T cell reactivity in inflammatory neuropathy

Abstract

This thesis deals with three subjects: inflammatory neuropathies, the (human) immune system, and microbial pathogens. The work is mainly focussed on Guillain-Barré syndrome (GBS), an acute inflammatory neuropathy that is often induced by a bacterium called Campylobacter jejuni, and chronic inflammatory demyelinating polyneuropathy (CIDP). In the broadest sense, the goal is to reveil how activation of the immune system causes inflammatory neuropathy. Much less is known about the T cell response than about the antibody response in inflammatory neuropathy and therefore the thesis is entirely focussed on T cells. The T cell response to myelin and to the microbial pathogen C. jejuni, and the status of the T cells during inflammatory neuropathy are described. The newly obtained data will be put together into a hypothesis on the pathogenesis of GBS. A hypothesis on the sequence of events leading to GBS, combining established ideas with the findings presented in this thesis may be formulated as follows. An infection with a gangliosidemimicking pathogen is the first event in the development of GBS. Initially, a normal immune response will develop which consists of a bactericidal or cytotoxic innate lymphocyte response, followed by an adaptive T cell response, and antibody production. For as yet unknown reasons a subset of T cells becomes hyperactivated followed by anergy or a certain T cell population was already non-responsive to stimulation with antigen before the actual infection took place. If these nonresponsive T cells are the ones that should normally support regulatory T cells, or should perform a regulatory function themselves, a physiological immune response now turns into a pathogenic one, characterized by a long duration and heightened intensity. As a consequence, pathogenic autoantibodies and immune-stimulatory molecules are produced in high amounts and gain access to the peripheral nerve where complement and macrophage activation damage the 99 nerve tissues. In this scenario, molecular mimicry alone is not sufficient to cause autoimmunity, but it is a condition for a pathogenic response. Only the combination of defective downregulation and a peripheral nerve-mimicking epitope on a pathogen may lead to GBS. The question that arises immediately is why T cells become non-responsive. Potential answers to this question are: 1) the infection is very severe due to an inherent property of the pathogen, or 2) due to an inadequate early defense of the host, both leading to hyperactivation and anergy, or 3) genetic host factors, or 4) other immunological host factors contribute to the observed T cell nonresponsiveness. It may for example be crucial how the host immune system was primed before the GBS-inducing infection was established.