Passive transfer of fibromyalgia symptoms from patients to mice, 2021, Goebel et al

[Milo]

Low dose naltrexone for FM patients makes about 10-15% who try it feel better. I would also point out that trying a supplement or LDN can invoke a placebo response that would fade after a period of time (not sure how long, maybe six weeks).

I worry that LDN has been hyped and promoted as a treatment for both ME and FM and "believed" as being helpful by doctors who frequently prescribe it. I worry that the subjective outcome measures are weak and there are few randomized, placebo controlled trials are scarce. To this day LDN is not FDA approved for ME or FM, therefore not reimbursable by the insurance companies.

I have never come across a case of fibromyalgia, either in practice or presented as a case, with symptoms of neuropathy

With due respect, did you look for it? Did you make the connection back then, that potentially there could be one?

And I'll be honest here, I would not discuss any symptoms of neuropathy with my doctor. Back then I had enough problems being believed with simply chest pain and shortness of breath, and even a bad case of cholecystits that I knew that adding other symptoms would not go well. My feet have been tingling non stop since very early years . I am not saying this is neuropathy, not been dx with SFN but then my doctor still doesn't know about that.

Honestly doctors have not paid attention or they have made up their mind long time ago.

 

[Mister Person]

7 in

Here's the small (n=25) Danish study which I guess is the one you referred to. A dosage study. Non-blinded.

They noted that in this study of up/down dosages, pain was not diminished for many subjects and that improved sleep and less fatigue were more prominent.

https://academic.oup.com/painmedicine/article/21/10/2253/5740044?login=false#209688203

Shak, you mistake me. I mean these 2 studies. Total enrolment combined will be 220. That'll be pretty big!!! One is done enrolling the other seems yet to finish enrol. Confusing though one is Phase 2 one is Phase 4!
https://clinicaltrials.gov/ct2/show/NCT04270877
https://clinicaltrials.gov/ct2/show/NCT04739995

https://clinicaltrials.gov/ct2/show...se+naltrexone&cond=Fibromyalgia&draw=2&rank=3
This was youngers study. I haven't parsed through the information but it looks like this is where we can find raw data. In his review of LDN as a novel... Smtng can't remember name he said he had data from an unpublished study. So there's another one out there by younger but I don't think we have the results

 

[Jonathan Edwards]

They're not similar? Okay I was under the impression they were, because if say 50% of fibromyalgia patients have SFN, why were they diagnosed with fibromyalgia? That was my logic.

I don't know what has happened in the last five years or so but my understanding was that the claim of finding SFN in 'fibromyalgia' cases was contentious and not widely accepted by rheumatologists at least. The huge problem with fibromyalgia is that some physicians will diagnose 100 cases where others will diagnose 1 or not use the term.

For most physicians fibromyalgia is pretty much defined as widespread pain that is not explained on history or examination or reliable tests to be due to ay specific pathology. Neuropathy produces particular patterns of symptoms and signs. They are not present inpatients diagnosed with fibromyalgia.

Which of course raises the question what do these 'SFN' findings mean if anything? Presumably there is no change on standard neuropathy electrophysiology studies - otherwise it would have been detected decades ago by routine electrophysiology exams. If so I am not sure that we know what we should expect the symptoms of this so called SFN to be, if it is present, so it would be circular to say that 'symptoms of fibromyalgia are similar to those of SFN'. Certainly the clinical picture of fibromyalgia is not one of neuropathy of any recognised sort.

All this stuff has been generally regarded as fringe and quite likely pseudoscience by rheumatologists I know. My colleague Maria Leandro, who is assiduous about keeping informed about background clinical science came to dinner last night and she had not heard of any of this stuff from Goebel.

It seems like such a convenient explanation doesn't it.

This is a significant part of what makes me sceptical. The explanation is exactly what someone without deep knowledge of immunology would come up with because it superficially sounds good. People have been making claims about transferring disease with antibodies for about seventy years. Most people have given up trying because it has never proven a useful research tool. Disease can be transferred with antibody, yes, but the conditions are limited, as in neonatal myasthenia or heart block. Goebel's experiments sound like what we used to hear about in the 1970s.

Re 'If anybody is taking it seriously', why would hundreds of fibromyalgia patients have recieved rituximab?

Because tens of thousands of people have been given rituximab for various other conditions - lymphoma, RA etc. According to the fibromyalgia enthusiasts about 10% of these (thousands) will by chance have also had FM.

if nobody is taking it seriously, that doesn't necessarily mean the wisdom of the masses is right, right?

Sure, but if it is a story we got bored of hearing fifty years ago because it never panned out then scepticism seems wise.

My final question would be, what is your take on non inflammatory auto antibodies in general?

Most autoantibodies are non-inflammatory. Nothing remotely new or contentious about that. Anti-thyroid antibodies are not primarily inflammatory, nor anti-platelet, nor anti-phospholipid, nor anti-intrinsic factor, nor... Even antibodies in lupus producing membranous nephropathy are not strictly inflammatory.

What is fringe is the implication of anti-neuronal antibodies in a whole host of conditions that have proved hard to explain when in fact that antibody levels are barely different from normal if they really are at all. The anti-receptor antibody levels (adrenergic and cholinergic) inME are essentially normal. The findings should be seen as negative.

'in regards to B-cell ablation approaches - no efficacy signal on
concomitant FMS has been reported, to our knowledge from trials con-
ducted in RA or Lupus

So at least the authors have thought about this. I actually think trying to assess FM independently in RA or Lupus would be impossible. Pain improves - I have seen patients putting their marks on the visual analogue scales for major improvement. But how does one know if that is RA or FM? I think any useful observations would have to come from lymphoma patients with FM.

 

[Jonathan Edwards]

With due respect, did you look for it? Did you make the connection back then, that potentially there could be one?

Yes, all new patients had a full locomotor history and examination and neither I nor anyone else seems to have identified clinical features of neuropathy as far as I know. Everyone gets a degree of tingling in hands and feet and some people have it all the time (I do these days) but that in itself is not a useful indication of neuropathy and anyway seems separate from what is called FM - persistent generalised pain.

 

[Jonathan Edwards]

I worry that LDN has been hyped and promoted as a treatment for both ME and FM and "believed" as being helpful by doctors who frequently prescribe it. I worry that the subjective outcome measures are weak and there are few randomized, placebo controlled trials are scarce. To this day LDN is not FDA approved for ME or FM, therefore not reimbursable by the insurance companies.

There is a current discussion in the UK government working party on research for ME on doing trials on LDN to settle this issue. I think it makes sense to do a good quality trial but I would be interested in the range opinion on S4ME. I will set up a thread.

 

[Jonathan Edwards]

Just wondering...those shooting nerve-like zaps (as well as lesser tingling), that I experienced a lot of in the first five years of FM or chronic widespread pain, how would you term those?

Shooting nerve-zaps seem to me to be a fairly common and hard to interpret symptom. Sometimes they can be put down to trapped soft tissues in joints or under ligaments. Muscle cramps may do it. Nerve root compression will give shooting pain but it tends to last a lot longer than a zap and there is a describable place of apparent origin. An S1 root nerve pain is clearly coming from the outer side and the sole of the foot for instance. But over the years I have had nerve-like zaps that seem to just be a bunch of nerve fibres having a sneeze for no obvious reason. That is very common in the ear, when you get a sudden ping noise that fades over a few seconds. I suspect nerves do that elsewhere. It may indicate some generalised irritability of the nerve tissue at the time but it doesn't seem to necessarily have anything to do with neuropathy.

There is an awful lot we don't know about the generation of pain, so I guess my main answer would be that. Some neuropathies may include shooting pains. I have not been a neurologist for 43 years and I forget details. But in terms of standard diagnostic practice zaps are probably not terribly interpretable.

 

[Mister Person]

I don't know what has happened in the last five years or so but my understanding was that the claim of finding SFN in 'fibromyalgia' cases was contentious and not widely accepted by rheumatologists at least. The huge problem with fibromyalgia is that some physicians will diagnose 100 cases where others will diagnose 1 or not use the term.

For most physicians fibromyalgia is pretty much defined as widespread pain that is not explained on history or examination or reliable tests to be due to ay specific pathology. Neuropathy produces particular patterns of symptoms and signs. They are not present inpatients diagnosed with fibromyalgia.

Which of course raises the question what do these 'SFN' findings mean if anything? Presumably there is no change on standard neuropathy electrophysiology studies - otherwise it would have been detected decades ago by routine electrophysiology exams. If so I am not sure that we know what we should expect the symptoms of this so called SFN to be, if it is present, so it would be circular to say that 'symptoms of fibromyalgia are similar to those of SFN'. Certainly the clinical picture of fibromyalgia is not one of neuropathy of any recognised sort.

All this stuff has been generally regarded as fringe and quite likely pseudoscience by rheumatologists I know. My colleague Maria Leandro, who is assiduous about keeping informed about background clinical science came to dinner last night and she had not heard of any of this stuff from Goebel.



This is a significant part of what makes me sceptical. The explanation is exactly what someone without deep knowledge of immunology would come up with because it superficially sounds good. People have been making claims about transferring disease with antibodies for about seventy years. Most people have given up trying because it has never proven a useful research tool. Disease can be transferred with antibody, yes, but the conditions are limited, as in neonatal myasthenia or heart block. Goebel's experiments sound like what we used to hear about in the 1970s.



Because tens of thousands of people have been given rituximab for various other conditions - lymphoma, RA etc. According to the fibromyalgia enthusiasts about 10% of these (thousands) will by chance have also had FM.



Sure, but if it is a story we got bored of hearing fifty years ago because it never panned out then scepticism seems wise.



Most autoantibodies are non-inflammatory. Nothing remotely new or contentious about that. Anti-thyroid antibodies are not primarily inflammatory, nor anti-platelet, nor anti-phospholipid, nor anti-intrinsic factor, nor... Even antibodies in lupus producing membranous nephropathy are not strictly inflammatory.

What is fringe is the implication of anti-neuronal antibodies in a whole host of conditions that have proved hard to explain when in fact that antibody levels are barely different from normal if they really are at all. The anti-receptor antibody levels (adrenergic and cholinergic) inME are essentially normal. The findings should be seen as negative.



So at least the authors have thought about this. I actually think trying to assess FM independently in RA or Lupus would be impossible. Pain improves - I have seen patients putting their marks on the visual analogue scales for major improvement. But how does one know if that is RA or FM? I think any useful observations would have to come from lymphoma patients with FM.

Very in depth explanation thank you. One more thing:what would the motivation for hype be? Why would somebody draw attention to themselves unless they think they've really found something? After all, more attention leads to more scrutiny? The hallmarks of hype, unless there was monetary gain, I can't think of a motive. Unless he's going to be like Haruko Obokata

1 more I forgot. If Goebel is right, he found that the IgG accumulated in mice DRG, can't it be confirmed by simply going through human autopsies of fibromyalgia patients??

 

[Mister Person]

https://doi.org/10.1007/s00296-012-2538-6
https://doi.org/10.1177/0004563213506413
doi:10.1093/rheumatology/40.7.743
PMID: 17543146
https://doi.org/10.1093/rheumatology/keab146
https://doi.org/10.1177/1099800409348328

Interesting to note that Goebel paper says no systemic change in cytokines. Whereas here we have about 4 papers saying there are from quite some time ago. Any implications I wonder. Jared Younger LDN study notes this, and an association with genderal inflammation markers. How could this be reconciled? If they aren't inflammatory.
Then there's this paper 10.1097/j.pain.0000000000002498 suggesting NK cells attack the nerves, suggesting it might be Goebel antibodies playing a role. Are these findings contradictory or? Goebel paper says the Glial cells might be the target and glial cells produce pro inflammation stuff, so how could his paper also have found no systemic changes? Only locally.

