Naturally occurring genetic polymorphisms determine the susceptibility to autoimmunity. Single nucleotide polymorphisms (SNPs) most likely evolved due to microbial pressure and reveal a consequence of natural selection for enhanced resistance/susceptibility to certain pathogens. Selective microbial pressure to promote functional variations in immune-related genes to resist infectious challenges may add to the pool of variants that alter susceptibility to autoimmune diseases. We have begun studying these mechanisms in a mouse model of infection-induced liver autoimmunity resembling primary biliary cirrhosis (PBC) in humans, a chronic cholestatic liver disease characterized by the immune-mediated destruction of biliary epithelial cells and auto-antibodies that bind to the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2).
Patients with PBC exhibit chronic immune responses against antigens of an ubiquitous alpha-proteobacterium, Novosphingobium, including antigenic structures that resemble the structure of the signature PDC-E2 antigen in PBC. In addition, the tissue distribution of natural killer T (NKT) cells is profoundly altered in PBC patients with apparent emigration from the blood into the liver. Those clinical reports and our own findings identifying Novosphingobium as a microbial agent that selectively activates NKT cells through its cell wall glycosphingolipids (GSLs) led us to explore the intriguing possibility that PBC may in fact be caused by NKT cells responding to Novosphingobium GSLs. Notably, we have replicated these clinical studies in mice, developing a model in which Novosphingobium-infection induces anti-PDC-E2 antibodies and PBC-like liver lesions. Onset and severity of liver disease in this model are dependent on: (a) mouse genetic background; (b) hepatic persistence of Novosphingobium; and (c) hepatic presence of natural killer T (NKT) cells activated by Novosphingobium GSLs. Once established, biliary lesions can be adoptively transferred by lymphocytes into irradiated congenic hosts.
Infection alone is likely not sufficient to confer disease, genetic susceptibility plays an important role. We found that NOD congenic mice - generated by the introgression of type 1 diabetes susceptibility loci from chromosome 3 and 4 of B6 and B10 mice onto the NOD background - are predisposed for the development of severe PBC upon infection. Using subcongenic NOD mice with defined genetic regions and specific gene-deficient knockout strains for molecules encoded within these introgressed regions, we are analyzing the candidate molecules within these genetic loci and their impact on the progression of liver disease. Our long-term goal is to evaluate if single nucleotide polymorphisms (SNPs) within genetic alleles of PBC patients defined as candidate genes in the mouse model alter the expression and/or function of the encoded molecules and subsequently NKT, T and/or B cell responses.
The susceptibility of an individual to autoimmune diseases is determined by environmental factors and genetic predisposition. However, the factors leading to the development of immune responses against defined antigens in a tissue-specific manner remain largely unknown. This compartimentalization of autoimmune responses is particularly surprising as many auto-antigens are ubiquitously expressed.
Using PET technology with 18F-labeled reporter markers specific for defined bacterial microorganisms, our group aims to identify tissues in which bacterial pathogens primarily persist. These studies may not only help to identify infectious foci during sepsis, but also elucidate mechanisms by which bacteria trigger tissue- or organ-specific autoimmune processes despite ubiquitous auto-antigen expression.
Infectious agents have long been considered as potential culprits for the activation of auto-reactive 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 Novosphingobium, “mimic” specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology and autoimmunity. Using novel mutant Novosphingobium strain that lack candidate antigens the immune system may cross-react to, we are currently studying the mechanisms by which infection with Novosphingobium activates/propagates auto-reactive T and B cells in our mouse model.
We are about to define the different antigens of Novosphingobium spp. recognized by sera of PBC patients. The identification of a latent infection with Novosphingobium in PBC patients by a screening ELISA would provide a useful tool for the diagnosis of PBC in the clinic. This simple clinical test would help to define the time frame where the application of antibiotics might be useful for the treatment of this devastating disease.