WIMM Research
Nick Willcox
Initiating processes in human autoimmunity
Laboratory Members
- Isabel Leite
Selected publications
- Leite Maria I, Jones Margaret, Strobel Philipp, Marx Alexander, Gold Ralf, Niks Erik, Verschuuren Jan JGM, Berrih-Aknin Sonia, Scaravilli Francesco, Canelhas Aurea, Morgan B P, Vincent Angela, and Willcox Nick (2007) Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status. Am J Pathol, 171(3):893-905.
- Leite Maria I, Strobel Philipp, Jones Margaret, Micklem Kingsley, Moritz Regina, Gold Ralf, Niks Erik H, Berrih-Aknin Sonia, Scaravilli Francesco, Canelhas Aurea, Marx Alexander, Newsom-Davis John, Willcox Nick, and Vincent Angela (2005) Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol, 57(3):444-8.
- Giraud Matthieu, Taubert Richard, Vandiedonck Claire, Ke Xiayi, Levi-Strauss Matthieu, Pagani Franco, Baralle Francisco E, Eymard Bruno, Tranchant Christine, Gajdos Philippe, Vincent Angela, Willcox Nick, Beeson David, Kyewski Bruno, and Garchon Henri-Jean (2007) An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature, 448(7156):934-7.
- Meager Anthony, Visvalingam Kumuthini, Peterson Part, Moll Kaidi, Murumagi Astrid, Krohn Kai, Eskelin Petra, Perheentupa Jaakko, Husebye Eystein, Kadota Yoshihisa, and Willcox Nick (2006) Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med, 3(7):e289.
Prof Nick Willcox
The muscle
weakness in ~80% of myasthenia gravis (MG) patients is caused by
autoantibodies to nicotinic acetylcholine receptors (AChR), which are
densely packed at motor endplates. About 5% of patients instead have
antibodies against the muscle-specific kinase MuSK. Because there is no
analogous test for the remaining 10-15% of
‘seronegative’ cases (AChR? in Fig), their
diagnosis is often delayed.
In patients with anti-AChR antibodies, the thymus parenchyma is compressed into medullary epithelial bands (MEB) by lymph node-like infiltrates (‘INF’ in Fig;) with AChR-specific germinal centres (GC), where B cells mutate/ diversify their antibodies. Rare AChR-expressing ‘myoid’ cells often co-localise with the GC. Dr Leite now finds deposition of the activated C3b complement component in the MEB, and also on many of the myoid cells exposed to the infiltrates (Fig).
In patients with anti-AChR antibodies, the thymus parenchyma is compressed into medullary epithelial bands (MEB) by lymph node-like infiltrates (‘INF’ in Fig;) with AChR-specific germinal centres (GC), where B cells mutate/ diversify their antibodies. Rare AChR-expressing ‘myoid’ cells often co-localise with the GC. Dr Leite now finds deposition of the activated C3b complement component in the MEB, and also on many of the myoid cells exposed to the infiltrates (Fig).
We conclude that:
- AChR-specific helper T cells (Th) are first primed by the isolated AChR subunits in thymic epithelial cells instead of being tolerised by them;
- the ensuing ‘early’ antibodies provoke complement attack on myoid cells and formation of GC, where
- the antibodies diversify to recognise native AChR.
Interestingly, the thymic changes are similar, though milder, in many of the ‘seronegative’ patients (Fig), suggesting that they belong to the same spectrum as the seropositives. In a further search for AChR antibodies, Dr Leite used embryonic kidney cells co-transfected with AChR and the rapsyn protein that normally clusters it at muscle endplates. She now finds clear positive staining (by immunofluorescence) by sera from many ‘seronegative’ patients, especially those with thymic changes. Not only should that form a basis for improved assays: it also suggests that many ‘early’ antibodies are pathogenic even though they have affinities too low to bind soluble AChR at the low nM concentrations available.
