HDL and Immunity

HDL – high-density lipoprotein – particles are good for you: High HDL levels are associated with lower mortality overall and lower mortality from many diseases – not only cardiovascular disease but also cancer and infection.

People with high HDL are only one-sixth as likely to develop pneumonia [1], and in the Leiden 85-Plus study, those with high HDL experienced 35% lower mortality from infection [2].

Each rise of 16.6 mg/dl in HDL reduced the risk of bowel cancer by 22% in the EPIC study. [3]

In terms of overall mortality, in the VA Normative Aging Study, “Each 10-mg/dl increment in HDL cholesterol was associated with a 14% [decrease] in risk of mortality before 85 years of age.” [4]

This must be surprising to those who think HDL is only a carrier of cholesterol. The lipid hypothesis presumed that the function of HDL is to clear toxic cholesterol from arteries, cholesterol having evolved for the purpose of giving us heart attacks. HDL then brings cholesterol to the liver which disposes of it returns it to the blood via LDL (which evolved for the purpose of poisoning arteries with cholesterol, and giving HDL something to do). (Hat tip to Peter for this formulation of the lipid hypothesis.)

But there is an alternative hypothesis: that infections cause disease, and that HDL has an immune function. This hypothesis would explain why HDL protects against infections and against all diseases of aging.

Immune Functions of HDL

I got interested in immune functions of HDL upon reading an article in ScienceDaily last year (“How Disease-Causing Parasite Gets Around Human Innate Immunity,” Sept 13, 2010). The article states:

Several species of African trypanosomes infect non-primate mammals and cause important veterinary disease yet are unable to infect humans. The trypanosomes that cause human disease, Trypanosoma brucei gambiense and T. b. rhodensiense, have evolved mechanisms to avoid the native human defense molecules in the circulatory system that kill the parasites that cause animal disease….

Human innate immunity against most African trypanosomes is mediated by a subclass of HDL (high density lipoprotein, which people know from blood tests as “good cholesterol”) called trypanosome lytic factor-1, or TLF-1….

The parasite that causes fast-onset, acute sleeping sickness in humans, T. b. rhodensiense, is able to cause disease because it has evolved an inhibitor of TLF-1 called Serum Resistance Associated (SRA) protein…. T. b. gambiense resistance to TLF-1 is caused by a marked reduction of TLF-1 uptake by the parasite….

To survive in the bloodstream of humans, these parasites have apparently evolved mutations in the gene encoding a surface protein receptor. These mutations result in a receptor with decreased TLF-1 binding, leading to reduced uptake and thus allow the parasites to avoid the toxicity of TLF-1.

“Humans have evolved TLF-1 as a highly specific toxin against African trypanosomes by tricking the parasite into taking up this HDL because it resembles a nutrient the parasite needs for survival,” said Hajduk, “but T. b. gambiense has evolved a counter measure to these human ‘Trojan horses’ simply by barring the door and not allowing TLF-1 to enter the cell, effectively blocking human innate immunity and leading to infection and ultimately disease.”

So HDL is actually an immune particle carrying proteins that poison pathogens. The TLF-1 HDL subclass consists of those HDL particles carrying two anti-trypanosome proteins, apolipoprotein L-1 and haptoglobin-related protein. [5]

Any HDL particle can become an anti-trypanosome defender simply by acquiring and carrying these proteins.

It turns out that HDL can carry a great assortment of immune proteins. The orchestrator of HDL’s immune functions seems to be a circulating plasma protein called phospholipid transfer protein (PLTP), which forms complexes with immune molecules and then associates with apolipoprotein A-I (the primary HDL protein). PLTP brings 24 different immune molecules into HDL particles, including apolipoproteins such as clusterin (apoJ), coagulation factors, and complement factors. [6] These immune protein complexes add protein but not fat to HDL particles:

Unexpectedly, lipids accounted for only 3% of the mass of the PLTP complexes. Collectively, our observations indicate that PLTP in human plasma resides on lipid-poor complexes dominated by clusterin and proteins implicated in host defense and inflammation. [6]

It looks like HDL may not be primarily a carrier of cholesterol, but rather a carrier of antimicrobial proteins. Its cholesterol and lipids may serve, as the ScienceDaily article suggests, to make the HDL particle attractive to pathogens so that it may enter as a “Trojan Horse.”

