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Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping, 2021, Castro-Marrero et al

Discussion in 'ME/CFS research' started by Sly Saint, Sep 16, 2021.

  1. Sly Saint

    Sly Saint Senior Member (Voting Rights)

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    Abstract
    Background: Routine blood analytics are systematically used in the clinic to diagnose disease or confirm individuals’ healthy status. For myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disease relying exclusively on clinical symptoms for its diagnosis, blood analytics only serve to rule out underlying conditions leading to exerting fatigue. However, studies evaluating complete and large blood datasets by combinatorial approaches to evidence ME/CFS condition or detect/identify case subgroups are still scarce.

    Methods: This study used unbiased hierarchical cluster analysis of a large cohort of 250 carefully phenotyped female ME/CFS cases toward exploring this possibility.

    Results: The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms.

    Conclusions: The results obtained have important implications for the research of ME/CFS etiology and, most likely, for the implementation of future diagnosis methods and treatments of ME/CFS in the clinic.

    https://www.mdpi.com/2077-0383/10/18/4171
     
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  2. Hutan

    Hutan Moderator Staff Member

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    It's good that the article is open access, and that it's possible to read the feedback of reviewers. The study was partly funded by a patient group, although I bear in mind the previous studies by Castro-Marrero that were funded by a supplement manufacturer.

    The study was of a good size (250 people), all females.

    The paper is a bit frustrating in that the charts shown in the paper relate to efforts at subgrouping the sample and really don't tell us much, whereas the scatter plots are hidden away in a supplementary file. It's disappointing to see peer reviewers simply say 'Well done!' or focus on the fact that numbers under nine should be spelled out as text rather than given as a number, when the paper could have been improved a lot by better choice of figures.

    Vitamin D
    A high percentage of the patients were low in vitamin D. While it is likely that that is a result of a lot of time being spent indoors rather than being a cause of ME/CFS or shedding light on the pathology of the illness, it does suggest that people with ME/CFS may need to try to spend more time in the sun, or take supplements.

    While Vitamin D deficiency is very common in populations, references I found suggest levels should be over 40 ng/ml. That suggests this sample of people (living in Spain, a sunny country) really are quite deficient. Given the symptoms of Vitamin D deficiency do overlap substantially with the symptoms of ME/CFS, it would be good to see some more attention being paid to this. I'd like to see a well-conducted supplementation trial, and guidelines should note that people with ME/CFS are at risk of vitamin D deficiency.

    Screen Shot 2021-09-17 at 6.24.28 AM.png
     
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  3. Hutan

    Hutan Moderator Staff Member

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    Complement factor C1Q
    The main finding of interest though was the high levels of C1q.

    Screen Shot 2021-09-17 at 6.45.41 AM.png
     
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  4. Midnattsol

    Midnattsol Moderator Staff Member

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    Sorry but "need to try to spend more time in the sun" :laugh: I'm surprised at these numbers from Spain, but even in sunny parts of the world vitamin D deficiency is not uncommon due to clothing, sunscreen use and what time of day people are typically outdoors. Not least what time of year the samples were collected.

    Many of those patients look to be deficient, although reference ranges for vitamin D vary a lot by country (I assume the red lines are the range used in Spain). If one only cares about skeletal health, the reference range for sufficiency is >7.5 ng/ml (25 nmol/L), but most countries use >20 ng/ml (50 nmol/L) "to be on the safe side" while taking into account that vitamin D might have extraskeletal effects. 35-40 ng/ml (>75 nmol/L) are advocated by some specifically due to extraskeletal effects and I think @Mij mentioned it had been implemented in Canada. I think it has been also in other countries. In Norway it is seen as a bit fringe to advocate for people to have such high levels of vitamin D (our threshold for sufficiency is >16-20 ng/ml depending on what lab is used).

