LMU researchers have made groundbreaking strides in understanding multiple sclerosis (MS) through CRISPR screening. In their pioneering study, they conducted a comprehensive molecular analysis of T cell infiltration into the central nervous system (CNS) among individuals with MS, shedding light on a critical aspect of the disease.
MS, a prevalent and disabling condition affecting the CNS in young adults, initiates when autoreactive T cells become activated and infiltrate the CNS, setting off a destructive chain reaction. This phenomenon has been extensively observed in animal models and human studies, underscoring its significance.
Martin Kerschensteiner, the Director of the Institute of Clinical Neuroimmunology at LMU, emphasized the gap in our understanding: “Despite our knowledge of this process, we lacked a comprehensive grasp of the key molecules governing the migration of autoreactive T cells into the CNS.” Addressing this gap, a collaborative team led by Kerschensteiner and Naoto Kawakami at LMU’s Biomedical Center Munich embarked on a mission.
Their findings, published in Nature Neuroscience, unveiled a remarkable discovery. Through genome-wide analysis, they pinpointed five crucial inhibitors and 18 vital facilitators of T cell migration to the CNS, advancing our comprehension of MS pathogenesis.
Genome-wide in vivo CRISPR screen in rat model
Researchers in Munich introduced a novel gene editing technique into the study of multiple sclerosis (MS), marking a departure from its previous applications. Naoto Kawakami, in explaining the innovation of CRISPR technology, pointed out that it opens the door to comprehensive and unbiased investigations within disease models in vivo. While genome-wide CRISPR screens have primarily been associated with cancer research, their application to MS was uncharted territory until now.
Their methodology involved employing a rodent MS model, marrying an unbiased genome-wide CRISPR screen with in vivo validation studies, multiphoton microscopy, and mechanistic experiments in vitro. This multifaceted approach allowed them to definitively characterize a pivotal aspect of MS pathogenesis: the infiltration of autoreactive T cells into the CNS, culminating in the identification of five crucial inhibitors and 18 essential facilitators.
These regulators can be classified into three functional categories vital for T cells to transition from the bloodstream to the brain. The initial step involves T cell adhesion to blood vessel endothelium, mediated by the molecule alpha-4 integrin. Subsequently, T cells exit the blood vessel, guided by messengers recognized by the chemokine receptor CXCR3. The third category relates to molecules governing how T cells respond to attractive signals from the bloodstream.
Martin Kerschensteiner underscores two primary advantages of this study. First, it reaffirms that key molecules within this mechanism are already the targets of existing MS therapies in clinical practice. Secondly, the approach used in this research, now validated for potential use in humans, can be extended to unravel less understood questions, such as the migration of other detrimental immune cell populations from the bloodstream to the nervous system.