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Scientists found a major clue why 4 of 5 autoimmune patients are women
- Thread starter Jaybee00
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- autoimmunity
The article is about this work Xist ribonucleoproteins promote female sex-biased autoimmunity. The paper hasn't been published yet, but will appear later today in Cell (the above preprint has been available for 1.5 years, so it's probably not spectular news for those working in this field).
Maybe this will put an end to gaslighting the female patients. Then again, it may not.
Sounds much like MECFS. I wonder if there is a "tantalizing clue" in MECFS equivalent to Klinefelter syndrome for autoimmunity. Something that scientists can zero in on, reproduce it in mice, etc, like this team did. Chasing nebulous statistics and features, like most long-COVID research seems to be doing, will never get us to the solution.
Jonathan Edwards
Senior Member (Voting Rights)
The paper is a complete joke, using an irrelevant mouse model.
Forget it.
We know why women have more autoimmunity - because they have two X chromosomes and that alters hormonal environment in a way that skews antibody repertoire.
It is a no-brainer that women should have different regulation of antibody repertoire because they have to make antibodies for babies. In fact making antibodies for babies may be the main point of having them, so that T cells can learn about microbes under cover of maternal antibody support during the first six months. For adults antibodies are mostly there to stop you getting il from the same bug twice. For infants they are there to keep you alive.
Forget it.
We know why women have more autoimmunity - because they have two X chromosomes and that alters hormonal environment in a way that skews antibody repertoire.
It is a no-brainer that women should have different regulation of antibody repertoire because they have to make antibodies for babies. In fact making antibodies for babies may be the main point of having them, so that T cells can learn about microbes under cover of maternal antibody support during the first six months. For adults antibodies are mostly there to stop you getting il from the same bug twice. For infants they are there to keep you alive.
Would that reasoning also apply to autoimmune diseases that many commonly classify as primarily T cell mediated?
Jonathan Edwards
Senior Member (Voting Rights)
Such as?
As far as I know the only autoimmune disease with reasonably good evidence of T cell drive is AIRE. Type I diabetes might be but I have yet to see a convincing story.
The diseases clearly associated with T cells - and often MHC Class I - do not appear to be truly autoimmune, or at least we have no evidence of specific anti-self clones. That includes psoriasis, ankylosing spondylitis etc.
The paper is not saying anything contrary as far as I can see. But it is showing the underlying mechanism for it by replicating the Xist action in mouse. What am I missing?
I couldn't tell you as I don't have a medical background.
All I can tell is that there seems to be a divide amongst autoimmunity researchers with one side of the group thinking "T-cells are everything" and many diseases, such as Type 1 Diabetes, Multiple Sclerosis, APSs, seemingly being widely classified as primarily T cell mediated autoimmune disorders without anybody contesting this, whilst there are further primarily T cell mediated autoimmune-like disorders such as Coeliac disease, myositis, psoriasis/psoriatic arthritis, Lichen planus etc. Then there is the other side of the group thinking "B-cells are everything" and that the T cell activation at some end-organ is predicted by B–T cell interactions and that the resulting tissue inflammation and destruction is due to specificity of the autoimmune B cell (or at least that’s my extremely limited ability to grasp the theory).
As I don’t have and never will have the knowledge to understand or judge any of those theories, my basic understanding of there being such a large divide is simply that neither group have been able to provide a fully convincing argument.
Of course you may contest this and express that the one side is simply chasing ghosts and provide RTX, which you helped implement, as wide ranging short-term and life-changing treatment as some sort of proof, but since thus far there hasn’t been a long-term treatment/cure focused on B-cells the proof remains illusive (at least to a layman like me).
Perhaps I should ask differently what do you believe is the reason that there is so much focus on T-cells, or at least not enough focus on treatments that involve B-cell depletion or B-cell targeting, including SLPCS and LLPCs, surely at least one great immunologist or rheumatologist works in the “T-cell field” as well? What do they think the holes in the "B-cell theories" are?
To get back to my original question: I was wandering whether if just one of these aforementioned diseases was a primarily T-cell medicated autoimmune disease and it primarily affects woman as well, whether your original reasoning for this would still hold or whether this would be an exception to the rule with a different reasoning.
