MECHANISMS LEADING TO TISSUE TARGETED IMMUNE DYSREGULATION IN THE BRAIN, LUNGS, AND GUT

Abstract

Immune dysregulation encompasses autoimmunity, autoinflammation, allergy, or lymphoproliferation and it can manifest in different organs depending on a variety of factors including genetics, microbial exposure, and autoantibodies. However, it is unclear how these factors interact and lead to organ-specific disease. In this study, we examined immune dysregulation in a range of organs, including brain, gut, and lungs. We primarily investigated the manifestation of immune dysregulation in the brain through the study of autoantibodies in autoimmune epilepsy. We identified 31 novel candidate autoantigens and 16 known autoantigens by immuno-precipitation mass spectrometry (IP-MS) and phage-immunoprecipitation sequencing (PhIP-Seq). Through a cell-based assay, we confirmed autoantibody binding to three novel autoantigens, YIPF5, SLC6A11, and SCN2A, and two known autoantigens, GFAP and NRXN3. The verification of autoantibody binding to GFAP in one of our anti-epileptic drug unresponsive patients suggests a GFAP astrocytopathy, which if clinically confirmed would provide a more precise diagnosis with treatment implications. In addition, we explored immune dysregulation in the intestines and lungs and the role of microbial exposure via a novel inborn error of immunity seen in iRHOM deficiency with Respiratory and Intestinal inflammation and cytokine Secretion defect (IRIS). Here, we found that differing microbial exposure could lead to pneumonia without colitis in one patient and colitis without pneumonia in another patient. Lastly, we investigated another organ-specific immune dysfunction caused by loss of integrity of the intestinal mucus barrier. The discovery of a novel monogenic disease, termed Enteropathy caused by AGR2 deficiency, Goblet cell Loss and ER Stress (EAGLES), demonstrated the importance of the mucosal barrier in preventing inflammatory gut disease.

Date of Award	2023
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences