Yves right here. KLG unpacks a brand new paper that has gotten lots of play within the fashionable press, which presents a brand new idea of why girls get autoimmune ailments extra usually than males. He explains the analysis and explains why it’s a really credible piece of labor. KLG additionally speculates why autoimmune ailments are on the rise and thinks ultra-processed diets are a probable suspect.
BTW my father had an autoimmune illness that’s terminal, dermatomyositis.
By KLG, who has held analysis and educational positions in three US medical colleges since 1995 and is at the moment Professor of Biochemistry and Affiliate Dean. He has carried out and directed analysis on protein construction, operate, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and meeting of the vertebrate coronary heart. He has served on nationwide assessment panels of each private and non-private funding companies, and his analysis and that of his college students has been funded by the American Coronary heart Affiliation, American Most cancers Society, and Nationwide Institutes of Well being.
As we speak we contemplate the urgent medical thriller of why autoimmune problems are way more widespread in females than males. Total, 80% of sufferers with autoimmune problems are feminine. These embrace Flannery O’Connor, Toni Braxton, and Selena Gomez, every of whom was recognized with lupus. Males who’ve suffered from lupus embrace the CBS Information reporter Charles Kuralt and “My Favourite Martian” Ray Walston. This sex-biased distribution of autoimmune illness has lengthy been a puzzle. Earlier hypothesis has centered on hormonal variations between females and males because the underlying issue. Though completely cheap, this has not but led to a believable mechanism for autoimmune illness.
A paper printed within the journal Cell on 1 February 2024 has proposed a molecular mechanism for these sex-biased diseases, together with systemic lupus erythematosus (SLE; 9:1 females to males) and Sjögren’s illness; 19:1 females to males): Xist ribonucleotide proteins promote feminine sex-biased autoimmunity (NB: sex-biased, not sex-based; this paper is open-access, 34 pages within the pdf together with among the supplemental materials). What does this imposing title imply?
From the Abstract:
Autoimmune ailments disproportionately have an effect on females.
The XX intercourse chromosome complement is strongly related to susceptibility to autoimmunity. Females are XX, males are XY. XXY males (Klinefelter Syndrome) usually tend to have autoimmune illness than XY males.
Xist (pronounced Ex-ist: quick video, 0:00 – 4:15) lengthy non-coding RNA (lncRNA; i.e., an extended RNA molecule distinct from mRNAs that code for proteins, as in COVID-19 vaccines) is expressed solely in females to randomly inactivate one of many two X chromosomes in every cell. This gene dosage compensation is important, as a result of just one intercourse chromosome needs to be energetic in any cell. X-inactivation can also be referred to as Lyonization after the geneticist Mary Lyon; Calico cat coat coloration is the results of random X-inactivation with every X chromosome carrying totally different pigmentation genes.
The Xist ribonucleoprotein (RNP) advanced comprising quite a few autoantigenic parts is a vital driver of sex-biased autoimmunity (the archetypal RNP is the ribosome, the intracellular machine that produces protein utilizing the mRNA template).
This graphical summary outlines Xist-mediated autoimmunity (all scientific papers ought to embrace a graphical summary):
How does this paper elucidate this mechanism? In plain English:
An Xist lncRNA assemble facilitated the meeting of RNP complexes that led to the manufacturing of autoantibodies related to autoimmune illness when expressed in male mice.
These male mice then developed lupus-like multi-organ pathology, whereas their immune cells resembled these of the traditional feminine.
Furthermore, in screens of affected person samples:
Human sufferers with autoimmune illness have autoantibodies to protein parts of the Xist RNP.
This demonstrates that the sex-specific lncRNA and its protein companions (Xist RNP) drive sex-biasedautoimmunity.
The experimental mannequin (A) used right here is predicated on a well-characterized mouse mannequin of SLE and rheumatoid arthritis (RA) during which injection of pristane results in SLE- and RA-like organ injury. Transgenic Xist (tgXist) mice during which the transgene is turned on by doxycycline (Dox) of their ingesting water are injected with pristane to induce SLE [1]. Blood was then collected for autoantibody profiling. Organs (lungs, liver, kidney, spleen, adipose, lymph nodes) from experimental and management mice had been additionally collected and examined for autoimmune injury, whereas immune cells had been remoted from the spleen for additional characterization.
The experiment (B): the optimistic management (1) is a wild-type feminine injected with pristane to induce SLE. The destructive management (2) is a wild-type male injected with PBS (phosphate-buffered saline), which shouldn’t result in SLE. The DOX tgXist management (3) is a male that expresses Xist however shouldn’t be handled with pristane to induce SLE. The remedy management (4) is a wild-type male injected with pristane and doxycycline; pristane ought to induce SLE whereas doxycycline within the absence of the tgXist assemble should not have any measurable impact. The take a look at (5) is a tgXist male during which the Xist transgene is induced with doxycycline plus injection with pristane to induce SLE.
The outcomes (C) primarily based on a rating of SLE-associated organ injury: As anticipated, the feminine (1, optimistic management) handled with pristane develops extreme SLE (15.54 whole). The wild-type male (2, destructive management) handled with PBS has no measurable SLE (0.80), and equally the tgXist male (3, uninduced management, PBS + Dox, no pristane) has no measurable SLE (1.00). The wild-type male (4, remedy management, Dox + Pristane) develops extreme SLE (6.22) however not as extreme as the feminine optimistic management. The take a look at tgXist male (5, tgXist, Dox + Pristane) develops SLE that’s extra extreme than the remedy management male (9.38). Thus, females develop extreme SLE when handled with pristane, which was anticipated. Males handled with pristane additionally develop extreme SLE that’s much less damaging than that in females. SLE is extra extreme in males expressing the Xist lncRNA they might not usually have. The clear result’s that the Xist RNP is related to autoimmune injury. The take a look at males (5) even have SLE-associated autoantibodies, which completes the present image within the mouse mannequin.