Re AIRE*, if that was relevant in ME/CFS then would you expect that (fact) to be identified via:
*Autoimmune regulator
Autoimmune regulator (AIRE) is an important transcriptional regulator that is mainly expressed in medullary thymic epithelial cells (mTECs) in the central immune system.
- GWAS [DecodeME] - looking for common variants which contribute to disease risk/protection from disease?
- genetic study [using whole genome sequences] looking for rare variants which increase risk to a much higher degree - families with more than 1 member affected ("preferably" at least 1 severe)?
*Autoimmune regulator
Autoimmune regulator (AIRE) is an important transcriptional regulator that is mainly expressed in medullary thymic epithelial cells (mTECs) in the central immune system.
Forgot to add this to my post -still waiting for the data from Ron Davis's study on HLA genes - not sure if they're related to this?
https://www.s4me.info/threads/ron-d...ere’s-the-story-simon-m-blog.4798/#post-86574
Jonathan Edwards
Senior Member (Voting Rights)
That the effect shown in mice may have nothing whatever to do with the origin of autoimmunity in humans. If you play around with mouse genes enough to generate autoimmunity through different mechanisms - which people have done for decades it is likely that all sorts of things will tweak that.
I just saw another press release.
I cannot judge the quality of their argument or how much of a problem it would be, but in this press release the authors propose that “Every cell in a woman’s body produces Xist. But for several decades, we’ve used a male cell line as the standard of reference. That male cell line produced no Xist and no Xist/protein/DNA complexes, nor have other cells used since for the test. So, all of a female patient’s anti-Xist-complex antibodies, a huge source of women’s autoimmune susceptibility, go unseen”.
Maybe one of those problems one should keep an eye on in ME/CFS research as well?
Jonathan Edwards
Senior Member (Voting Rights)
A very long post for those interested.
It isn't quite like that. There is a divide between the general herd of immunologists who, since around 1980, have assumed that autoimmunity was T cell driven and a small group of people who look at the evidence and think that for the majority, but not all, conditions, the evidence for B cell mechanisms is all we have to go on. That does not exclude a contribution from autoreactive T cells, or that these may hang around and explain relapse after rituximab, but we have no evidence for that. The original concept of autoimmunity, from, I think, Landsteiner in 1908 with antibodies to red cells, was based on the presence of antibodies and for most conditions it still is.
It is more that the T cell people have provided no evidence at all, yet have blind faith that they must be responsible. Nobody has a full explanation but we have an adequate explanation for B cells driving most autoimmune diseases whereas there is none that fits any known evidence for T cells, except, very much so, in AIRE.
Yes, I can explain this in detail, at least for rheumatology. Up until 1970 all the evidence for autoimmunity related to antibodies. In the 1970s and 1980s Henry Kunkel continued work on autoantibody mechanisms, in RA in particular, and identified immune complexes as likely involved. However, there appeared to be a paradox relating to complement involvement so there was some scepticism about his proposal. (Twenty years later we worked out that the complement paradox was a misconception and that it fitted perfectly, but Kunkel died in 1983 and his ideas were carried on only by Jacob Native and for a while by Ivan Roitt.)
In the 1970s all interest in immunology had shifted to the newly discovered T cells and their role in graft rejection. Antibodies seems to be understood, following Rodney Porter and Gerald Edelman's explanation of the variability of their binding capacity. In the UK the Arthritis and Rheumatism Council had set up professorships to encourage physicians with a knowledge of immunology to come into clinical rheumatology. These included Gabriel Panayi and Ravinder Maini. (The US Immunology community will have a different narrative but the reality is that in the early 1980s UK physicians dominated the debate about autoimmunity in rheumatology - these two in particular.) Panayi had done his doctorate on the new T cells and was wedded to T cells. Maini had a broader interest but by the mid 1980s he had hired Marc Feldman as his main lab scientist. Marc was a protégé of Avrion Mitchison, who had worked with Peter Medawar on T cells (pedigrees dominate science).
Now comes the real irony.
