How to deal with autoimmune disease flares- A Rheumatologist POV

Flares happen. We do everything we can to prevent them and understand why they occur, but sometimes, they just happen. This is true regardless of the inflammatory or autoimmune disease: lupus, arthritis, fibromyalgia, vasculitis, and all the others. As frustrating as they can be, there are things you can do to manage them with care and grace.

Possible trigger for autoimmune diseases discovered

B cells (green) in thymus tissue

One of the mysteries of immunology is that the function of B cells (green) in the thymus gland was previously unknown. Researchers have now been able to show that the immune cells help to prevent T cells from attacking the body. CREDIT Jan Böttcher, Thomas Korn / TUM

Immune cells must learn not to attack the body itself. A team of researchers from the Technical University of Munich (TUM) and the Ludwig Maximilian University of Munich (LMU) has discovered a previously unknown mechanism behind this: other immune cells, the B cells, contribute to the “training” of the T cells in the thymus gland. If this process fails, autoimmune diseases can develop. The study confirms this for Neuromyelitis optica, a disease similar to Multiple Sclerosis. Other autoimmune diseases may also be linked to the failure of this new mechanism. 

The thymus gland functions as a “school for T cells” in children and adolescents. The organ in our chest is where the precursors of those T cells that would later attack the body’s own cells are discarded. Epithelial cells in the thymus present many molecules that occur in the body to the future T cells. A self-destruction program is triggered if any of them reacts to one of these molecules. T cells that attack the body’s own molecules remaining intact and multiplying, on the other hand, can cause autoimmune diseases.

New mechanism discovered

In Nature, the team led by Thomas Korn, Professor of Experimental Neuroimmunology at TUM and a Principal Investigator in the SyNergy Cluster of Excellence, and Ludger Klein, Professor of Immunology at LMU’s Biomedical Center (BMC), describe another previously unknown mechanism behind this.

In addition to the precursors of T cells, the thymus gland also contains other immune cells, the B cells. They develop in the bone marrow but migrate to the thymus in early childhood. “The function of B cells in the thymus gland has been a mystery that has puzzled immunologists for many years,” says Thomas Korn. The researchers have now been able to show for the first time that B cells play an active role in teaching T cells which targets not to attack.

MS-like disease due to malfunction in tolerance formation

Neuromyelitis optica is an autoimmune disease similar to multiple sclerosis (MS). While it is not yet known which molecules are attacked in MS, it is well-established that T cells respond to the protein AQP4 in neuromyelitis optica. AQP4 is most prominently expressed in cells of the nervous tissue, which then becomes the target of the autoimmune reaction. Frequently, the optic nerve is affected.

The researchers were able to show that in the thymus gland of humans and mice not only the epithelial cells but also B cells express and present AQP4 to the T cell precursors. If the B cells were prevented from doing so in animal experiments, AQP4-reactive T cell precursors were not eliminated and the autoimmune disease developed. This was also the case when the epithelial cells still presented the molecule. The team concludes from this that B cells in the thymus are a necessary condition for immune tolerance regarding AQP4.

Protection against subsequent interactions between T cells and B cells 

“We suspect that this previously unknown process has evolved particularly to prevent dangerous interactions between autoreactive T and B cells in the lymph nodes and spleen, the so-called peripheral immune compartment,” says Ludger Klein. Once the immune system is developed, B and T cells can communicate and thus trigger highly effective immune reactions. This is useful when it comes to fighting pathogens quickly. On occasion, however, B cells may accidentally present the body’s own proteins, such as AQP4. If the T cells that react to AQP4 had not been sorted out in the thymus, this could lead to a sudden and violent large-scale attack on the body.

Possible cause of other immune disorders

“We assume that problems with the training of T cells by the B cells in the thymus can cause other autoimmune diseases as well,” says Thomas Korn. “After all, the B cells in the thymus present a whole range of the body’s own proteins. The corresponding interactions must be investigated in further studies.”

According to the researchers, likely suspects include antiphospholipid syndrome (APS) and certain forms of cerebral amyloid angiopathy. “Looking further into the future, this interaction in the thymus might be exploited to treat existing autoimmune diseases in a very targeted manner,” says Thomas Korn. 

Study shows why women are at greater risk of autoimmune disease.

Women and pain

omewhere between 24 and 50 million Americans have an autoimmune disease, a condition in which the immune system attacks our own tissues. As many as 4 out of 5 of those people are women.

Rheumatoid arthritis, multiple sclerosis and scleroderma are examples of autoimmune disorders marked by lopsided female-to-male ratios. The ratio for lupus is 9 to 1; for Sjogren’s syndrome, it’s 19 to 1.

Stanford Medicine scientists and their colleagues have traced this disparity to the most fundamental feature differentiating biological female mammals from males, possibly paving the way for a better way to predict autoimmune disorders before they develop.

“As a practising physician, I see a lot of lupus and scleroderma patients because those autoimmune disorders manifest in the skin,” said Howard Chang, MD, PhD, dermatology professor and genetics professor and a Howard Hughes Medical Institute investigator. “The great majority of these patients are women.”

Chang, the Virginia and D.K. Ludwig Professor in Cancer Research and director of the RNA Medicine Program, is the senior author of the study, to be published Feb. 1 in Cell. Basic life research scientist Diana Dou, PhD, is its lead author.

The silence of the second X

Women have too much of a good thing: It’s called the X chromosome.

Throughout the mammalian kingdom, biological sex is determined by the presence of two X chromosomes in every female cell. Male cells pack just one X chromosome, paired with a much shorter one designated the Y chromosome.

The stubby Y chromosome contains only a handful of active genes. It’s quite possible to live a full life without a Y chromosome. In fact, more than half of the people on Earth — women — lack Y chromosomes and do just fine. But no mammalian male or female cell can survive without at least one copy of the X chromosome, which holds many hundreds of active protein-specifying genes.

Still, having two X chromosomes risks the production, in every female cell, of twice the amount of the myriad proteins specified by the X but not the Y chromosome. Such massive overproduction of so many proteins would be lethal.

Nature has devised a clever, if complicated, workaround called X-chromosome inactivation. Early in embryogenesis, each cell in the nascent female mammal decides to shut down the activity of one or the other of its two X chromosomes. Once that decision is made, it’s handed down to these cells’ progeny in the developing fetus. That way, the same amount of each X-chromosome-specified protein is produced in a female cell as in a male cell.

As the researchers discovered, X-chromosome inactivation can lead to autoimmune disorders, but other factors can also cause these disorders — which is why men sometimes develop them.

The great equalizer

X-chromosome inactivation is achieved courtesy of a molecule called Xist. The gene for Xist is present on all X chromosomes, including the single one male cells have. But Xist itself is produced only when the X chromosome that its gene resides on is one of a matched XX pair — and is produced and deployed on only one pair member.

Xist consists of RNA, a substance best known for being a simple-minded messenger that shuttles genes’ instructions for making proteins to the intracellular machines that make them. Yet RNA can do a whole lot more than schlep genetic information. There are as many different kinds of so-called long noncoding RNA (lncRNA) molecules — lengthy RNA stretches that don’t carry instructions for making proteins — as there are of the protein-encoding RNA variety. These lncRNA molecules can park themselves on stretches of chromosomes and change the likelihood that the cellular machinery charged with reading the genes in those locations will do so.

Xist, a type of lncRNA, is much longer than most. Xist coats long sections of one of a female mammalian cell’s two X chromosomes — but always just one — cutting that chromosome’s output to zero or close to it. The other X chromosome, left undisturbed, pumps out just enough RNA-encoded instructions to keep the cell humming.

But Xist’s nestling into the extra X chromosome generates odd combinations of lncRNA, proteins that bind to it, other proteins that bind to those proteins, and DNA some of those proteins cling to. These complexes can trigger a strong immune response, Chang and his colleagues have learned.

In 2015, Chang’s group identified close to 100 proteins that either bound to Xist or that bound to those proteins, collectively enabling this molecule to lay anchor along gene-specifying regions of the X chromosome.

Inspecting this Xist “parts list,” Chang realized that many of Xist’s collaborator proteins were known to be associated with autoimmune disorders. Might the RNA-protein-DNA complexes generated in the course of X-chromosome inactivation be triggering the notoriously high rate of autoimmunity in women compared with men? That question was the impetus for the new study.

What if males made Xist?

To eliminate possible competing causes such as female hormonal action or aberrant protein production by the supposedly silenced second X chromosome, the researchers tossed the Xist ball into the male court. They sewed the gene for Xist into the genomes of two different strains of male lab mice. One strain is quite susceptible to autoimmune symptoms mimicking lupus, with females more susceptible than males. The other is resistant to it.

The inserted Xist gene had been modified in two ways. It could be turned on or off by chemical means, pumping out Xist only when the scientists wanted it to. The Xist gene was also tweaked slightly so that its RNA product would no longer silence the genes of the male mouse’s chromosome into which it was stitched.

Merely inserting that modified Xist gene had no noticeable effect on the mice. But the Xist produced from the inserted gene, once that gene was activated, still formed characteristic complexes with almost all the proteins found earlier to be collaborating closely with Xist.

Now, the scientists could ask: Is a bioengineered male mouse that’s been coaxed to produce Xist more prone to autoimmunity than a normal male mouse, which never produces it, or than a male in whom the gene for Xist has been inserted but not activated?

By injecting an irritant known to induce a lupus-like autoimmune condition in the susceptible mouse strain, the investigators could compare its effect on males who made Xist with its effect on normal males, who made none.

In these susceptible mice, males in which the Xist gene was activated developed lupus-like autoimmunity at a rate approaching that of females — and considerably more so than non-bioengineered males.

The absence of autoimmunity in some female or Xist-activated male mice in the susceptible strain showed that not just activation of Xist but also some kind of tissue-damaging stress (caused, in this case, by injection of the irritant) is required to get the autoimmunity ball rolling.

In the autoimmune-resistant strain, activating Xist in bioengineered male mice wasn’t enough to induce autoimmunity — as might be predicted by the fact that in this strain even females seldom develop autoimmunity. That suggests that not only Xist activation but also an appropriate genetic background is necessary for autoimmunity to develop.

These constraints on autoimmunity are fortunate, because if there were none all women might be more susceptible to develop immunity, Chang noted.

Toward a better autoimmunity-screening panel

An early step in the development of autoimmunity is the appearance of autoantibodies: antibodies targeting one’s own tissues or cell products. Autoantibodies to the contents of cell nuclei are called anti-nuclear antibodies. Close examination of blood samples from about 100 patients with autoimmunity showed the presence of autoantibodies to many of the complexes associated with Xist. Some of these autoantibodies were specific to one or another autoimmune disorder, indicating their potential utility in identifying particular emergent autoimmune disorders before symptoms develop. Autoantibodies to still other Xist-associated proteins spanned several disorders, designating them as possible common markers of autoimmunity.

“Every cell in a woman’s body produces Xist,” Chang said. “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.”

New immune system-targeting compounds show early promise in treating lupus and other autoimmune conditions.

Scripps Research scientists developed a compound that can block a protein previously considered challenging to drug and is implicated in autoimmune diseases, including lupus.
Scripps Research scientists developed a compound that can block a protein previously considered challenging to drug and is implicated in autoimmune diseases, including lupus.

Scientists from Scripps Research have developed a small molecule that blocks the activity of a protein linked to autoimmune diseases, including systemic lupus erythematosus (SLE) and Crohn’s disease. This protein, known as SLC15A4, has been considered largely “undruggable,” as most researchers had long struggled to isolate the protein, determine its structure, or even pin down its exact function within immune cells—until now.

The research, published in Nature Chemical Biology on January 8, 2024, shows that the compound successfully reduced inflammation in mouse models of inflammation and in isolated cells from people diagnosed with lupus. This provides scientists with a new tool to study the role of SLC15A4 in autoimmunity and a potential new therapy to move toward additional preclinical trials.

“This is an example of a protein that had been correlated with disease in a number of ways, including human genetics and various disease models, but no one had been able to develop small molecules to target it,” says senior author Christopher Parker, PhD, associate professor in the Department of Chemistry at Scripps Research. “We not only created such a compound but validated that it can have therapeutic effects.”

SLC15A4 was first characterized in 2010 by Bruce Beutler, MD, the Chair of Genetics at Scripps Research (now at the University of Texas Southwestern Medical Center). His work established that SLC15A4 proteins play a key role in controlling immune responses and that higher levels of the proteins are associated with inflammation. Beutler and Ari Theofilopoulos, MD, now professor emeritus in the Department of Immunology and Microbiology, also showed that removing the SLC15A4 gene from mice with lupus ameliorated their disease.

Other studies have since found that SLC15A4 is present at higher levels in some patients with lupus and Crohn’s disease and that certain people with SLC15A4 mutations make them less likely to develop these diseases. However, researchers have struggled to study the protein.

“It is an incredibly complicated protein embedded in very specific membranes within immune cells,” says John Teijaro, PhD, professor in the Department of Immunology and Microbiology and co-senior author of the new work. “It doesn’t behave very well when you remove it from this environment, which makes it incredibly difficult to carry out most typical assays or drug screens.”

Parker’s lab, however, has pioneered methods to introduce chemical probes to living cells and screen which probes bind to a protein of interest—like SLC15A4—without ever removing the protein from its environment in the cell. The new study used this approach to discover nine different molecular fragments that could bind to SLC15A4 proteins inside human immune cells. They carried out various experiments to prove that one of these fragments, FFF-21, was physically attaching to SLC15A4 and impeding its function in promoting inflammation.

“This not only helps move forward research on SLC15A4 but also validates our overall approach,” says Parker. “This general strategy can be applied to many other challenging drug targets.”

Clear link between autoimmune disease and perinatal depression

Women with autoimmune disease are more likely to suffer from depression during pregnancy and after childbirth; conversely, women with a history of perinatal depression are at higher risk of developing autoimmune disease, a new study from Karolinska Institutet published in the journal Molecular Psychiatry reports.

In autoimmune disease, the immune system mistakenly attacks the body’s own healthy tissue. Some of the most common autoimmune diseases are gluten intolerance (coeliac disease), autoimmune thyroiditis, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis (MS).

In the present study, researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the resulting group of approximately 815,000 women and 1.3 million pregnancies, just over 55,000 women had been diagnosed with depression during their pregnancy or within a year after delivery.

The researchers then compared the incidence of 41 autoimmune diseases in women with and without perinatal depression, controlling for familial factors such as genes and childhood environment by also including the affected women’s sisters.

Strongest association for MS

The results reveal a bidirectional association between perinatal depression and autoimmune thyroiditis, psoriasis, MS, ulcerative colitis, and coeliac disease. Overall, women with autoimmune disease were 30 per cent more likely to suffer perinatal depression. Conversely, women with perinatal depression were 30 per cent more likely to develop a subsequent autoimmune disease.

The association was strongest for the neurological disease MS, for which the risk was double in both directions. It was also strongest in women who had not had a previous psychiatric diagnosis.

“Our study suggests that there’s an immunological mechanism behind perinatal depression and that autoimmune diseases should be seen as a risk factor for this kind of depression,” says the study’s first author Emma Bränn, researcher at the Institute of Environmental Medicine at Karolinska Institutet.

Can have serious consequences

The researchers will now continue to examine the long-term effects of depression during pregnancy and in the first year following childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” says Dr Bränn. “We hope that our results will help decision-makers to steer funding towards maternal healthcare so that more women can get help and support in time.”

Since this was an observational study, no conclusions on causality can be drawn.

The study was financed by Karolinska Institutet, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Councill and the Icelandic Research Fund. The researchers report no conflicts of interest.