And finally stuff I don't understand at all.
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03662-7
COMT pain?
https://www.sciencedirect.com/science/article/abs/pii/S1567724915000215
Oxidative stress?

Is it okay to assume, if it's not autoimmune, that immune processes are involved

Also fellow laypeople, the earlier sgc paper was too complex to understand. I found this one simpler explaining, but not exactly the same topic. https://journals.physiology.org/doi/full/10.1152/physrev.00011.2002

 

[Jonathan Edwards]

One more thing:what would the motivation for hype be?

Acclaim, basically.
Every scientist wants to be seen as a groundbreaker.
The pressure to produce high impact work is also great. You don't get your contract renewed if you don't produce hot papers.

 

[Jonathan Edwards]

Is it okay to assume, if it's not autoimmune, that immune processes are involved

I don't think we can assume anything because at present we have no reliable evidence of any particular mechanism.

You need to be aware that a high proportion of research papers in this sort of area are just garbage. Sad to have to say that because it was not always the case, but it is the reality now.

 

[Mister Person]

Acclaim, basically.
Every scientist wants to be seen as a groundbreaker.
The pressure to produce high impact work is also great. You don't get your contract renewed if you don't produce hot papers.

Don't you get fired if your hot papers are garbage though, unless nobody is ever bothered to replicate your work. Also I note you haven't read the autoimmunity reviews paper have you, cause I said he showed that 4 conditions had these autoantibodies, I was wrong. It wasn't actually he himself. I thought it was him because health rising said he did.

Also, why would lymphoma patients have fibromyalgia? Is there a high comorbidity because I can't seem to find information on it

Also found what I think to be another erm... Impactless paper doi: 10.3390/jcm9061814 Gene Expression Profiling in Fibromyalgia Indicates an Autoimmune Origin of the Disease and Opens New Avenues for Targeted Therapy. Published in 2020.

[21] Tekus V, Hajna Z, Borbely E, Markovics A, Bagoly T, Szolcsanyi J, et al. A CRPS-
IgG-transfer-trauma model reproducing inflammatory and positive sensory signs
associated with complex regional pain syndrome. Pain 2014;155:299–308.
[22] Li WW, Guo TZ, Shi X, Czirr E, Stan T, Sahbaie P, et al. Autoimmunity contributes
to nociceptive sensitization in a mouse model of complex regional pain syndrome.
Pain 2014;155:2377–89.
[23] Wigerblad G, Bas DB, Fernades-Cerqueira C, Krishnamurthy A, Nandakumar KS,
Rogoz K, et al. Autoantibodies to citrullinated proteins induce joint pain
independent of inflammation via a chemokine-dependent mechanism. Ann Rheum
Dis 2016;75:730–8.
[24] Dawes JM, Weir GA, Middleton SJ, Patel R, Chisholm KI, Pettingill P, et al. Immune
or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to
enhanced primary afferent excitability. Neuron 2018;97:806–822 e10.
[25] Guo TZ, Wei T, Tajerian M, Clark JD, Birklein F, Goebel A, et al. Complex regional
pain syndrome patient immunoglobulin M has pronociceptive effects in the skin
and spinal cord of tibia fracture mice. Pain 2020;161:797–809.
[26] Goebel A, Krock E, Gentry C, Israel MR, Jurczak A, Urbina CM, et al. Passive
transfer of fibromyalgia symptoms from patients to mice. J Clin Invest 2021;131
(13):e144201.
[27] Ishikura T, Kinoshita M, Shimizu M, Yasumizu Y, Motooka D, Okuzaki D, et al.
Anti-AQP4 autoantibodies promote ATP release from astrocytes and induce
mechanical pain in rats. J Neuroinflammation 2021;18:181.
[28] Jurcak A, Delay L, Barbier J, Simon N, Krock E, Sandor K, et al. Antibody-induced
pain-like behavior and bone erosion - links to subclinical inflammation, osteoclast
activity and ASIC3-dependent sensitization, Pain in press. 2021.
[29] Guo TZ, Shi X, Li WW, Wei T, Clark JD, Kingery WS. Passive transfer autoimmunity
in a mouse model of complex regional pain syndrome. Pain 2017;158:2410–21

Sigh. I'm too emotionally attached to this idea. My bias I can't let it go. Sorry PEJE.

