Pathogenesis of Inflammatory Bowel Diseases Linked to Absence of Crucial Molecule

The absence of the cellular heat shock protein gp96 in the gut microbiome increases the likelihood of developing inflammatory bowel disease.

Maintaining a balance of inflammatory and tolerant T cells in the gut is important for an individual’s health. But in patients with colitis, inflammatory T cells in the lower intestine go awry and begin destroying food and healthy gut bacteria, mistaking them for dangerous pathogens.

In a study published in Scientific Reports, investigators sought to figure out why this phenomenon happens, hypothesizing that patients with IBDs may have poorly trained adaptive immune systems.

Normally, tolerogenic professional antigen-presenting cells (pAPCs) in the gut train tolerant T cells to recognize harmless antigens, while inflammatory pAPCs train T cells to attack antigens on microbes or molecules.

The results of the study showed that gp96 is crucial to maintain a balanced immune system in the gut.

The investigators created a genetic knockout mouse that lacked gp96 in its pAPCs, and found that without gp96, pAPCs were less able to travel to lymph nodes or respond to bacterial antigens. Notably, inflammatory pAPCs significantly outnumbered tolerant ones in the lymph nodes and the colon.

Overall, mice without gp96 had more inflammatory T cells and less tolerant T cells in the colon compared with wild mice.

Although the findings showed promise, the investigators sought to link their findings to a biological function relevant to humans by focusing on oral tolerance.

Oral tolerance is the suppression of immune responses to antigens that have been administered via the oral route. But studies suggest that the loss of oral tolerance may be an early change in individuals who go on to develop food allergies and IBDs.

For the experiment, ovalbumin—–the main protein in chicken egg whites–– were fed to wild and gp96 knockout mice. Next, the animals received donor T cells via adoptive transfer that had not been exposed to ovalbumin, meaning it was not recognized as a tolerable antigen. The investigators hoped to determine whether the naïve donor T cells would receive antigen-specific training from the pAPCs and become tolerant to ovalbumin.

In wild mice, the results of the study showed that donor T cells adopted a tolerance state, but not in gp96 knockout mice.

The gp96 knockout mice grew normally at first, but at 24 weeks, 70% developed spontaneous colitis compared with none of the wild-type mice. Furthermore, mice without gp96 had higher levels of gut immunoglobulin A.

“This study shines a light on the pathogenesis of inflammatory bowel disease and offers a positive impact on its future clinical management,” said author Bei Liu, MD.