Yet another autoantigen

Ayoglu B, Mitsios N, Kockum I, Khademi M, Zandian A, Sjöberg R, Forsström B, Bredenberg J, Lima Bomfim I, Holmgren E, Grönlund H, Guerreiro-Cacais AO, Abdelmagid N, Uhlén M, Waterboer T, Alfredsson L, Mulder J, Schwenk JM, Olsson T, Nilsson P.Anoctamin 2 identified as an autoimmune target in multiple sclerosis. Proc Natl Acad Sci U S A. 2016. pii: 201518553. [Epub ahead of print].

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.

If MS is an autoimmune disease what is the target autoantigen?

This is an age old problem.

The question we first have to ask is it a T cell problem or a B cell problem?

There is a lot of hope placed on B cells at the moment and it is relatively easy to see what B cells are recognising, because this is the target of their B cell receptors, which are the antibody molecules.

Recently we have has a sea of papers reporting on what the antibodies are recognising whether they are proteins or lipids. 

There are many ways to do this you can use arrays of proteins and peptides (although antibodies of importance tend to recognise 3D shapes rather than straight short peptides) or you can make the heavy and light chains of the antibody molecule and make them genetically and go fishing for the target.

Both approaches are “fishing expeditions” rather than hypothesis led research. In this trawl they pull out Anoctamin2. The find that people with the gene associated with MS are more likely to make antibodies to this target.

Recently we had Kir4.1 as a target in MS. This is a potassium channel. But it wasn’t replicated and is, this is yet another paper that shoots this one down in flames. So why should we believe that Anoc2 a chloride channel is the answer? 

We can’t until it is replicated. 

Chances are this may fall by the ways side too, because other similar studies have not found this target.

Where is Anoc2 expressed. In the mouse it is in the eye and the olfactory system and if you knock it out there are problems with sensing odour….so does this new one smell fishy.

ProfG will be happy because one of the number one targets is good old EBV but then Anoc2 stands out too.

However as the antibodies target the fragments inside the cell, which is confirmed in the histology in the paper and so antibodies produced are not going to get to them and also the antibodies are expressed in people with established MS, points that this is an epiphenomenon and is the chicken rather than the egg. So as a consequence of damage the protein gets liberated and sets off a B cell response and as it is inside the cell it may not be of too much functional consequence.

Many groups will have to replicate this finding before it is accepted or rejected but as a cause of MS don’t hold your breath

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  • Are there not a lot of red herrings in MS, a lot of complicated biochemical goings on in the body once the disease starts rolling – primary changes/molecules/damage, then secondary, then tertiary… What we need is the trigger, then the appropriate annhilation. I'd put my bet on EBV, Charcot, Professor Giovannoni.

  • "….and is the chicken rather than the egg. So as a consequence of damage the protein gets liberated and sets off a b-cell response…" When I read about putative auto antigens and MS I think about a shot gun blast or explosion. People are then rummaging through the debris and picking up fragments announcing that this particular piece is the source of the destruction.

  • I think just like the comments above, they are looking at the consequences of the damage caused by MS, perhaps hoping to sift through damage will find whom are causing. Since I started to follow research on MS I've seen studies on a variety of antigens, ion channels to unregulated antibodies to sperm … But the search is necessary and must continue … Perhaps Charcot 2 throw more light on this way, perhaps you have missed a great opportunity to stop looking at the Alpha Beta Crystalline …

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