Autoimmunity triggered by infection
Jochen Mattner, Cincinnati Children's Hospital
Complex cellular pathways and genetic traits are common to multiple autoimmune disorders. Environmental factors are considered as triggers of overt autoimmune disease. However, those have been challenging to identify and to associate a defined factor with a specific autoimmune disease.
Infectious agents have long been considered as potential culprits for the activation of autoreactive T and B lymphocytes in the periphery. Structural similarities between host and bacterial/viral antigens (so called molecular mimicry) may underlie the activation of these T and B cells that elicit cross-reactive immune responses. While these may contribute to the eradication of viruses and/or bacteria, “mimic” specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology and autoimmunity. Whereas the eliciting bacterial agents for rheumatic fever, autoimmune gastritis and Guillain-Barré syndrome induce an overt clinical disease beforehand, just recently published studies reveal compelling evidence that undetected infections (without inducing classical symptoms of infection like fever,…) may underlie various forms of autoimmunity. Patients with primary biliary cirrhosis (PBC), for example, a chronic inflammatory liver disease, exhibit chronic immune responses against antigens of an ubiquitous alphaproteobacterium, Novosphingobium, that resemble the structure of the signature antigen in PBC, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). Notably, we have replicated this in mice, developing a model in which Novosphingobium-infection induces antibodies to PDC-E2 and PBC-like liver lesions. We are currently studying the mechanisms by which infection with Novosphingobium activates/propagates autoreactive T and B cells in this mouse model.
The discovery of infectious triggers of autoimmunity and the elucidation of the mechanisms by which they induce tissue damage will change our current concepts about the etiology of various autoimmune syndromes and may suggest new, simpler ways to diagnose and treat these debilitating diseases.