 

[Jonathan Edwards]

Don't you get fired if your hot papers are garbage though, unless nobody is ever bothered to replicate your work.

No, research assessment exercises do not go back to see if your paper in a top journal proved unreplicable. Did any of the PACE authors get fired? Sadly not. In medicine, if major progress is made with mechanisms or treatments, with readily replicable evidence then all tends to go quite well. But in areas where progress isn't being made - like ME or FM - fashion rules. So garbage becomes the norm. Bad studies even get replicated, as with XMRV.

I haven't bothered to read the Autoimmunity Reviews paper. The journal is generally regarded as a joke - a bit like Fox News I guess.

Enough lymphoma patients would have fibromyalgia just by chance coincidence.

 

[Mister Person]

No, research assessment exercises do not go back to see if your paper in a top journal proved unreplicable. Did any of the PACE authors get fired? Sadly not. In medicine, if major progress is made with mechanisms or treatments, with readily replicable evidence then all tends to go quite well. But in areas where progress isn't being made - like ME or FM - fashion rules. So garbage becomes the norm. Bad studies even get replicated, as with XMRV.

I haven't bothered to read the Autoimmunity Reviews paper. The journal is generally regarded as a joke - a bit like Fox News I guess.

Enough lymphoma patients would have fibromyalgia just by chance coincidence.

So if you're sincere enough with bad science, you can get away... With nothing but oh well we made an oopsie. Hmm.

1 final final thing, if Goebel is right, does that mean fibromyalgia can be diagnosed in an autopsy via staining of the DRG. That would seem to be a quick way to see if he is, would it

Update on the anecdote poster had autoimmune thyroid stuff going on, thus if they did have fibro it was secondary, or their symptoms were just thyroid related and not unexplained fibro pain. Sigh. Because thyroid related pain also seems unclear, it's another unknown. Is fibro pain the same mechanism or, are they 2 different mechanism. And some of thyroid related pain may be the same mechanism.

Also, instead of lymphoma trial, wouldn't the cfs trial had been enough? Some cfs patients would have had fibromyalgia right?

 

[Mister Person]

I don't know what has happened in the last five years or so but my understanding was that the claim of finding SFN in 'fibromyalgia' cases was contentious and not widely accepted by rheumatologists at least. The huge problem with fibromyalgia is that some physicians will diagnose 100 cases where others will diagnose 1 or not use the term.

For most physicians fibromyalgia is pretty much defined as widespread pain that is not explained on history or examination or reliable tests to be due to ay specific pathology. Neuropathy produces particular patterns of symptoms and signs. They are not present inpatients diagnosed with fibromyalgia.

Which of course raises the question what do these 'SFN' findings mean if anything? Presumably there is no change on standard neuropathy electrophysiology studies - otherwise it would have been detected decades ago by routine electrophysiology exams. If so I am not sure that we know what we should expect the symptoms of this so called SFN to be, if it is present, so it would be circular to say that 'symptoms of fibromyalgia are similar to those of SFN'. Certainly the clinical picture of fibromyalgia is not one of neuropathy of any recognised sort.

All this stuff has been generally regarded as fringe and quite likely pseudoscience by rheumatologists I know. My colleague Maria Leandro, who is assiduous about keeping informed about background clinical science came to dinner last night and she had not heard of any of this stuff from Goebel.



This is a significant part of what makes me sceptical. The explanation is exactly what someone without deep knowledge of immunology would come up with because it superficially sounds good. People have been making claims about transferring disease with antibodies for about seventy years. Most people have given up trying because it has never proven a useful research tool. Disease can be transferred with antibody, yes, but the conditions are limited, as in neonatal myasthenia or heart block. Goebel's experiments sound like what we used to hear about in the 1970s.



Because tens of thousands of people have been given rituximab for various other conditions - lymphoma, RA etc. According to the fibromyalgia enthusiasts about 10% of these (thousands) will by chance have also had FM.



