Tuesday, 27 December 2016

The search for the MS autoantigen - fools gold or a reality?

Sci Rep. 2016 Dec 23;6:39430. doi: 10.1038/srep39430.

Antibodies from multiple sclerosis patients preferentially recognize hyperglucosylated adhesin of non-typeable Haemophilus influenzae.

Walvoort MT, Testa C, Eilam R, Aharoni R, Nuti F, Rossi G, Real-Fernandez F, Lanzillo R, Brescia Morra V, Lolli F, Rovero P, Imperiali B, Papini AM.


In autoimmune diseases, there have been proposals that exogenous "molecular triggers", i.e., specific this should be 'non-self antigens' accompanying infectious agents, might disrupt control of the adaptive immune system resulting in serious pathologies. The etiology of the multiple sclerosis (MS) remains unclear. However, epidemiologic data suggest that exposure to infectious agents may be associated with increased MS risk and progression may be linked to exogenous, bacterially-derived, antigenic molecules, mimicking mammalian cell surface glycoconjugates triggering autoimmune responses. Previously, antibodies specific to a gluco-asparagine (N-Glc) glycopeptide, CSF114(N-Glc), were identified in sera of an MS patient subpopulation. Since the human glycoproteome repertoire lacks this uniquely modified amino acid, we turned our attention to bacteria, i.e., Haemophilus influenzae, expressing cell-surface adhesins including N-Glc, to establish a connection between H. influenzae infection and MS. We exploited the biosynthetic machinery from the opportunistic pathogen H. influenzae (and the homologous enzymes from A. pleuropneumoniae) to produce a unique set of defined glucosylated adhesin proteins. Interestingly we revealed that a hyperglucosylated protein domain, based on the cell-surface adhesin HMW1A, is preferentially recognized by antibodies from sera of an MS patient subpopulation. In conclusion the hyperglucosylated adhesin is the first example of an N-glucosylated native antigen that can be considered a relevant candidate for triggering pathogenic antibodies in MS.

Merry Christmas everyone! 🎄🎄🎄🎄🎄

Anyone on a tenure track will happily inform you that if you wanted an uneventful, yet guaranteed research career, stay away from the fools gold. These are the flamboyant areas of research that are everywhere, but literally worth nothing; sucking your combined research budget dry at the blink of an eye! In the field of MS, the never ending search for the MS autoantigen, that mimics host molecules initiating autoimmunity, is undoubtedly one of these ventures. But with technology, comes hope.

MOG (myelin oligodendrocyte glycoprotein) found on the surface of myelin sheaths is a potential antigen involved in the process of demyelination in MS.  Here, Walvoort et al. report on another potential candidate, the glycan (carbohydrate) gluco-asparagine (N-Glc) CSF 114 (N-glc)glycopeptide structure that decorate the cell-surface of bacteria. These are normally present to avoid immune detection as they are similar to motifs present in the host, but can unfortunately lead to the host antigen being recognized as foreign, leading to activation of the immune system against self. Previously, anti-CSF114(N-Glc) have been found in the blood of PwMS, and have been shown to correlate with disease activity and GAD+ brain lesions. Gluco-asparagine (N-Glc) modification are virtually absent in multicellular organisms but present in organisms that lack a nucleus, e.g. bacteria. Walvoort et al. report that the construction of gluco-asparagine (N-Glc) using the machinery present in H. influenza (bacteria that causes upper respiratory tract infection) is critical to isolating the anti-N-Glc antibodies from MS patients blood. Moreover, they demonstrate that antibodies isolated using these antigens react with myelin in the nervous system.

So gluco-asparagine (N-Glc) from H. influenza can trigger formation of autoantibodies in MS. The problem lies in that there may be as yet other unidentified mimics that may be recognized by anti-N-glc antibodies in MS. And so the story begins. It would appear in the case of Walvoort et al. it's only fools gold if you lack aspiration.

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