Here's an interesting paper that may be useful, especially regarding differences in microbiota between males and females. http://www.cell.com/immunity/abstract/S1074-7613%2813%2900341-5 I think since microbiota is likely mostly established in younger ages or by a geographic basis (disregarding repopulation post antibiotics or other infection), the likelihood of very similar gut flora between spouses would likely be somewhat rare.

Karen, thanks for the comment. I'll check the paper

Is there any reason to think that either diet or microbiota have any relevance to auotimmunity? My understanding of the epidemiology of autoimmunity is that in general there is no reason to think there are any environmental trigger factors. There may be threshold factors like smoking but I know of no evidence or reason to propose immunogenic triggers. There are no epidemics. The non-genetic causation seems much more likely to be due to the stochastic nature of antibody generation internally.

What do we understand for autoimmunity? I believe there is no general agreement to that question, but to me, and many others, there is much more to autoimmunity than just auto-antibodies. In fact, healthy people do have B cells and antibodies that are, to some extend, capable of self recognition. On my view, autoimmunity is the result of the lose of self tolerance and/or the ability to control the immune response (I know I am stepping onto hypersensitivities ). Both genetic and environmental factors can have an impact on the loose of immune tolerance and it is not just a question of stochastically generated B cells responding to auto-antigens. Immune tolerance and control of the immune response are complex matters that we do not understand entirely. However, it involve T cells ( e.g. Treg) which addition listen to other cell types such as dendritic cells and macrophages.

Dear Pedro,

I think we have to start with autoimmunity being something we observe in the clinic - that is real autoimmunity. We then want to try and explain that. I don't think we should start with an idea of 'loss of self tolerance' because that may not exist. The autoimmunity we see in the clinic is associated with autoantibodies, but as far as I know is rarely if ever associated with any evidence of loss of T cell tolerance - i.e. increased autoreactive T cells. Since the 1980s many people have assumed that such autoreactive T cells, or maybe defective suppressor or regulatory cells must exist, but there has never been the evidence to support this. We have very good evidence for autoantibodies in situations where relevant abnormalities of T cells have been looked for for thirty years and found to be absent.

There will be some exceptions to this, which may include rare situations like AIRE defects. There are also spontaneous inflammatory disorders without any evidence of adaptive autoreactivity of either B or T cells, such as FMF etc. But for the vast majority disease in the clinic with adaptive autoreactivity that can reasonably be called autoimmunity there are autoantibodies and no evidence of any T cell abnormality.

This may seem strange but I spent twenty five years trying to work out how it could be like that and in 1999 published an explanation, with Jo Cambridge and Vikki Abrahams, which you can find highlighted on my site. We tested the idea using rituximab in rheumatoid disease and you will see the resulting study there too. Rituximab has proved useful in perhaps forty autoimmune disease now and specific T cell depletion has failed in every case. I think the general idea of the 1999 paper must be right. Autoantibodies are not produced because of autoreactive T cells but because of aberrant feedback loops caused by the autoantibodies themselves. The mechanisms are explored in detail. So this is not just 'a question of stochastically generated B cells responding to autoantibgens'. It is a much more sophisticated concept based on the nature of B cell self-regulation. Autoantibody production is quite clearly not just production of antibodies to the wrong antigen, it is **dysregulated antibody production** as indicated by the aberrant isotype profiles seen. The most obvious thing to dysregulate antibody production is an antibody generating an aberrant signal, since all antibody production involves a positive feedback loop through antibody. The story seems to fit for a very wide range of diseases. Certainly some normal people have autoantibodies without disease but that is not surprising because we have reason to believe that the antibodies that are responsible for aberrant feedback signalling are not the same as those responsible for end organ tissue effects. That is why rituximab often blocks tissue effects without leading to permanent breakage of the feedback cycle.

I do not think we have any good evidence for environmental antigens triggering autoreactivity. That idea was raised in the days of rheumatic fever and people have remained quite extraordinarily narrow in their thinking since. There never was good evidence for cross reactivity even for rheumatic fever and rheumatic fever does not behave like autoimmunity anyway. It was just an empty idea from the 1960s. Coelicac disease does relate to an environmental antigen but I think it is particularly interesting that the autoreactivity is not a cross reactivity here, and the autoreactive B cell response is not associated with an autoreactive T cell response. Aberrant signalling by antibody seems almost certain to play a part.

