Helicobacter hepaticus as disease driver in a novel CD40-mediated model of colitis

Abstract

ABSTRACTGut microbiota and the immune system are in constant exchange, which shapes both, host immunity and microbial communities. Here, improper immune regulation can cause inflammatory bowel disease (IBD) and colitis. Antibody therapies blocking signaling through the CD40 – CD40L axis showed promising results as these molecules have been described to be deregulated in certain IBD patients. To better understand the mechanism, we used transgenic DC-LMP1/CD40 animals, which lack intestinal CD103+ dendritic cells (DCs) and therefore cannot induce regulatory T (iTreg) cells due to a constitutive CD40-signal in CD11c+ cells. These mice rapidly develop spontaneous fatal colitis with an increase of inflammatory IL-17+IFN-γ+ Th17/Th1 and IFN-γ+ Th1 cells. In the present study we analyzed the impact of the microbiota on disease development and detected elevated IgA- and IgG-levels in sera from DC-LMP1/CD40 animals. Their serum antibodies specifically bound intestinal bacteria and we identified a 60 kDa chaperonin GroEL (Hsp60) from Helicobacter hepaticus (Hh) as the main specific antigen targeted in absence of iTregs. When rederived to a different Hh-free SPF-microbiota, mice showed few signs of disease without fatalities, but upon recolonization of mice with Hh we found rapid disease onset and the generation of inflammatory Th17/Th1 and Th1 cells in the colon. Thus, the present work identifies a major bacterial antigen and highlights the impact of specific microorganisms on modulating the host immune response and its role on disease onset, progression and outcome in this colitis model.