In 1979 I was talking to my brother (who had worked in Mitchison's lab as a student) about immune cells in joints. He suggested that I looked to see if the joint macrophages expressed a molecule then calle IA (immune associated). In humans this was a family of molecules we now call HLA-DR,DP,DQ. We already knew that RA was genetically linked to the variant HLA-DR4. He recommended that I did some immunostaining and that I contacted a young researcher, Alero Thomas, who was working in the lab of George Janossy. Alero helped me do the staining and we found the IA (i.e. DR). I presented this to a meeting at which Maini and I think Panayi were present, in Holland.
My interpretation of the presence of DR was that the macrophages were the same as macrophages elsewhere (which have DR) - that was what I was wanting to know, no more than that. However, within a few months an article appeared in the Lancet by Janossy and Panayi claiming to show that RA must be a T cell disease because DR was present in the joint! The triviality and irrelevance of the argument took me aback. I had worked for Panayi. Someone in Janossy lab had got wind of what Alero and I had done and Janossy and Panayi set up a collaboration to further their theory. Nothing much came of it. But the idea that RA was a T cell disease became the dogma. The idea fell apart when Tak and colleagues showed that macrophages in joints are activated before any T cell infiltrate occurs, but the boulder was rolling. Even Roitt had largely given up on antibodies. Natvig's programme petered out. I was working in Riott's department and I really had to reconstruct the whole antibody story from scratch. Maini and Feldman persisted with T cell studies, that in the end fizzled out, but along the way they caught sight of the importance of TNF alpha. TNF alpha is made by T cells, but macrophages make about 100 times more. Maini managed to show that blocking TNF alpha was very good treatment for RA - I had been working on the same thing but he gets the credit for getting there first. But by 1997 we could see why joint macrophages would specifically produce TNF in response to antibody complexes. Joint T cells were a red herring.
There are different stories for MS and diabetes but the Medawar T cell clan was influential throughout I think. Mitchison was a powerful figure and pretty much the whole of autoimmune immunology research in the 1990s was T cell based. Moreover, it has continued to a large extent that way, I suspect because the B cell story is complex and initially counterintuitive. Our model for the pathogenic drive in RA involved 55 individual signalling steps. The T cell theory just needed some 'bad cross-reactive T cells'. I suspect that MS is fairly similar to RA in that you have to look very hard to see how the aberrant signalling loop works. I spent a lifetime on one mechanism. I never had the practical experience to make headway with MS. Again it may look like T cells are driving it but I suspect it is another Achilles heel in B cell control. Diabetes (type 1) I know even less about and I am not sure whether it is autoimmune at all.
An excellent question. The sex ratios for the autoimmune and auto inflammatory diseases vary quite a bit and we need an explanation. There is a recurring ration of F:M of 3:1 in most of the diseases with easily identified autoantibodies. Lupus is 9:1, which may suggest that the B-related risk factor 'acts twice' to give 3 squared. Clearly T cell related diseases (or at least those with little or no evidence of B cell involvement) tend to be male dominant (ank spond) but very variably. Crohn's is a bit of a hybrid. Coeliac is unique in that it has a T cell response to a foreign antigen that should be tolerated as food and an autoreactive B cell response (no autoreactive T cells as far as I know). Coeliac is slightly more common in women. But I don't think there are any diseases that we can confidently say are T ell based the are commoner in women at 3:1. Maybe someone can dig one up but I don't think I have ever seen one.
The exception that probes the rule is Wegener's granulomatosis which has a form that predominantly affects elderly males but is associated with an autoantibody. Does this kibosh the theoretical framework? I think not. A key point of our general theory of B cell involvement in autoimmune disease published in Immunology in 1999 was that every disease exploits a unique Achillles heel in B cell feedback control. So the demographics of each disease might differ depending on what signal it 'parasitises'. Lupus may depend on fooling two signals. If a triggering antigen behaved a bit differently in the two sexes you could have either sex predominance.
The test of a proven T cell based disease that is more common in women remains a good one. But there is also the point that most if not all these diseases have roles for both T and B. The rituximab story for RA was based on the idea that autoreactive memory was held in B cells. It was also built on a theory that said that inflammatory effector mechanisms in joints were B cell mediated. But there was never any suggestion that T cells were not involved - just not autoreactive ones. Antigen presentation to T cells was obviously the basis for the DR4 association.