Sure, but if it is a story we got bored of hearing fifty years ago because it never panned out then scepticism seems wise.



Most autoantibodies are non-inflammatory. Nothing remotely new or contentious about that. Anti-thyroid antibodies are not primarily inflammatory, nor anti-platelet, nor anti-phospholipid, nor anti-intrinsic factor, nor... Even antibodies in lupus producing membranous nephropathy are not strictly inflammatory.

What is fringe is the implication of anti-neuronal antibodies in a whole host of conditions that have proved hard to explain when in fact that antibody levels are barely different from normal if they really are at all. The anti-receptor antibody levels (adrenergic and cholinergic) inME are essentially normal. The findings should be seen as negative.



So at least the authors have thought about this. I actually think trying to assess FM independently in RA or Lupus would be impossible. Pain improves - I have seen patients putting their marks on the visual analogue scales for major improvement. But how does one know if that is RA or FM? I think any useful observations would have to come from lymphoma patients with FM.

Professor, after some thinking and more reading I realise I failed to even grasp the basic underlying concepts. Why are most autoantibodies non inflammatory? I thought they induce an immune response. What is the definition of inflammatory? Inflammatory as in induce immune response?
From my googling there are 3 things antibodies can do block receptor, bind substrate? And activate complement.

Also, the Antibody targets were not neuronal in RA, and CRPS. The targets were unknown for RA I think, not sure because didn't understand what I read. But for pCRPS the targets were unknown and for ECRPS the target keratin type 16.

Also regarding satellite glial cells, they are implicated in CRPS too aren't they! Ain't that interesting. I saw that something sympathetic sprout, glial cell proliferate and activate and recruit cells

Also, re rituximab why doesn't it work for all autoimmune illnesses? And would the cfs trial had tested pain?

Also, why do steroids induce remission in autoimmunity, aren't there still antibodies floating around?.

Also, how long do cytokines bind for? How fast can glial cells release cytokines? How fast would cytokines travel the 20nm between neurons and SGC?
And can nerve signals trigger SGC?

Lidocaine stops fibromyalgia pain.

I've seen VGKC antibodies mentioned a few times regarding autoimmune pain, but they're non destructive and non inflammatory, so why do they respond to steroids?

If SGC are being activated in the DRG, does that affect both sensory neurons, and the autonomic neurons? And how would pro nociceptive molecules interact with motor neurons?

They say immune suppressants don't cross bbb, thus it may not help with cfs, how could this be true when immune suppressants are used for autoimmune encephalitis?

Blood nerve barrier should be preventing infiltration of neutrophils into sensory ganglia?

Lotta questions I know, I wish to be schooled

 

[Mister Person]

Professor, after some thinking and more reading I realise I failed to even grasp the basic underlying concepts. Why are most autoantibodies non inflammatory? I thought they induce an immune response. What is the definition of inflammatory? Inflammatory as in induce immune response?
From my googling there are 3 things antibodies can do block receptor, bind substrate? And activate complement.

Also, the Antibody targets were not neuronal in RA, and CRPS. The targets were unknown for RA I think, not sure because didn't understand what I read. But for pCRPS the targets were unknown and for ECRPS the target keratin type 16.

Also regarding satellite glial cells, they are implicated in CRPS too aren't they! Ain't that interesting. I saw that something sympathetic sprout, glial cell proliferate and activate and recruit cells

Also, re rituximab why doesn't it work for all autoimmune illnesses? And would the cfs trial had tested pain?

Also, why do steroids induce remission in autoimmunity, aren't there still antibodies floating around?.

Also, how long do cytokines bind for? How fast can glial cells release cytokines? How fast would cytokines travel the 20nm between neurons and SGC?
And can nerve signals trigger SGC?

Lidocaine stops fibromyalgia pain.

I've seen VGKC antibodies mentioned a few times regarding autoimmune pain, but they're non destructive and non inflammatory, so why do they respond to steroids?