HDL-associated immune proteins under strong selection

As pathogens evolve, immune proteins have to evolve. It turns out that apolipoprotein L-1, the immune protein that protects against trypanosomes, is under strong selection in both Africa and Europe.

The version selected in Europe does not protect against Trypanosoma brucei rhodesiense, cause of one of the African sleeping sickness diseases, but the version selected in Africa does. Unfortunately, the African version also increases risk of kidney disease – which may explain why African-Americans have higher rates of kidney disease than white Americans. [7]

So Africans have sacrificed kidney health for greater immunity against sleeping sickness. This suggests that African sleeping sickness may be a relatively recently evolved human disease.

HDL neutralizes toxins

HDL binds bacterial endotoxins, especially lipopolysaccharide (LPS), and neutralizes their toxicity. As a result, people with high HDL have substantially less release of tumor necrosis factor-alpha (TNF-α) during infection. [8]

TNF-α is an inflammatory molecule that stimulates the acute phase response to infections. Levels of C-reactive protein are a good index of TNF-α levels, so generally speaking high HDL will lead to low TNF-α and low CRP.

What’s the best HDL profile?

It should be desirable to have more HDL particles. Since each HDL particle is capable of poisoning a pathogen, the more you have, the stronger your immune defenses.

However, the weight of each HDL particle is likely to be an indicator of infection severity. An infection-free person will have few immune proteins to pick up; the HDL particles will be fat-rich and buoyant. But a person with extensive infections will have heavier HDL particles freighted with immune proteins.

Conventional tests in the doctor’s office measure the weight of HDL in mg per deciliter of blood. Since having more HDL particles (which raises the weight) is good, but having heavy HDL particles indicates infection which is bad, mass is not the best measure of HDL status. We would expect the number or concentration of HDL particles to provide a better indicator of health.

Indeed, this appears to be what is observed. The most important determinant of HDL status is the number of HDL particles:

The association between HDL size and CAD risk was abolished on adjustment for apolipoprotein B and triglyceride levels (adjusted odds ratio, 1.00 [95% CI, 0.71 to 1.39] for top vs. bottom quartile), whereas HDL particle concentration remained independently associated with CAD risk (adjusted odds ratio, 0.50 [CI, 0.37 to 0.66]). [9]

Conclusion

HDL particles are “Trojan Horses” that attack pathogens and neutralize their toxins.

If you want to remain free from infectious diseases – which is to say, all diseases – to a ripe old age, it’s important to make your HDL particles numerous.

On Thursday, I’ll discuss ways to do that.

References

[1] Gruber M et al. Prognostic impact of plasma lipids in patients with lower respiratory tract infections – an observational study. Swiss Med Wkly. 2009 Mar 21;139(11-12):166-72. http://pmid.us/19330560.

[2] Berbée JF et al. Plasma apolipoprotein CI protects against mortality from infection in old age. J Gerontol A Biol Sci Med Sci. 2008 Feb;63(2):122-6. http://pmid.us/18314445

[3] van Duijnhoven FJ et al. Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition. Gut. 2011 Mar 7. [Epub ahead of print] http://pmid.us/21383385.

[4] Rahilly-Tierney CR et al. Relation Between High-Density Lipoprotein Cholesterol and Survival to Age 85 Years in Men (from the VA Normative Aging Study). Am J Cardiol. 2011 Apr 15;107(8):1173-7. http://pmid.us/21296318.

[5] Kieft R et al. Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor. Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16137-16141. http://pmid.us/20805508.

[6] Cheung MC et al. Phospholipid transfer protein in human plasma associates with proteins linked to immunity and inflammation. Biochemistry. 2010 Aug 31;49(34):7314-22. http://pmid.us/20666409.

[7] Genovese G et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010 Aug 13;329(5993):841-5. http://pmid.us/20647424.

[8] Henning MF et al. Contribution of the C-terminal end of apolipoprotein AI to neutralization of lipopolysaccharide endotoxic effect. Innate Immun. 2010 May 25. [Epub ahead of print] http://pmid.us/20501516.