    I do with people would have their vitamin/mineral status checked (this will include a diet interview as there isn't a blood test for many nutrients), so deficiencies could be discovered and treated. Having those on top of ME feels so unnecessary :(
     
    Last edited: Sep 16, 2021
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  5. Hutan

    Hutan Moderator Staff Member

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    So C1Q -
    thanks to wikipedia, this is my understanding, which may be wrong and will certainly be incomplete, so do correct me:

    1. CIQ binds to molecules that suggest the immune system needs to do something
    C1Q can bind directly to bacterial and viral surface proteins, dying cells, and acute-phase proteins*. C1Q can also bind to [antibody (an IgM or IgG) + antigen] complexes.

    * Acute-phase proteins - proteins associated with inflammation which include CRP, and the mannose-binding lectin that another recent study looked at in ME/CFS).


    2. The binding sets a cascade of reactions off
    The binding activates the C1 complex which activates the 'classical complement pathway'.

    Classical complement pathway: That's a series of reactions that produces molecules that
    1. attract phagocytes;
    2. tags cells for phagocytosis;
    3. forms the Membrane Attack Complex that damages a cell membrane to kill the cell

    3. So, C1Q is a useful thing
    A lack of C1Q is therefore not a good thing, as the immune system won't work so well. A deficiency of C1Q apparently leads to lupus, where, Wikipedia says, there is an accumulation of autoantibodies and dying cells that aren't being cleaned up.

    4. But too much won't be good either
    Some of the molecules produced along in the cascade of reactions are called anaphylatoxins (fragments of C3,C4,C5 - namely C3a, C4a, C5a)
    A deficiency of C1-inhibitor can cause angioedema. C1-inhibitor defiency can be hereditary or acquired.

    So, it looks as though a substantial proportion of the women in this study had high levels of C1Q. I guess one question is, are the levels high enough to be contributing to their ME/CFS symptoms? Another one is 'why are the levels elevated?'
     
    Last edited: Sep 17, 2021
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  6. Hutan

    Hutan Moderator Staff Member

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    Is the level of elevation of the C1Q significant?

    The unit of measure in this study is miligrams/dL. (1 mg/dL =10 ug/ml)

    This study suggested the normal range is 10 to 25 mg/dL.
    Mayo clinic's normal range is 12 -22 mg/dL. Using that range, most of this study population have high C1Q.
    Medscape suggests the normal level is 7 mg/dL, and the acute phase serum level is 13% higher.
    Clearly, there's variation in the ranges, maybe depending on the test method.

    It doesn't seem like the C1Q level in serum needs to be massively higher to suggest something is going on. C1Q levels can be much higher at the site where the action is taking place.

    (The Medscape article also talks about the lectin/ mannose-binding pathway, as an alternative to the classic pathway that involves C1Q. In that pathway, the acute phase serum level of MBL is 1000% of that of the normal level. So, you'd probably be wanting to see much higher levels in ME/CFS compared to controls in order to be convinced that higher levels of MBL are important.)
     
  7. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    The key question would be why a difference inC1q has not been picked up before. It is not measured routinely in the UK but probably would be in the US. I have not looked through the whole paper but I don't know if it gives a trawl of previous studies of C1q. Sorensen and colleagues did detailed studies on complement in CFS about ten years ago. The ME Biobank would have another cohort to study and may already have looked at C1q. Several groups looked for lupus-associated antibodies and are likely to have looked for C1q.
     
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  8. Hutan

    Hutan Moderator Staff Member

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    I've made a thread for a Sorensen paper from 2003 here:
    Complement activation in a model of chronic fatigue syndrome, 2003, Sorensen et al

    It's an interesting paper with an exercise challenge. It looks as though they tested C1Q and did not find a significant difference - but I couldn't find any data reported for the C1Q comparison. The Medscape article suggested that the difference between normal and activated levels serum may not be big, and some of the articles I read suggested that levels change with age. So, perhaps the smallish sample size of the Sorensen study made it hard to get a significant difference given background noise.
     
  9. Midnattsol

    Midnattsol Moderator Staff Member

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    I don't think it is used routinely in Norway, although mine was checked before I was eventually diagnosed with ME (I apparently presented with lupus-like symptoms).