If SGC are being activated in the DRG, does that affect both sensory neurons, and the autonomic neurons? And how would pro nociceptive molecules interact with motor neurons?

They say immune suppressants don't cross bbb, thus it may not help with cfs, how could this be true when immune suppressants are used for autoimmune encephalitis?

Blood nerve barrier should be preventing infiltration of neutrophils into sensory ganglia?

Lotta questions I know, I wish to be schooled

1 answer to 1 q I found : motor neurones sit in cns but project into PNS, but are also in the drg. But I think they still have receptors then for nociceptive stuff? I'm not sure. I was thinking if they could cause muscle twitches and tremors and I think they could, even if there wasn't receptors, in the same way touching something really hot causes reflex

 

[Jonathan Edwards]

An awful lot of questions?
I would need a whole immunology textbook and the ones out there don't always make the simple things clear.

Antibodies bind antigen and can simply block its function without generating any inflammation.
To generate inflammation antibodies need to bind either complement or macrophage Fc receptors. They will do either or both if several antibody molecules are brought together - either bringing arms of complement C1q together or cell surface Fc receptors together.

Binding complement in the circulation is anti-inflammatory because the activated complement binds clearing receptors on red cells (CR1). Binding complement outside circulation releases C3a and C5a (chemotaxis) and binds to receptor CR3 leading to cell activation. Binding of Fc receptors leads to cytokine release - TNF and IL-1 - which produces much more destructive inflammation than complement.

The antibodies in RA are directed to immunoglobulin itself (Fc portion) and called rheumatoid factors. There are also antibodies to citrullinated peptide sites. The detail is very complicated but in simple terms the autoantibodies in RA are small enough to evade clearance by complement receptor 1 but just big enough to activate cytokines through Fc receptor IIIa. That receptor is preferentially expressed in joint lining - which is why it is a disease mostly of joints. Complexes of similar size contribute to lupus, which also often includes arthritis.

The complexes most typical of lupus are large. They cause damage because the clearing receptor CR1 is to operating effectively. That means that complexes can get big enough in the circulation to silt up in the kidney and brain with nephritis and encephalitis (never seen in RA where CR1 is working properly).

It is a lifetime's learning getting to see all the ways antibodies can cause trouble.There is still a lot to work out but by 2000 we had a pretty good idea of the main mechanisms.

 

[Mister Person]

An awful lot of questions?
I would need a whole immunology textbook and the ones out there don't always make the simple things clear.

Antibodies bind antigen and can simply block its function without generating any inflammation.
To generate inflammation antibodies need to bind either complement or macrophage Fc receptors. They will do either or both if several antibody molecules are brought together - either bringing arms of complement C1q together or cell surface Fc receptors together.

Binding complement in the circulation is anti-inflammatory because the activated complement binds clearing receptors on red cells (CR1). Binding complement outside circulation releases C3a and C5a (chemotaxis) and binds to receptor CR3 leading to cell activation. Binding of Fc receptors leads to cytokine release - TNF and IL-1 - which produces much more destructive inflammation than complement.

The antibodies in RA are directed to immunoglobulin itself (Fc portion) and called rheumatoid factors. There are also antibodies to citrullinated peptide sites. The detail is very complicated but in simple terms the autoantibodies in RA are small enough to evade clearance by complement receptor 1 but just big enough to activate cytokines through Fc receptor IIIa. That receptor is preferentially expressed in joint lining - which is why it is a disease mostly of joints. Complexes of similar size contribute to lupus, which also often includes arthritis.

The complexes most typical of lupus are large. They cause damage because the clearing receptor CR1 is to operating effectively. That means that complexes can get big enough in the circulation to silt up in the kidney and brain with nephritis and encephalitis (never seen in RA where CR1 is working properly).

It is a lifetime's learning getting to see all the ways antibodies can cause trouble.There is still a lot to work out but by 2000 we had a pretty good idea of the main mechanisms.

Thank for explaining. Yea... I was hoping to get answers without needing to do a degrees worth of study. I don't understand your explanation but thank you for pointing me so I know what to read.