[9] El Harchaoui K et al. High-density lipoprotein particle size and concentration and coronary risk. Ann Intern Med. 2009 Jan 20;150(2):84-93. http://pmid.us/19153411.

Leave a comment ?

42 Comments.

  1. Interesting.

    Not sure about the association of kidney disease and african americans.

    I think it is important to remember that all these process clearly evolved for reasons other than killing us. Glucose levels and insulin is the same problem. We focus on a few components because in today’s world they are dangerous, but we are missing out on their larger picture in our systems.

  2. Awesome, I was not aware of this.

    Since I already have high HDL, I will pat myself on the back.

    • High HDL and high hs-crp inflammatory markers may indicate an infection. Elevated HDL and low hs-crp would be good news.

  3. Excellent article as always. I had been aware for a while that HDL has immunological and anti-inflammatory functions but certainly not this in-depth.

    Looking forward to Thursday’s article, then. Something tells me it won’t be called “Introduction To Low Fat Veganism”

    Cheers!

  4. Hi Stabby,

    Maybe it’ll be “30 Prunes a Day”!

  5. My great uncle died of trypanosomal sleeping sickness in the early 20th century. He did not have the protective HDL!

  6. Paul,

    This is also why I tend to view HDL >85 or 90 in the presence of other inflammatory or immunological markers as a potential sign of infection or immune dysregulation.

    I don’t have the reference handy, but I came across a study associating elevated HDL and CRP (occurring together) with INCREASED risk of heart disease.

    So tempting to say a molecule is “good” or “bad”. And often so wrong, as you’ve pointed out elsewhere.

  7. Hi Emily,

    It was a bad time to visit Africa!

    Hi Chris,

    Great point. We’ll upregulate immunity during infection. Doesn’t necessarily mean we’re well defended.

  8. I’ve been taking niacin (1.5g/day) for awhile. Recently you said that’s not a good idea because niacin is pathogen food.

    But niacin increases HDL.

    Sigh. Waiting for Thursday…

    (At my most recent assay, HDL-C 73; HDL-P 35.1 umol/L.)

  9. This is also the reason why it is not so smart for humans to live very long lives.

    It is necessary for our survival as species to die young so that the next generation can mutate genes/functions to fight the parasites that inevitably infect us.

    Parasites have the advantage of very short lives and will thus mutate faster causing new types of attacks.

    They have however, over the last century found out that killing the host is not necessary a good thing and have resorted to more parasite type activity : coexisting with and influencing the host.

  10. Hi Paul,

    Interesting stuff. Does HDL’s fluffy versus dense ratio provide any insights on LDL’s ratio, immunity-wise?

  11. Hi Poisonguy,

    I think I’ll do an LDL and immune function post next week. That may clear up some issues, and allow me to touch on the relation between LDL and HDL.

  12. Glad to see this Paul, I expressed some scepticism before that reducing cholesterol would be an unqualified good for immunity (http://paleohacks.com/questions/26610/low-cholesterol-good-for-the-immune-system#axzz1JHwBL97A). I’ll add a link to this post.

  13. Hi David,

    The relation between cholesterol and immunity is complex. It is a nutrient for pathogens as well as for immune cells.

    I would trust my body to regulate cholesterol optimally and cooperate with it. Taking statins in the hope it will enhance immunity is at best premature, at worst potentially disastrous – it’s most unlikely that interfering with our evolved immune defenses by a systemic intervention will improve immunity.

    Best, Paul

  14. Hi Paul,

    I am unclear what constitutes an “infection”?

    You have highlighted pathogens, (existing in different states and therefore tough to kill) as a likely cause of disease, but does this necessarily mean an infection is present in terms of what CRP can measure or can the, lets say bacteria, be present without infection markers?

    In other words if CRP is low does this imply the body is likely free of pathogens and likewise if HDL is high but CRP low does that imply low level of pathogens or simply just a low level of immune reaction? Thanks so much.

  15. Hi Perry,

    No, low CRP doesn’t mean you don’t have infections. It does signify a low level of inflammatory immune response (esp. low acute phase response). This usually means the infectious burden is low. But it can also mean that you have more “stealth” types of infections — present in isolated locations, like the brain, or infections with pathogens that successfully suppress the immune response, or infections that are hiding in vesicles or are dormant in some fashion.