So the story is very very complex - and the B cell enthusiasts recognise this. The T cell people just think there are bad cross reactive cells as far as I can see. And by and large nobody can find them. An interesting feature of the immunology scene in 2000 was that every single B cell enthusiast used a Mac and the T cell enthusiasts used a PC. Draw whatever conclusion you like!
It isn't quite like that. There is a divide between the general herd of immunologists who, since around 1980, have assumed that autoimmunity was T cell driven and a small group of people who look at the evidence and think that for the majority, but not all, conditions, the evidence for B cell mechanisms is all we have to go on. That does not exclude a contribution from autoreactive T cells, or that these may hang around and explain relapse after rituximab, but we have no evidence for that. The original concept of autoimmunity, from, I think, Landsteiner in 1908 with antibodies to red cells, was based on the presence of antibodies and for most conditions it still is.
It is more that the T cell people have provided no evidence at all, yet have blind faith that they must be responsible. Nobody has a full explanation but we have an adequate explanation for B cells driving most autoimmune diseases whereas there is none that fits any known evidence for T cells, except, very much so, in AIRE.
Yes, I can explain this in detail, at least for rheumatology. Up until 1970 all the evidence for autoimmunity related to antibodies. In the 1970s and 1980s Henry Kunkel continued work on autoantibody mechanisms, in RA in particular, and identified immune complexes as likely involved. However, there appeared to be a paradox relating to complement involvement so there was some scepticism about his proposal. (Twenty years later we worked out that the complement paradox was a misconception and that it fitted perfectly, but Kunkel died in 1983 and his ideas were carried on only by Jacob Native and for a while by Ivan Roitt.)
In the 1970s all interest in immunology had shifted to the newly discovered T cells and their role in graft rejection. Antibodies seems to be understood, following Rodney Porter and Gerald Edelman's explanation of the variability of their binding capacity. In the UK the Arthritis and Rheumatism Council had set up professorships to encourage physicians with a knowledge of immunology to come into clinical rheumatology. These included Gabriel Panayi and Ravinder Maini. (The US Immunology community will have a different narrative but the reality is that in the early 1980s UK physicians dominated the debate about autoimmunity in rheumatology - these two in particular.) Panayi had done his doctorate on the new T cells and was wedded to T cells. Maini had a broader interest but by the mid 1980s he had hired Marc Feldman as his main lab scientist. Marc was a protégé of Avrion Mitchison, who had worked with Peter Medawar on T cells (pedigrees dominate science).
Now comes the real irony.
In 1979 I was talking to my brother (who had worked in Mitchison's lab as a student) about immune cells in joints. He suggested that I looked to see if the joint macrophages expressed a molecule then calle IA (immune associated). In humans this was a family of molecules we now call HLA-DR,DP,DQ. We already knew that RA was genetically linked to the variant HLA-DR4. He recommended that I did some immunostaining and that I contacted a young researcher, Alero Thomas, who was working in the lab of George Janossy. Alero helped me do the staining and we found the IA (i.e. DR). I presented this to a meeting at which Maini and I think Panayi were present, in Holland.
My interpretation of the presence of DR was that the macrophages were the same as macrophages elsewhere (which have DR) - that was what I was wanting to know, no more than that. However, within a few months an article appeared in the Lancet by Janossy and Panayi claiming to show that RA must be a T cell disease because DR was present in the joint! The triviality and irrelevance of the argument took me aback. I had worked for Panayi. Someone in Janossy lab had got wind of what Alero and I had done and Janossy and Panayi set up a collaboration to further their theory. Nothing much came of it. But the idea that RA was a T cell disease became the dogma. The idea fell apart when Tak and colleagues showed that macrophages in joints are activated before any T cell infiltrate occurs, but the boulder was rolling. Even Roitt had largely given up on antibodies. Natvig's programme petered out. I was working in Riott's department and I really had to reconstruct the whole antibody story from scratch. Maini and Feldman persisted with T cell studies, that in the end fizzled out, but along the way they caught sight of the importance of TNF alpha. TNF alpha is made by T cells, but macrophages make about 100 times more. Maini managed to show that blocking TNF alpha was very good treatment for RA - I had been working on the same thing but he gets the credit for getting there first. But by 1997 we could see why joint macrophages would specifically produce TNF in response to antibody complexes. Joint T cells were a red herring.