    The Wikipedia article (sans the lupus part, which I found a bit oversimplified) is in line with what we learned about the complement system in immunology @Hutan. A bit off topic, but recently some Norwegian researchers proved that a "truth" about the complement system and coagulation is in fact not true, and they discussed how it came to be a truth in the first place (bad data) https://www.jimmunol.org/content/207/6/1641 so I wonder if there are other things we don't know about these proteins.

    Vitamin D can regulate the immune system, so vitamin D status may be important to see certain differences? This is where the threshold for >75 nmol/L may be important. Since endothelium permeability was mentioned, vitamin D may play a role in that too. Vitamin D has been found to regulate epithelium permeability in response to various pathogens, but only when above a certain threshold (in cell culture and animal models, I've also seen it in human studies but they are often of poor quality. Such as the one that gave supplements, said "vitamin D levels and epithelium integrity improved" but did not provide any measurements on vitamin D serum levels pre/post supplementation...). I'm not 100% sure but I think some of the proteins between epithelium cells that can be regulated by vitamin D is also found between endothelium cells.
     
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  10. Grigor

    Grigor Senior Member (Voting Rights)

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  11. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I cannot work out what Prusty's slide is supposed to indicate.It doesn't seem to have anything to do with high C1q levels.

    C1q contributes to formation of C1 complex, not the other way round.
     
  12. Hutan

    Hutan Moderator Staff Member

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    It's not clear to me what that slide is suggesting. That exercise and anti-C1q antibodies reduce levels of functioning C1q? So C1q can't do it's job helping to defeat pathogens and clear the rubbish up?
    But, I don't think we have any evidence of high levels of Anti-C1Q antibodies in ME/CFS (unlike the situation with Lupus). I mean, if we had high levels of Anti-C1q antibodies, wouldn't we have been diagnosed with Lupus?
     
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  13. Hutan

    Hutan Moderator Staff Member

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    Responding to a deleted post

    Thank you, that's really interesting. My son and I get generalised swelling when in PEM - I don't wear rings, and lately now don't wear my watch either for that reason. There is facial swelling too, around the eyes. My son has had a couple of episodes of very obvious facial swelling when exhausted. And I know some other members here have problems with oedema too.

    So, you have normal levels of the C1 inhibitor but it isn't functioning well? How is that tested for? Does it mean that you have high levels of C1Q? From what I read, problems with C1 inhibitor don't seem to automatically mean high levels of C1Q, and in fact levels of C1Q can be low in people with angioedema.

    It's certainly complicated.
     
    Last edited by a moderator: Nov 20, 2023
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  14. Hutan

    Hutan Moderator Staff Member

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    Responding to a deleted post

    Doctors don't seem to be interested. My record of lab tests doesn't have any complement-related tests, but I've been slack about copying results into it these last couple of years. I don't recall any complement-related tests.
     
    Last edited by a moderator: Nov 20, 2023
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  15. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Given the absence of other excessive inflammation markers in circulation in most patients, I wonder about the other functions C1Q has (non classical complement cascade), and why it might be of high abundance in the first place...

    Emerging and novel functions of complement protein C1q
    https://www.frontiersin.org/articles/10.3389/fimmu.2015.00317/full

    C1q: A fresh look upon an old molecule
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582005/

    C1q as an autocrine and paracrine regulator of cellular functions
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366276/

    Endothelial cells in particular can secrete significant amounts of C1q in certain circumstances.
     
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  16. Samuel

    Samuel Senior Member (Voting Rights)

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    i haven't been able to determine if angioedema is associated with m.e. i have been assuming it isn't really, but really want to know.

    https://www.researchgate.net/figure/Algorithm-of-HAE-diagnosis_fig3_324737619

    this algorithm alone is enough to confuse me. but that's me.

    it is not clear to me if "ae with normal c1-inh" is a broad category or a distinct entity. i will assume broad category. but why does the flowchart stop there?

    i do not understand what 95% refers to.

    in my case, if you take my c4 as low [is low-normal], then i pass through to the quantitative, which is normal, then thus to function, which i was told was normal. there is no entity attached to that. the flowchart stops there. my case is a non-entity yet again.

    i have technical issues tring to get access to the paper. might have brain issues reading it. perhaps it clarifies.


    i have not had c1q tested. i did try 4-6x normal amounts of cetirizine for many months, with no apparent effect on angioedema. that is an uptodate protocol. thus, it is non-histaminergic. if it is histaminergic, you pay for cetirizine. if it is not, you pay 400,000+ usd per year.

    i do have a note that some of these tests, including c1q, might not be reliable.

