Thursday, November 06, 2008

HLA-B27 some more

Well, there have been a few interesting developments in the last few days. The most interesting was being invited to lunch by Prof Ebringer. That was a very long conversation and has produced a stack of papers to read and a whole lot of ideas, plus a Drs appointment for myself to see if I can get HLA-B27 tested on the NHS. At £209 per test privately, I'm rather hoping to get my GP to fund this even if I have to offer a decent bottle of wine to cover the £20 odd it costs the practice!

The HLA-B27 discussion was very interesting. Apparently the allele is very common among the Eskimo and their descendants and very rare in people from equatorial regions. This fits nicely with the carnivorous HG in temperate or extreme climates vs more starch based gathering in the tropics. By a quirk of migration the gene is also very rare in Japan, but even there the link with ankylosing spondylitis is strong.

A medic, Dr Tani, working in Japan, was looking to publish a paper on AS and approached the Kings College group to get the Klebsiella antibody titres done. Prof Ebringer suggested sending the samples coded, plus some controls and some RA samples thrown in. This is the paper which came out of the collaboration.

The Kings College group did the same with a set of coded Dutch samples, written up here. Interestingly, two other labs failed to get the same result, using the same samples. But if Ebringer can get consistent results on both the Japanes and Dutch samples, I tend to think his group is quite good at immunology.

Obviously the AS hypothesis generates the starch avoidance protocol which seems to be in fairly widespread use in places like the KickAS site. The proof of the pudding is in the eating ie, do patients get better on a behaviour based on a hypothesis. If so that seems to support the hypothesis to me...

I think it is worth noting that AS primarily involves an IgA antibody, which suggests exposure to the trigger across a mucosal surface, typically the gut. Rheumatoid disease involves an IgG response and suggests a non surface immune response, in this case classically through a low grade chronic urinary infection. This gives a simple explanation for the response seen to minocycline and doxycycline in RA patients. Of course without antibiotics (or with them) you might approach starving the proteus which triggers RA by using a dilute urine approach (the proteus bug derives energy by splitting urea in the urinary tract) and possibly eating a low protein diet might well help too. It's worth noting that the true Optimal Diet is actually rather low in protein at around 40-50g/d, once you are well established on the diet. By eating the minimum amount necessary of the highest quality protein you produce the least quantity of waste, ie urea, which is better known as proteus fodder. I'm not down at this level of protein intake but it's another option for fighting RA. I guess getting your immune system back by dumping sugar would potentially get rid of the proteus bugs completely... There's an interesting study.

Of course we spent a lot of time talking about BSE, scrapie, CJD, vCJD and MS. There is probably a book could be written here so I'll stop until I think I understand it a bit better and have had chance to tease out a few of the more problematic features of both the prion hypothesis and the auto immune hypothesis...



gunther gatherer said...

Hi Peter,

I've read your other posts on HLA-B27 and I'm not following how it relates to overall health. Are you suggesting that it has a far higher occurrance in humans in general or that it somehow relates to your celiac disease, or to general aging degeneration?

Do you think AS is just another form of chronic inflammation brought on by diet? Why would less dietary protein be protective against antigens in general?


Peter said...

Hi Gunther,

The HLA B27 issue is only directly relevant to those who carry the gene. It is a rare gene in populations who are starch based and common in the Inuit. If you carry it you get trashed by starches. If you add gluten the immune system has a much better "view", through the damaged gut lining, of the specific protein in the gut made (by klebsiella) in response to starch. It's this protein that triggers the immune system to make an antibody which damages your spine.

The low protein comment was a bit obscure. It's only related to the seperate problem of rheumatoid arthritis. The bug proteus can live in your kidneys and it "eats" urea, using a urease enzyme to convert urea to ammomnia, releasing energy. This enzyme can be "seen" by your immune system (if you have the correct white blood cell type) and "seeing" it triggers the response of making an antibody against the urease. The anti urease antibody unfortunately fits your joints so you get collateral joint damage, called rheumatoid arthritis.

Less urea means less urease, so less problem. Diluting the urine helps too. So does killing the proteus bug. Complete elimination with antibiotics appears very difficult. Whether the OD allows the immune system to get rid of the bug is open to negotiation.

Interestingly Lutz warns about suddenly reducing carbs to very low levels in auto immune diseases as the immune system is depressed by hyperglycaemia. Sudden normoglycaemia can cause a flare by allowing the immune system to work correctly. He was talking about MS at the time, another bacterially triggered problem. He dropped peoples carb intakes gradually to avoid this.

Does that make it a bit clearer?


Taka said...

Hi Peter,

I have never heard that sugar depresses the immune system. Is that what you mean when you are saying the immune system is depressed by hyperglycaemia? AFAIK sugar triggers the arachidonic acid release (PLA2) what stimulates immunity but by downregulating its synthesis at the same time it could possibly have the immunosuppressive effects long term ...