Before this I assumed antibodies just bound to the cell, then called on their friends to come take apart the cell, engulf or releasing damaging things.

 

[SNT Gatchaman]

The trope is brain surgery and rocket science. Perhaps it should be: "Brain surgery eh? Still... not exactly immunology is it?".

 

[Mister Person]

The trope is brain surgery and rocket science. Perhaps it should be: "Brain surgery eh? Still... not exactly immunology is it?".

https://www.bmj.com/content/375/bmj-2021-067883 somebody took this very seriously

Shak I got an email for your reply but you seem to have disappeared completely. Unfortunately videos pem me too fast now, I can only read

Gee. Is there any autoimmune illness where the pathophysiology is simple as autoantibody, cause attack. That's how the websites always described it, I've been mislead

 

[Mister Person]

An awful lot of questions?
I would need a whole immunology textbook and the ones out there don't always make the simple things clear.

Antibodies bind antigen and can simply block its function without generating any inflammation.
To generate inflammation antibodies need to bind either complement or macrophage Fc receptors. They will do either or both if several antibody molecules are brought together - either bringing arms of complement C1q together or cell surface Fc receptors together.

Binding complement in the circulation is anti-inflammatory because the activated complement binds clearing receptors on red cells (CR1). Binding complement outside circulation releases C3a and C5a (chemotaxis) and binds to receptor CR3 leading to cell activation. Binding of Fc receptors leads to cytokine release - TNF and IL-1 - which produces much more destructive inflammation than complement.

The antibodies in RA are directed to immunoglobulin itself (Fc portion) and called rheumatoid factors. There are also antibodies to citrullinated peptide sites. The detail is very complicated but in simple terms the autoantibodies in RA are small enough to evade clearance by complement receptor 1 but just big enough to activate cytokines through Fc receptor IIIa. That receptor is preferentially expressed in joint lining - which is why it is a disease mostly of joints. Complexes of similar size contribute to lupus, which also often includes arthritis.

The complexes most typical of lupus are large. They cause damage because the clearing receptor CR1 is to operating effectively. That means that complexes can get big enough in the circulation to silt up in the kidney and brain with nephritis and encephalitis (never seen in RA where CR1 is working properly).

It is a lifetime's learning getting to see all the ways antibodies can cause trouble.There is still a lot to work out but by 2000 we had a pretty good idea of the main mechanisms.

Professor, a few more.
SFN neuropathy produces different signs and symptoms to fibromyalgia, what would this difference be?

What were these other attempts to transfer disease with antibodies? I would like to read them

'Most autoantibodies are non-inflammatory' is this true? Because after googling, lupus antibodies and ra antibodies are inflammatory, are they not. This statement lead me to believe most autoimmune illnesses are non inflammatory at least directly. So in some illness they do activate immune cells, but in others they don't? Or most autoimmune illnesses don't activate immune cells.
Or have I confused myself, since auto antibodies are not synonymous with autoimmune disease. Most autoantibodies are non inflammatory, but most autoimmube diseases with autoantibodies are inflammatory?

When science is considered Fringe, are there skeptics who go on and prove that it is Fringe, or do they just say its Fringe, and nobody tries replicating or digging deeper? Because if something is Fringe, and nobody digs, it stays Fringe? Also what is the definition of Fringe here? Is the evidence not compelling, or is the hypothesis not compelling. Concerning just this fibromyalgia paper alone, and not me, crps, RA. I've had a thought and I don't think this mechanism applies to me, my symptoms are too different and thus I am no longer so attached to the idea. However, I am open to the idea that maybe something similar is going on, and that some people may have this. I know you said it's the claim that's Fringe, so is the evidence Fringe too? Im guessing yes because you said old technique and unsuccessful in others

On a reddit thread, medical professionals, but not necessarily immunologist and definitely not researchers, they're clinicians were rather impressed by the paper. With one saying that perhaps old techniques may still give new results.

And another, perhaps unnecessary more personal question, has Maria Leandro heard of Goebel's paper now? I take it that hearing/reading about it changed nothing regarding perspective on fibromyalgia