endogenous makes adding a pathogen less practical, as this only increases the load by an unknown percentage. And third, clearing the retroelement in experimental settings has been a challenge; it is, however, not impossible, and we accomplish this with the use of anti-retroviral drugs and enzymes (see projects).