BTW there is an interesting new article from Ebringer on the Proteus HLA–DRB1 issue in Medical Hypotheses (PMID: 17983708) I cannot get full text. I have a kidney stone disease and RA running in my family.


ItsTheWooo said...

Oh I find it extremely easy to believe that high blood sugar suppresses the immune system.

If I spike my blood sugar I always, always get a transient E/N/T infection *without fail*. My ears feel stuffy, I get feverish, I will have sore throat, etc. In fact I can tell if I overdid the carbs based on whether or not I get sick a few hours later.

The symptoms of sickness are a combination of the immune system responding to pathogens, as well as your body reacting to the waste products of microbiota. I reason that the transient infection is a combination of my rather low baseline immune system being taken advantage of by a rather rapid increase in baddies as a result of a rare spike in blood sugar. My white blood count is very low at baseline, often below normal, which reflects my low weight/low average blood sugar. I don't need white blood cells, my body has no inflammation, because there is nothing to feed bacteria (my blood glucose is rather low every time I check it, if it is over 80 it is high, and fasting it is 50-60).
So, like, when I eat sugar suddenly there is this food available for the bacteria to eat, and they start to multiply, which triggers my immune system to freak out, which produces the symptoms of illness. It's very temporary because my sugar returns to normal shortly and my immune system easily catches up with the transient increase in bugs.

Just something I noticed myself, eh.

BTW it's common knowledge among healthcare workers that diabetics are constantly sick and have crap for an immune system. If you know the patient is diabetic, automatically you should be thinking of that person as if they were immunosuppressed.

Taka said...

ItsTheWooo, don't you realize that most of the symptoms you are experiencing are the direct consequence of arachidonic acid release and metabolization into eicosanoids like LTB4 and PGE2? It isn't the bugs which cannot amplify so fast and only a few of them could produce truly damaging toxins when stressed. It's the overactivation of your immune system by sugar what gives you sorethroat. You can dampen the response easily by extra virgin olive oil (the bitter one) or ginger which both contain the COX/LOX inhibitors. More on this is here:


emil henry said...

Hi. Just re: your reply to my hypoglycemia-like reaction (thanks, by the way):

Did a blood test. Elevated infection markers. Didn't tell me which. They suspected mononucleosis prior to the test. It's a bit early, so we can't know anything for sure as of yet. Something on my lower left feels inflamed. New test on Monday.

Seen no new shock-like reactions yet. My guess: the body expends all glucose to fuel thermogenesis to create a fever, seeing the low thermogenic effect of fat. Thus, hypoglycemia. I've done some physical activity, yet I seem fine, having kept carbs around 50+ g daily. Usually mashed almond potatoes, or just whipped mocca cream (with dextrose and honey).

Kwasniewski is probably right... again. Damn.

Peter said...

Hi ItsTheWoo,

The original paper on oral carbohydrate and depressed neutrophil action is here in full text.

I picked it up through Barry Groves' here.

The other feature of hyperglycaemia is the activation of NFkappaB which turns on about 1000 genes, all pro inflamatory. As we all know, arachidonic acid can be metabolised to pro or anti inflammatory eicosanoids. Probably NFkappaB decides which you get. So we have the cracker of depressed immunity with increased inflammation from hyperglycaemia.


When you see lines like this

"Primitive Eskimos rarely live beyond age 50, long before CHD symptoms emerge in the vast majority of people"

you realise it's cr*p you are reading and you should hit the back button asap.

This was Ancel Keys' argument against Stephansson. Keys simply made it up. Steffanson checked ages by finding out how many Eskimo had witnessed known historical events. They're not all dead at 50. Keys and anyone else with this level of accuracy is simply wrong. They didn't get cancer or fatty liver from all of those omega 3s either. Duh.

It was so nice when Bruce gave up on me. Please don't bring him back second hand to haunt me.


Peter said...


Thanks for the udate. Hope it goes well. You are not supposed to get ill at all on the OD. That would be nice but not true at the level we eat at!

Actually, I rarely get ill, but my wife gets rather more of Squiggs' colds than I do. At nursery Squiggs is off diet but not too far. He gets the colds but is rarely unwell with them. Lots of snot though (oops, sorry, too much information there).


gunther gatherer said...

Hi Peter,

Thanks for explanation dedicated to non-biochemists like myself.

In return, I send you some truly evil news on the statin front...

Thanks again,

arnoud said...

Hi Gunther,

the "Jupiter" study subjects all had elevated CRP: inflammation. Most probably high counts of small dense LDL, resulting from high carbohydrate diet/high serum glucose.

