Elucidating the mechanisms of Autoimmune Hepatitis

We created a Traf6ΔTEC mouse in which aberrant central tolerance in the thymus leads to production of autoreactive T cells and spontaneous liver autoimmune hepatitis (AIH). In this project, we will examine the mechanisms of AIH development in this mouse model.

We will examine whether the aberrant T cell compartment of TrafΔTEC mice is linked to the Payers’s Patch (PP) where it associates with defective production of T follicular cells and IgA, and to AIH development (Year 1). 2) We will examine whether perturbations in the PP associate with altered gut microbiota composition and identify bacteria that promote AIH (year 2). 3) We will examine whether bacterial antigen recognition via Toll-like receptors (TLRs) and TLR signaling regulates AIH development and whether T cell subpopulations (Foxp3+ Treg and CD8+ T cells) play a role in disease development (year 3).

Liver tissue and lymphocytes will be examined via histology, immunohistochemistry and flow cytometry. RNA sequencing will be performed on liver sections and microbial species.

Serum biomarkers will be assessed by ELISA.In the absence of a known cause and therapy, current methods for alleviating AIH symptoms rely on corticosteroid administration and in extreme or relapsed cases liver transplantation.

Because the Traf6ΔTEC mice mimic human AIH, our findings may facilitate a better understanding of AIH pathology and for the first time implicate the gut microbiota and TLR signaling in AIH development.