Sunday, October 12, 2008
HLA-B27 and Ebringer
This review [EDIT: the review has gone pay only and the abstract is yet to arrive on pubmed so I'll link to this when I can] was forwarded to me off blog and makes some very interesting reading. It's also a great excuse to post this picture: Now, this might look like a plastic sausage in a plastic bun, forming a plastic hot dog, all from my son's toy cooking set, but to an immunologist (my wife) it's obviously an MHC molecule presenting a peptide. The sausage is the peptide, it's not to scale! The primary function of MHC class I molecules is to signal to the immune system that something is very wrong inside the cell, something represented by the peptide fragment, and the organism would be better off without that particular cell. Usually immune cells with a CD8 receptor get in and do the killing when MHC class I molecules present peptide. The paper links a broad array of arthritic conditions to gut inflammation, much of which is subclinical (ie the person has arthritis and gut problems but considers their state of gut dysfunction to be "normal") and spends rather a lot of time discussing the role of HLA-B27 in this process. HLA-B27 is one of those buns, an MHC class I molecule. Your genetics determine whether you carry this particular MHC bun/molecule or not. The identity of the sausage is skirted around in the paper and never mentioned, except it is considered to be derived from the gut bacteria. The rat model used to prove this has to have the human HLA-B27 gene inserted. Err, but not just one or two copies the way HLA-B27 occurs in humans. More like 55 copies! You have to wonder about the cause of some of the problems these rats develop (clogged endoplasmic reticulum for a start) and how typical of the human condition they are! To summarise the paper: there's something in common between gut and joint problems. We don't know what. But the answer will lie in tinkering with the immune system (an aside, does anybody remember Northwick Park? TGN1412 was looking to cure problems like ankylosing sponylitis, something of a high risk stratagem it seems). I had a look through the references and the main citations, especially about HLA-B27, are by Mielants, who looks to be the group leader of Jacques and Elewaut (review authors). Nothing wrong with citing your boss. Mielants is also an author on the recent consensus report on evidence based management of ankylosing spondylitis, an Opinion Leader. Jacques and Elewaut didn't mention Ebringer. Who is Ebringer? If you go to pubmed and search on "Ebringer" "HLA B27" you will get the idea of the size of the hole in the Nature paper. Ebringer's first HLA-B27/AS paper was published in 1980. Jacques and Elewaut must know this. But Ebringer is a maverick, as far as I can see. He is the main proponent for the role of klebsiella pneumoniae, a gut bacterium, as the origin of the peptide in the HLA-B27 bun. There are a number of groups who have worked with him on this, but I suspect Mielants and his group represent the mainstream view. I've yet to see personal exchanges of the type seen between Nottingham neurologists and Sheffield neurologists, but Ebringer is not going to get a mention in a conventional review. He just doesn't get rated. This is a pity. Carol Sinclair wrote a book based on Ebringer's work. The book is not perfect but it will get remission of GI and arthritic problems for a lot of AS/IBS sufferers. In it she recounts the anecdote she heard from Ebringer, about how he found the dietary treatment for AS. The episode has a lot in common with my own experience. Ebringer was managing a patient with AS using conventional drugs. The patient wanted to loose weight. Ebringer gave him advice derived from the low carbohydrate approach (shows how dodgy he is!), possibly influenced by Yudkin who was London based around the time that Ebringer would have been coming through medical school (I'm guessing the dates). The patient went LC and his AS went in to remission. The standard medical approach to this sort of phenomenon is to ignore it (prime example was my relative handing her beta blockers back to her cardiologist, he was uninterested). Ebringer didn't do this. He went on to fix more people using the LC diet approach, modified to a low starch approach. Why low starch? The whole situation relating to HLA-B27, klebsiella and AS is horribly complex, but at the core is the enzyme pullulonase, which provides the peptide sausage which fits the HLA-B27 bun. I've been trying to find exactly which sugar triplet pullulonase degrades and it's not clear from Wiki. What is clear is that the triplet is present in starch and the enzyme pullulonase is produced whenever