Abstracts (complete list) - Wissenschaft Online

Gurumoorthy Krishnamoorthy, Florian C. Kurschus, Klaus Dornmair, Reinhard
Mentele, Hans Lassmann, Hartmut Wekerle
Paradoxical autoimmunity: Molecular self mimicry initiates
spontaneous autoimmunity in myelin-specific T cell receptor
transgenic mice deficient of cognate self antigen
We describe here the identification of neurofilament medium (NF-M), a neuron-specific
cytoskeletal intermediate filament protein, as a cross-reactive autoantigen for a myelin
oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR). Studying the
mechanisms of spontaneous autoimmunity in MOG-specific TCR transgenic mice (2D2),
we bred the TCR transgene into MOG deficient (MOG-/-) mice of appropriate C57BL/6
background. Surprisingly, MOG-deficient 2D2 TCR transgenic mice (2D2 x MOG-/-)
developed experimental autoimmune encephalomyelitis (EAE) with frequency and
symptoms undistinguishable from single transgenic MOG+/+ 2D2 mice. About 10 - 20%
of the 2D2 and 2D2 x MOG-/- mice developed spontaneous EAE at around 5-8 weeks of
age. The T cells isolated from the inflamed central nervous system (CNS) predominantly
contained transgenic T cell populations ruling out any endogenous T cells might be
responsible for autoimmunity. The clinical and histological features of the EAE were
similar between these two strains.
Having excluded failed gene ablation in our MOG-/- strain, we scanned MOG-/- CNS
tissue for 2D2 T cell activating activity. We identified one fraction which induced a
strong proliferative response of 2D2 T cells. Mass spectrometry analysis identified
neurofilament proteins as major components. Sequence alignment of NF-M and MOG
revealed a motif shared by the MOG 35-55 peptide and a segment of NF-M. We
confirmed cross-reactivity between MOG and NF-M on the level of recombinant proteins
and synthetic peptides.
This is the first report of a pathogenic, myelin specific T cell clone cross-reacting with
another CNS self-protein which can serve as target of an autoimmune attack.