Nonetheless, the truthful query is whether or not these knowledge have medical relevance for human sufferers with autoimmune illness. The reply to that is sure, because the excerpt beneath from Determine 6 exhibits that autoimmune illness sufferers expertise elevated serum reactivity towards antigens of the Xist RNP. Three autoimmune illness teams (DM, dermatomyositis; SSc, scleroderma; and SLE) had been considerably reactive to 79 distinctive proteins within the array of autoimmune antigens, as compared with a management consisting of samples from the final inhabitants.
Twenty-seven (27) of those proteins had been illness controls and 53 had been related to the Xist RNP. Of the 9 proteins widespread to all three ailments, 8 had been Xist RNP proteins. As well as, 37 of the 53 Xist-associated proteins had been a part of the group of 118 high-confidence Xist RNP advanced proteins beforehand recognized. These outcomes present that a number of proteins from the Xist RNPs are novel autoantigens in sufferers with DM, SSc, and SLE.
Lastly, why is that this analysis vital? Greater than 100 autoimmune ailments have been described. They afflict 50 million People, or roughly 15% of the present inhabitants of 336 million and are a number one reason behind dying worldwide for ladies beneath the age of 65. These numbers are growing. Thus, a deeper understanding of danger elements for autoimmune illness is important if we’re to develop interventions with out training what Sir William Osler (1849-1919) referred to as “a form of pop-gun pharmacy, hitting the illness and once more the affected person…often not realizing which.”
Autoimmune illness is heterogenous with overlapping traits, however as famous on this paper, “Our discovery of seropositivity towards a number of XIST-associating proteins in autoimmune sufferers introduces a novel antigen set with medical potential for enhancing illness detection and monitoring, as autoantibodies are sometimes detected previous to or early in illness onset.” Whereas directed and efficient interventions haven’t but been recognized, this can’t even be contemplated with no deeper understanding of autoimmune illness.
This examine could be very sturdy, with well-chosen controls at each step, however has limitations attribute of all such analysis. The experiments don’t utterly recapitulate the illness in people, however no mannequin will ever do this. The Xist transgene can also be an incomplete assemble that’s expressed ubiquitously within the take a look at topics. However that can also be why utilizing male mice because the take a look at case has labored: Xist RNP expression exacerbated recognizable autoimmune illness within the well-characterized pristane-induced SLE mannequin. It has been mentioned concerning using animal fashions to review human illness that “mice lie, monkeys exaggerate.” Typically. However that is dependent upon the character of the query requested. Right here this was whether or not Xist RNP autoantigens contribute to autoimmune illness. The information demonstrating this within the mouse mannequin are sturdy and the experimental outcomes have been correlated with autoimmune illness markers in human illness. It is a excellent begin, a lot better than our lengthy and winding largely futile expertise with different scary afflictions,Alzheimer’s illness being a outstanding instance.
Lastly, the incidence of autoimmune ailments is growing, and never solely as a result of they’re now recognized extra usually than earlier than. The strong framework produced right here is probably going to supply the means to guage putative danger elements for autoimmune illness. That is one thing I hope to return to quickly. It has been addressed obliquely within the just lately printed Extremely-Processed Folks: The Science Behind Meals That Isn’t Meals by Chris Van Tulleken.
There might be no single danger issue for autoimmune illness, however in my opinion a great case might be made that the food-like substances of the so-called (Extremely-Processed) Western Eating regimen are a probable offender. We eat industrial concoctions which can be digestible and natural, within the chemical sense. They solely resemble meals, nevertheless, because the merchandise of recent “meals science.” A easy examine that would present significant outcomes could be to determine these susceptible to autoimmune illness and correlate markers and illness development with their eating regimen.
No, correlation shouldn’t be causation. That’s, till a mechanism might be adduced that features, amongst different issues, a dose-response curve [2]. Just by consuming, the overwhelming majority of us are getting giant doses of issues by no means earlier than consumed by any animal. The responses are apparent, such because the weight problems epidemic in international locations the place this eating regimen is the default. One other of those responses could also be autoimmune illness, as our our bodies react to the parts of our handy and ostensibly low-cost eating regimen offered by our the “Nice American Meals System.”
Because the title says, “science we are able to use” if solely we are going to.
A short notice on biomedical analysis: Nobody ought to ever learn a scientific paper with out contemplating how the analysis was supported. From the Acknowledgments: “This work was supported by Scleroderma Analysis Basis (H.Y.C.), NIAMS T32 AR007422 and NIAMS K99/R00 (D.R.D.), and NIAMS T32 AR050942 (B.T.A.). The Hopkins Lupus Cohort is supported by a grant from the Nationwide Institute of Arthritis and Musculoskeletal Ailments beneath award R01-AR069572. H.Y.C. is an Investigator and J.A.B. is a Hanna Grey Fellow of the Howard Hughes Medical Institute.” Nothing untoward right here.
Notes
[1] Scroll right down to “Analysis reagent” part; this method has been utilized in 1000’s of research of gene expression for 30+ years, together with a number of in my laboratory.
[2] See Bradford Hill Standards. Bradford Hill and Richard Doll confirmed conclusively that smoking causes lung most cancers greater than 70 years in the past, lengthy earlier than the molecular mechanisms of most cancers had been understood.
