Natural Anti-Tau Autoantibodies in Health and Disease

Abstract

The microtubule-associated protein tau plays a pivotal role in several neurodegenerative diseases such as Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration and frontotemporal dementia. In line with this, anti-tau immunotherapy strategies have emerged as a line of investigation with the goal of clearing pathology and improving function in Alzheimer’s disease and other tauopathies. Active immunization with phosphorylated tau epitopes has been shown to reduce tau pathology and to slow the progression of behavioral deficits in mouse models. Passive immunization against full-length, N-terminally cleaved or phosphorylated tau has also shown to reduce tau pathology in animal models. However, the initial clinical trials of tau passive immunotherapies in patients with progressive supranuclear palsy and Alzheimer’s disease have been disappointing. Recently, the study of natural anti-tau autoantibodies has emerged as an alternative for the discovery of new potential diagnostic and therapeutic paradigms.

Natural autoantibodies are antibodies generated in the absence of external antigen stimulation. They can contribute to homeostatic function posing a line of defense against infection, promoting the physiological clearance of damaged cells, mounting an immune surveillance of malignancy, and modulating the immune response. The boundaries between homeostatic autoreactivity and pathogenic autoimmunity are, however, unclear and even if they have essential physiological roles, natural autoantibodies can also cause several autoimmune disorders. The study of autoantibodies has the potential to identify unknown factors in human health and disease. The investigation of the association of autoantibodies with health outcomes can provide new knowledge about their own role as well as the roles of its target antigens in physiology and pathology.

In this thesis, I investigated the seroepidemiology of natural IgG autoantibodies against the microtubule binding domain of the tau protein (MTBD-tau) and explored associations between MTBD-tau-autoreactivity and demographic and clinical features.

This is the first large-scale study of the seroepidemiology of natural anti-MTBD-tau IgG autoantibodies. I used an automated miniaturized indirect ELISA high-throughput platform to economically test more than 40’000 human plasma samples.

I recovered and characterized anti-MTBD-tau autoantibodies and show that they bind specifically to MTBD-tau without evidence of polyreactivity to other structurally different unrelated self-antigens or non-self-antigens. I show that anti-MTBD-tau autoantibodies are able to specifically bind to tau in different orthogonal assays. The majority of plasma MTBD-tau autoreactive samples were polyclonal and all IgG subclasses and both light chain types were represented without a clear predominance. Anti-MTBD-tau autoantibodies exhibited the ability to inhibit MTBD-tau aggregation in vitro and I also show that anti-MTBD-tau autoantibodies can impair the detection of plasma tau in an immunoassay.

MTBD-tau-autoreactivity was surprisingly prevalent in a hospital cohort and was associated with older age and female sex and specific diseases. In this study, MTBD-tau-autoreactivity was not associated with neurological disorders but was associated with systemic disorders. Different lines of evidence including medical diagnosis data and clinical laboratory tests supported the hypothesis that MTBD-tau-autoreactivity is associated with kidney and urinary disorders. This is a previously underexplored disease association which highlights unrecognized roles for tau and natural anti-tau autoantibodies in disease outside the central nervous system. These findings have implications for the current clinical trials of tau-targeting therapies and also for the widespread use of plasma tau measurements as a biomarker of disease.