    > C1-INH functional assays were available to 93% of
    responding CHAEN physicians. However, confidence in this
    assay was relatively low; 41% said they did not trust the
    results, citing concerns about the handling and storage of
    samples, as well as the sensitivity and specificity (the
    chance of getting a false positive or negative,
    respectively) of different assays. ---
    https://angioedemanews.com/2019/01/10/canadian-dcotors-need-more-info-hereditary-angioedema-tests/
     
    Last edited by a moderator: Nov 20, 2023
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  17. Wyva

    Wyva Senior Member (Voting Rights)

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    Yes, I'm one of those too, I have generalized swelling that fluctuates perfectly in sync with my other ME/CFS symptoms and which I never had before my viral onset. I understand this is not a common symptom but to me it is a big part of it (mine can be quite excessive and causes a lot of physical discomfort when it gets really bad).

    I haven't had any of these tests but a couple of different doctors checked it (internalist, endocrinologist, also ultrasound etc) and the conclusion was that it just doesn't exist. Even though it is one my very few actually visible symptoms (the other being swollen lymph nodes) and I even took photos to show them how strikingly different my body can look on two consecutive days (my face is also affected too and yes, it is very noticeable around the eyes for me too). However, all I got was "you've gained weight you just didn't notice it", "it is fat", "you must be pregnant", then after the pictures: "OK, if it changes so quickly, then it is gas". :banghead::banghead::banghead:
    So it's quite nuts, taking those pictures wasn't really worth it at all.

    So so far it is unexplained the exact same way.
     
    Last edited by a moderator: Nov 20, 2023
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  18. Wyva

    Wyva Senior Member (Voting Rights)

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    Sorry for being probably too off-topic, but for whoever is interested: I started to dig around a bit and found some information:

    How Not to Be Misled by Disorders Mimicking Angioedema: A Review of Pseudoangioedema

    https://www.researchgate.net/public...cking_Angioedema_A_Review_of_Pseudoangioedema

    There are a lot of different edemas listed here with a short description and pictures of patients' faces. I'm not sure about other pwME's experiences but this one seems to be the most similar to mine, except it is not self-limiting, not only menstruation but ME/CFS affects it (most frequently the latter and I did not have it before ME/CFS, not even during my period) and diuretics don't seem to do too much.

    Also, here is the picture from the same article. There is a lot of puffiness in general, especially in the upper eye area but the nose is bigger too, it is thicker in general. The edema is everywhere and you kind of end up looking overweight even if you are not, because the whole face is just bigger. This is exactly the same for me in the morning (after recumbent position at night) as in this photo. Then later it accumulates mostly on my abdomen and legs. Severity depends on ME/CFS fluctuations.



    I've also found a paper from 2004 about the risk factors for idiopathic edema:

    Unexplained swelling symptoms in women (idiopathic oedema) comprise one component of a common polysymptomatic syndrome

    https://academic.oup.com/qjmed/article/97/11/755/1597531

    In the discussion section it mentions CFS, fibromyalgia, IBS etc:

    (But the list of symptoms they used is not particularly great: it is a mix of very general symptoms + obvious PMS symptoms + anxiety, panic attacks etc while more distinctive ME/CFS symptoms are missing.)
     
    Last edited: Sep 19, 2021
  19. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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    Looks like a useful paper with data from 250 women that meet Fukuda and Canadian criteria. The full dataset has been made available in the supplementary material. Patients must have been really ill with a mean score for SF-36 physical functioning of 26.9.
     
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  20. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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    Don't understand the figures for medication use in table 1. How come the numbers (n) are so low but the percentages between brackets are so high?

    upload_2021-9-19_14-39-29.png
     

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