    Different pathogens excite different immune pathways. I haven’t looked into which types of infections raise CRP. It’s an interesting question.

    Best, Paul

  16. Thanks Paul.

    Infection markers would actually make a great post or even series. Thank you

  17. Check the links… | Pure Spontaneity - pingback on April 13, 2011 at 2:47 pm
  18. Hi Paul,

    I love reading your articles on this site. I recall in your book talking about short chain fatty acids being released from the activity of gut bacteria and there many health benefits associated with it. Given HDL seems to have more immunological roles based on your sited sources, do you think the activity of gut bacteria can raise HDL levels? Perhaps it is a feedback response by the body to raise HDL when short chain fatty acids are being released from gut bacteria.

    Coconut oil seems to raise HDL quite well and is made up of short chain fatty acids. Perhaps when we ingest coconut oil we are mimicking gut bacteria activity and HDL goes up.

    Erik

  19. Hi Erik,

    Excellent point!

    You’re anticipating some of my upcoming discussion, so why don’t we continue the conversation when my “How to Raise HDL” post appears.

    Best, Paul

  20. Random Thoughts on Men’s Gymnastics - 04/24/11 | StickItMedia - pingback on April 24, 2011 at 11:49 am
  21. Paul,

    Thanks for explaining how HDL helps us. I have always heard that high HDL is a good thing but never had a good explination why.

    Thanks again.

    Kenny

  22. Not sure about the kidney disease issue and how this relates to African Americans vs. European Americans. I think the study referenced was simply an observational study and not a clinical study. Big difference!

  23. Managing Cholesterol | Soil to Sustenance - pingback on March 26, 2012 at 1:41 pm
  24. Hello Paul,
    Just came across this article, can your throw some light on this please, Thanks

    http://www.independent.co.uk/life-style/health-and-families/health-news/egg-yolks-linked-to-heart-disease-8007762.html

    • Hi Manoj,

      Dumb, dumb study which tells us nothing of the healthfulness of egg yolks. It was too poor a study to deserve commentary, but Chris Masterjohn wrote about it if you want to look further.

  25. Michal Piják, MD

    I´d like to note that although high high-density lipoprotein (HDL)-cholesterol levels are associated with decreased cardiovascular risk in epidemiological studies, recent genetic and pharmacological findings have raised doubts about the beneficial effects of HDL. In fact, it has been shown that the cardioprotective effects of are compromised in the presence of elevated high-sensitivity C-reactive protein (hsCRP), report researchers.

    Furthermore , HDL from animal models of atherosclerosis or from humans with atherosclerosis or from humans or animals with other chronic inflammatory diseases does not prevent the inflammatory reaction characteristic of atherosclerosis and may even enhance the inflammatory reaction.

    It is assumed that tystemic inflammation and other factors, such as myeloperoxidase-mediated oxidation, can impair HDL production and HDL function, with regard to its reverse cholesterol transport, antioxidant, and anti-inflammatory activities. HDL particles can be modified in a way that increases recruitment and activation of macrophages and promotes the oxidation of LDL.

    Furthermore, studies with apolipoprotein A-I mimetic peptides suggest that the SMALL INTESTINE is a major tissue regulating systemic inflammation in mouse models of atherosclerosis and may be important for determining the functionality of HDL. In fact, in mice and perhaps humans, ?30% of the steady-state plasma HDL-cholesterol pool is derived from the small intestine. The metabolism of phospholipids by gut bacteria has been recently implicated in atherosclerosis in both mice and humans.

    Thus, the CRP level might reflect underlying inflammation that contributes to dysfunctional HDL by mechanisms other than CRP or by mechanisms that also increase CRP. It has been suggested that tests of HDL function, which have not yet been developed as routine diagnostic assays, may prove useful and be a better predictor of cardiovascular risk than HDL-cholesterol levels.

    • Hi Michal,

      Great observations and I would agree that tests of specific HDL composition and function would be much better diagnostic markers than HDL cholesterol. HDL particles can carry a diverse mix of proteins and the distribution will reflect the immune/inflammatory state of the body, so that would certainly have diagnostic value.