The study was stopped after a cuple of years. It makes one wonder what such unnatural low levels of cholesterol will do to the subjects taking Crestor after a few more years. For starters, cancer risk would be expected to increase significantly.

Taka said...

Peter, you say "the cracker of depressed immunity with increased inflammation from hyperglycaemia". Do you think that inflammation is not part of immunity? Could there be immunity without inflammation? I have believed the immunity was always inflammatory in nature ... Perhaps when the neutrophils are starving they just upregulate the phagocytosis to get some food not to be primarily meant as a directed assault on the bacteria. Just my opinion, sorry if this resembles Bruce.


Peter said...

Hi Taka,

Yes, inflammation, immunity and wound healing are all parts of the same process. Inhibiting the conversion of arachidonic acid to pro inflammatory eicosanoids may make you feel better but gives a small yet statsistically, and possibly biologically, significant delay in recovery. An extra half day of cold, but you feel better on NSAID. Not that I use NSAID.

The problem with hyperglycaemia is that it stops the neutrophils eating while simultaneously increasing gene expression for pro inflammatory enzymes. Increased inflammation is not necessarily good per se. If you have a cold you could increase your systemic inflammatory state by injecting yourself with bacterial endotoxin or undergoing severe multisystem physical trauma. This would send your immune system in to overdrive and cause massive inflammatory damage, but not necessarily cure your cold... Actually, I guess it might cure the cold I suppose, thinking logically. I don't know if this has ever been tried...

Re feeding activity, I'm not sure I would view phagocytosis as a method of obtaining food in the immune system. I agree it has parallels to amoeba like behaviour but the neutrophil is pretty well looked after by the body. It does live in a sea of glucose and NEFA.


Oops , sorry for the typo in Stefansson in the last comment.

Tessan said...

I'm not sure where a question about clarification would fit in your blog comments, so I take a chance and put it here.

First regarding AS and starch. Would a small amount of glucose carrying vegetables be better for the AS sufferer, than leafy greens (presumably containing more starch)?

I have psoriatic arthritis and HLA-B27+, would that equal AS?
I also have no rheumatoid factor and low crp. Is that common in AS?

Does a low reading for crp mean I have lower inflammation of the kind that increases risk of heart disease? Does it also say anything about sensitivity to wheat or sucrose/glucose?

I have been overweight/obese since childhood but have had good bg until recently, and I have also aquired some abdominal fat in the last few years. I'm 42 now. My LC diet is focused on normoglycema, health, and pain management. But I would'nt mind losing weight either.

I really admire your ability to take a very complex subject and explaining it simply. As well as seeing through all the half lies and low fat bias. Things get much less confusing when I read your blog. But on the issues I mention above I'm still confused.

Peter said...

Hi Tessan,

Prof Ebringer's comment was that the law of mass action applies. I think this means that the dose makes the poison... Generally the amount of starch in green veggies is too small to matter. Fruit in moderation is okay too but some commercial "big" fruits are picked green and marketed with significant starch present. Berries should be fine.

I'd go starch free for any sort of arthritis, especially if I was B27+ve. I too am low on CRP, ESR and RhF. This is normal if you are in remission. I would assume that this gives low cvd risk. I really don't know about CRP and gluten but it does suggest your blood glucose is quite well controlled. I feel that wheat consumption is fine if it doesn't gift you an auto immune problem. Unfortunately, if you have normal gut function, you might not realise you have gluten issues as the nurse helps you in to the wheelchair with cerebellar ataxia................ It's sad but for me wheat is off the list of Foods. I know not everyone agrees, that's fine by me too.


Tessan said...

Thanks a million for the further explanations! My rheumy is actually unusually open to the idea that it is all gut related. He even suggested that I try a gluten free diet. Problem was that I tried the run of the mill (pun intended) gluten free bread/pasta based diet, which I hated.

I'm not sure I have my insulin sensitivity under control. Before going back to LC (I went off because of my fat phonograph nagging husband) I was going to show my 4 year old son how to measure blood glucose. 2 hours after a sushi lunch I demonstrated how to self-induce a mini panic. Meter said 11 mmol. Pre diabetic.

I have focused on fructose, glucose, pufas, starches, in that order. But I might try to focus more on getting absolutely grain free. Being Swedish, I tend to nibble on rye crackers every now and then. And working as a chef I really need to taste all food I cook even if I wouldn't eat it myself. But I can keep that down to a minimum, which would probably do the trick.

I'm looking forward to improved health now that I'm on the right track.

Peter said...

Oddly my wife was having low grade arthritis problems a year or so before we hit LC. We tried conventional gluten free eating for a month or so, total failure. My wife had forgotten that she ever had hip arthritis issues but we can both remember how worried she was during her BSc year. She blamed it on the benches and lab work. But 3 years of bench work for the PhD was no issue eating LC, gluten free, real food......