So I would recommend moving away from a fifty year old idea that never got off the ground to fly and think more in terms of dysregulation and the evidence from the patients and treatments in the clinic!

Dear Jonathan,

Thanks for the comments. I will check your work. It is very interesting. Environmental factors that might contribute to the loose of tolerance are not necessarily environmental antigens. Nonetheless, gluten can be a good example of an environmental antigen that triggers autoimmunity in celiacs. Of course, we could then argue whether celiac disease is an autoimmune disease or a kind of allergic disease. I do not see much difference and I believe all arguments on autoimmunity are merely semantic. We we simply do not agree of what autoimmunity is. In my opinion, we should go beyond the classic definition of having auto-antibodies. There are 4 mechanisms of hypersensitivity and each of them is known to be behind some autoimmune condition, including type IV, which does not involve antibodies that cause pathology.

Have a look at this:

J Autoimmun. 2010 Aug;35(1):52-7. doi: 10.1016/j.jaut.2010.02.001. Epub 2010 Mar 11. Autoimmune diseases and autoantibodies in the first degree relatives of patients with systemic sclerosis. Arora-Singh RK1, Assassi S, del Junco DJ, Arnett FC, Perry M, Irfan U, Sharif R, Mattar T, Mayes MD.

J Rheumatol. 1999 Jul;26(7):1495-9. Familial aggregation of lupus and autoimmunity in an unusual multiplex pedigree. Sestak AL1, Shaver TS, Moser KL, Neas BR, Harley JB.

But Pedro, the concept of autoimmune disease arose in the days when antibodies were all that were known about to be auto - and there were some. So autoimmune disease was originally disease with autoantibodies. Why change it to something hypothetical when there is a reality well documented? This is not an issue of semantics, it is an issue of evidence for adaptive autoreactivity, and so far we have only found that for antibodies. Allergy is something quite different - a reaction to something other (allo- ergy). Coeliac conforms to both categories which is confusing but OK.

My old friend Robin Coombs may have suggested that 'hypersensitivity' could be divided into 4 types in 1963 but I think he would laugh to think his classification was still used in the present era when we know of so many mechanisms of inflammatory triggering. Even before he died we already had type 5 and a whole raft of other pathways. I remember discussing with him the new subtypes of type 3 around 1997. Lupus uses type 2 and several different versions of type 3. Rheumatoid I think is just one type of type 3 (CD16 mediated) although there are secondary mechanisms. Grave's is type 5. But I don't know of any type 1 autoimmunity, nor type 4. In fact I doubt type 4 is a useful category any more. It was based on the tuberculin reaction which is a very odd aberrant reaction to an organism that subverts the response. Sarcoidosis looks a bit similar but the intriguing thing there is that the only autoreactivity we know of is the presence of antibodies to peanut agglutinin epitopes. I think Robin would want his classification buried. He was not a man to stick to ideas for the sake of it. (I looked up hypersensitivity groupings on Wikipedia and what is there is a dreadful muddle. I think immunology needs to move with the times. Summer evenings on Grange Road are a thing of the past.)

Jonathan, you are right. I do not either any type I hipersensitivity causing autoimmune disease. You are also right on the need for moving immunology with times. To me this means looking beyond autoantibodies as the only explanation for autoimmunity. I believe we should seek for unifying views in immunology as researches do in physics. Instead, we immunologist put a lot of efforts to keep appart concepts that are just two sides of the same coin.

I've found some articles by Hemminki K et al that answer my question. Swedish has nation-wide health registry which enabled these authors to study the epidemiology of various autoimmunity diseases, including Grave's disease (PMID: 20056533 ), inflammatory bowel disease (PMID: 1970719), rheumatoid arthritis (PMID: 19248111) and multiple sclerosis (PMID: 18843511). The standardized incident ratio in these patients for various autoimmune diseases is greater than 1 in relatives but not in spouses. An exception, however, was in Grave's disease in which they found a significant concordance between spouses of 2.75.

That is interesting Pedro. The Scandinavians and Icelandics are good at these epidemiological issue. Why Grave's I wonder? One might wonder about sea, fish and iodine in Sweden but that seems unlikely in a supermarket society. Viruses? Needs thinking about.