      For the moment I’m inclined to think that in epidemiological studies the people who have high HDL are the people eating diets that raise HDL, and so their good outcomes are the result of the healthfulness of their diets. I think this is supportive of the healthfulness of dietary shifts that raise HDL, but not of pharmaceutical interventions that raise HDL. So the pharmacological findings don’t move me.

      Genetic selection is also an issue. If two alleles coexist in a population, we would expect their difference in healthfulness to be minimal — each allele may provide certain benefits and harms, but overall their impact should be similar. So the genetic variations that have risen to high levels in the population may vary HDL levels, but shouldn’t affect health, because they will impact something else in a way that compensates for the impact of the HDL change.

      Best, Paul

    • Paul,

      ‘Pharmacological findings don’t move me.’ Well said! I entirely concur!

      Michal,

      There currently are ways to test the functionality of HDL. The surrogate marker IMHO is the HDL2b fraction in the context of buoyancy of lipoprotein particles (Pattern A v. Pattern B) on a VAP or NMR laboratory test.

      Chronic infection, heavy metals, low hormones (T, thyroid, Progesterone, etc), and cellular inflammation correspond well and reliably with Pattern B and low levels of HDL2b. Why? Lipoproteins not only are the ancient transporters of nutrients to the peripheral immune cells (MK4 to MK9/VitK2, cholesterol, vitamin A/retinol, tocopherols, etc) but also play a role in cell signalling.

      HDL has also been shown to prevent pro-adhesive oxidized LDL from harming the endothelium.
      http://m.cardiovascres.oxfordjournals.org/content/43/2/308.full.pdf

      The best way that I’ve seen improvements in HDL functionality are: improvement of hormone profiles, removal heavy metal toxicity, lower carb/higher saturated fat intakes, antioxidant consumption (EPA/DHA (mercury free fish oil), astaxanthin, pycnogenol, vitamin D, etc).

      G

  26. (The human trials back up the important role of HDL for improvements in all-cause and CAD mortality: ERA, GISSI, Lyon Heart, FATS1, FATS2, CDP, HATS)

  27. Paul,
    On my recent health assessment, my LDL level was excellent but my HDL level was 44 which was indicated as an increased risk factor for a female age 48. I have been less physically active due to a serious knee infection being treated with surgery and follow-up antibiotics. At the time of the test, I was infusing the antibiotic vancomycin and taking levofloxacin orally. Would the antibiotics have altered my HDL level?

  28. Raising HDL levels - pingback on July 15, 2013 at 9:25 pm
  29. Hi Paul, Greetings from Hong Kong. Just wanted your comments on my lipid profile. My November 2012 lipids were TC 268, HDL 87, LDL Direct 147, VLDL 34, TRI 135. I got another test done a few days ago and it was TC 205, HDL 104, LDL Direct 89 VLDL 13 and TRI 64. My diet has changed between tests in the sense that I have cut out more sugars, vegetarian twice a week (religious reasons) stopped eating beef (religious reasons also). On my vegetarian days I eat slightly higher carb and my intake of vegetable oils and soy products has obviously increased on those vegetarian days. On other days I am low carb and try to do high fat/moderate protein but it is less so now due to the elimination of beef from my diet. My questions are should I be concerned about my high HDL and low LDL? And if my LDL is too low, how do I raise it? I understand from your site LDL should be around 130 (lower mortality). I also haven’t done anything specific to raise my HDL apart from my diet. I am male, 44 years old and do not take any supplements or medication at all. No Chronic illnesses. Thank you.

    • Hi Arun,

      I think these are OK. LDL and triglycerides were high before, now LDL is a bit low but not really concerning and triglycerides are good. HDL of 104 is unusually high but it is not known to be harmful.

      So I would just continue improving diet. Dropping the sugars did you good.

      Best, Paul

      • Thank you Paul for your prompt response. The LDL drop was obviously because I am now a vegetarian twice a week and also I do not eat beef products anymore. I am going to try and bring LDL up to about 120-130. Please let me know if you have any suggestions. Cheers.

  30. De waarheid over cholesterol (7) - Project Gezonder - pingback on July 27, 2014 at 4:40 am
  31. De waarheid over cholesterol (7) - Paleo.be - pingback on February 21, 2015 at 10:05 am

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