Characterization of autoreactive T cells in Guillain-Barré syndrome

Dr. Daniela Latorre, ETHZ

Abstract (Lay summaries see below)

Guillain-Barré syndrome (GBS) is a rare disabling neuromuscular disease that affects the peripheral nervous system (PNS) being characterized by an acute onset, rapid progression of muscle weakness, loss of tendon reflex and sometimes, paralysis. Despite the fact that the first description of the disease occurred more than a century ago, the mechanisms underlying the pathogenesis of GBS remain unclear. A better understanding of the cellular and molecular players involved in the immunopathology of GBS is needed to develop more specific and effective treatments as well as reduce/prevent diseaserelated disability. GBS is thought to be an autoimmune disease where molecular mimicry occurs since evidence suggests that auto-antibodies (auto-Abs), generated by preceding Campylobacter jejuni infection, may attack gangliosides expressed in human peripheral nerves inducing axonal damage. Since the first report describing the involvement of humoral immune response in GBS, most studies have focused on the identification of auto-Abs with different specificities in GBS patients’ sera. However, only a minor fraction of GBS patients has detectable serum auto-Abs, thus suggesting that additional immune-mediated mechanisms may be involved. Nevertheless, the involvement of pathogenic autoreactive T lymphocytes in the etiology of experimental autoimmune neuritis (EAN), the animal model of GBS, together with observations showing T cell infiltration in the peripheral nerves and alteration in T cell activation and cytokine expression in the blood of GBS patients, indicate that autoreactive T cells may exist and contribute to the pathophysiology of the disease in humans. However, a systematic analysis of autoreactive T cells in GBS patients is still lacking.

This project aims at filling this gap by investigating the existence and providing a comprehensive characterization of autoreactive T cells in GBS patients. In this research, I propose to use established approaches as well as to implement new methodologies to study autoreactive T cell response in GBS patients through 3 Objectives: Objective 1 is to explore variations in the frequency and distribution of circulating T cell subsets ex vivo in the blood of GBS patients during different phases of the disease (acute vs recovery phase); Objective 2 is to examine the existence, distribution, T cell receptor (TCR) repertoire as well as the phenotype of self-reactive T cells ex vivo from the blood of GBS patients by combining in vitro T cell culture screenings and highthroughput single cell analysis, such as single cell RNA sequencing and TCR sequencing; Objective 3 is to investigate the molecular mimicry mechanism in GBS by using a novel unbiased approach that combines sequential in vitro screening with TCR sequencing of microbe-specific T cells to study cross-reactive autoimmunity. The outcomes of this project may have a substantial impact in the understanding T cell immunity in GBS, as well as medical implications for the development of new therapeutic options for GBS and, potentially, a larger spectrum of neuromuscular disorders. 

Lay summary (italian)

Questo progetto si propone di testare l’ipotesi di un’origine autoimmune della sindrome di Guillain-Barré (GBS), una rara malattia demielinizzante che colpisce il sistema nervoso periferico (PNS) e si sviluppa generalmente in seguito ad infezione microbica. Nonostante la prima descrizione di questa patologia sia avvenuta più di cento anni fa, i meccanismi cellulari e molecolari coinvolti nella sua patogenesi non sono ancora chiari. In questo progetto utilizzeremo nuovi approcci sperimentali che abbiamo recentemente sviluppato per caratterizzare la risposta dei linfociti T contro antigeni espressi dal PNS in pazienti affetti da GBS. Ci aspettiamo che questa ricerca possa espandere significativamente la nostra comprensione di base della funzione delle cellule T nelle risposte autoimmuni e portare allo sviluppo di nuove terapie per curare GBS ma anche un più largo spettro di malattie neuromuscolari.

Lay summary (german)

Der Fokus des Projekts liegt auf dem Guillain-Barré Syndrom (GBS), einer seltenen demyelinisierenden Erkrankung des peripheren Nervensystems (PNS), die sich im Allgemeinen infolge einer mikrobiellen Infektion entwickelt. Es soll der Hypothese nachgegangen werden, dass GBS als Autoimmunkrankheit zu verstehen ist.  Obgleich die erste Beschreibung der Erkrankung bereits vor über hundert Jahren erfolgte, sind die zellulären und molekularen Prozesse noch nicht bekannt. In unserem Projekt setzen wir auf neue experimentelle Ansätze, die wir kürzlich entwickelt haben, um die direkte T-Zell-Antwort gegen vom PNS exprimierte Antigene bei GBS-Patienten zu charakterisieren.

Wir erwarten uns von diesem Projekt eine signifikante Erweiterung des grundlegenden Verständnisses der Funktion der T-Zellen in der Autoimmunantwort. Weiterführend sollen die Erkenntnisse der Entwicklung neuer Therapien sowohl von GBS als auch neuromuskulärer Erkrankungen im Allgemeinen dienen.