klebsiella meets starch. The enzyme is surface mounted on the bacterium and is in an ideal position to be seen by the immune system. If an HLA-B27 carrying white blood cell kills a klebsiella microbe it will easily produce the short peptide from pullulonase which fits the HLA-B27 molecule on its surface. That signals to both the innate and the adaptive immune systems to become active and (a) attack and (b) make antibodies against the peptide fragment. It's a bit unfortunate that the antibodies made against pullulanase, presented by HLA-B27, also fit the collagen around your spine, knees and often fingers. This labels the collagen as foreign, as well as doing a few other things. Result: ankylosing spondylitis, plus gut problems from the local damage. I get the impression that neither Mielants, Jacques nor Elewaut believe a word of this. That's tough, as the Ebringer/Sinclair diet works pretty well. I used to have a moderate osteopath/chiropracter habit, just a few hundred pounds a year. When I went to Atkins induction I eliminated all starches, essentially by accident. My back pain simply disappeared. I had my first episode of neck pain at about 12 years of age and started with low back pain at about 20 years of age. It persisted through to Atkins induction at 46ish. It fluctuated quite a bit and the sciatica was thankfully very intermittent. I have learned many of those tricks needed to get dressed without bending your spine. You know, sitting down to get you underpants around both ankles, then using one foot to pull them up to the knees, where you could just about reach them to pull them the rest of the way up. Easy really. You just do it. Suddenly it all stopped with LC eating. I remember sitting in my car and turning around in the seat to reverse out of the drive, a few yards down the road and then in to a small side road, an "S" shaped reversing maneuver (a necessity of the road layout). Now I could do it, every day, easily, with no neck or lumbar pain. A joy! I used to sit there on the drive and grin at the thought I could turn around and look out of the back windscreen. So, personally, I have a lot of time for Ebringer. How wacky is he, that the rest of rheumatology would rather not mention him? This wacky: Does anybody remember Bovine Spongiform Encephalopathy, known as BSE or Mad Cow Disease? This paper shows how Ebringer views the disease. It does not make him popular. Frankly I'm amazed he got it published. This is the Royal Society for the Promotion of Health [link is down permanently]. It looks quite respectable to me. The society makes various awards for outstanding work. Ebringer got the 2004 RSPH Gold Medal. From the [original] website: "This medal is awarded for any major innovation or development which has significantly improved or promises to improve the quality and dignity of human life" Ebringer got it for his work on BSE. This is the text of Ebringer's acceptance speech and these are the implications of his point of view as regards BSE, taken from that pdf: [EDIT here's the full text as the RSPH website revamp deleted it] (1) Consumption of meat is safe and has always been safe. (2) Culling of cattle was unnecessary. (3) There will be no epidemic of CJD. (4) An ante-mortem test for detecting BSE in live cattle is feasible. It is worth noting that cutting edge researchers in to the prion hypothesis of BSE (currently the mainstream paradigm) are very careful to maintain that their hypothesis is an hypothesis. This subtlety tends to get lost in political decision making. Of course Ebringer may be completely wrong about both BSE and AS and we should be grateful for the cattle cull and TNFA blocking antibodies. If so I guess my spine problems just went in to spontaneous remission five years ago when I changed my diet, by coincidence. Phew, was I lucky. And so too was my daughter, a few months ago, when she did the same diet change with the same result! Strange, that... Back to HLA-B27: On an evolutionary basis HLA-B27 would be no problem for a primarily carnivorous hunter gatherer. Probably some degree of intestinal wall damage is needed for the immune system to "see" klebsiella in the gut. So woe betide when grains arrived in the Nile valley, gluten and starch as a continuous combination! Perhaps you need to build pyramids as your ticket to future happiness because life is currently so awful, there must be something better than the ancient Egyptian everyday arthritis grind. An afterlife would need to be blissful and pain free as a reward for the daily suffering which was life with ankylosing spondylitis. Peter PS there's a nice link to this paper about Egyptian arthritis in DrBG's post on "300". I think she likes the film.