There are different stories for MS and diabetes but the Medawar T cell clan was influential throughout I think. Mitchison was a powerful figure and pretty much the whole of autoimmune immunology research in the 1990s was T cell based. Moreover, it has continued to a large extent that way, I suspect because the B cell story is complex and initially counterintuitive. Our model for the pathogenic drive in RA involved 55 individual signalling steps. The T cell theory just needed some 'bad cross-reactive T cells'. I suspect that MS is fairly similar to RA in that you have to look very hard to see how the aberrant signalling loop works. I spent a lifetime on one mechanism. I never had the practical experience to make headway with MS. Again it may look like T cells are driving it but I suspect it is another Achilles heel in B cell control. Diabetes (type 1) I know even less about and I am not sure whether it is autoimmune at all.
An excellent question. The sex ratios for the autoimmune and auto inflammatory diseases vary quite a bit and we need an explanation. There is a recurring ration of F:M of 3:1 in most of the diseases with easily identified autoantibodies. Lupus is 9:1, which may suggest that the B-related risk factor 'acts twice' to give 3 squared. Clearly T cell related diseases (or at least those with little or no evidence of B cell involvement) tend to be male dominant (ank spond) but very variably. Crohn's is a bit of a hybrid. Coeliac is unique in that it has a T cell response to a foreign antigen that should be tolerated as food and an autoreactive B cell response (no autoreactive T cells as far as I know). Coeliac is slightly more common in women. But I don't think there are any diseases that we can confidently say are T ell based the are commoner in women at 3:1. Maybe someone can dig one up but I don't think I have ever seen one.
The exception that probes the rule is Wegener's granulomatosis which has a form that predominantly affects elderly males but is associated with an autoantibody. Does this kibosh the theoretical framework? I think not. A key point of our general theory of B cell involvement in autoimmune disease published in Immunology in 1999 was that every disease exploits a unique Achillles heel in B cell feedback control. So the demographics of each disease might differ depending on what signal it 'parasitises'. Lupus may depend on fooling two signals. If a triggering antigen behaved a bit differently in the two sexes you could have either sex predominance.
The test of a proven T cell based disease that is more common in women remains a good one. But there is also the point that most if not all these diseases have roles for both T and B. The rituximab story for RA was based on the idea that autoreactive memory was held in B cells. It was also built on a theory that said that inflammatory effector mechanisms in joints were B cell mediated. But there was never any suggestion that T cells were not involved - just not autoreactive ones. Antigen presentation to T cells was obviously the basis for the DR4 association.
So the story is very very complex - and the B cell enthusiasts recognise this. The T cell people just think there are bad cross reactive cells as far as I can see. And by and large nobody can find them. An interesting feature of the immunology scene in 2000 was that every single B cell enthusiast used a Mac and the T cell enthusiasts used a PC. Draw whatever conclusion you like!
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There is no doubt we have female bias in ME/CFS. So, this work might have an implication. But then, they also admit:
In any case, I'd agree this is something ME/CFS research community should keep on eye on, as it may lead to a clue. They need get off the obsession on viral/post-viral cause, the focus that long COVID brought back, and widen their net in search of the clues.
Jonathan Edwards
Senior Member (Voting Rights)
“Clearly there’s got to be more, because one-tenth of lupus patients are men,” said David Karp, chief of the division of rheumatic diseases at the UT Southwestern Medical Center in Dallas. “So it’s not the only answer, but it’s a very interesting piece of the puzzle.”
It looks as if Dr Karp has completely missed the point, even if the study is meaningful. But then that's standard for rheumatologists I fear.
It looks as if Dr Karp has completely missed the point, even if the study is meaningful. But then that's standard for rheumatologists I fear.
And what point that might be?
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