Are predatory brain immune cells eating nerve cells in Amyotrophic lateral sclerosis (ALS)?

Good news!

"Highlights

• Salk scientists discover that central nervous system-resident immune cells called microglia use TAM receptors (discovered by study senior author Greg Lemke in 1991) to eat specific nerve cells in mouse model of ALS
• The study is the first to show TAM receptors can be used to kill living nerve cells
• The insights contribute to ongoing efforts to harness TAM receptors in clinical settings to treat cancers, autoimmune disorders, and more

...

Neurons are often the center of attention in brain and neurodegeneration research, but other cells in the central nervous system are important, too. Recent studies have shown microglia, which are immune cells specific to the brain and spinal cord, are very active during human ALS. The question is: Why? ...

Active microglia can be easily identified in research by assessing their expression of TAM receptors. ... discovered this family of proteins, which are critical bridges between the immune system and the rest of the body, more than three decades ago. ...

To determine whether the TAM system was the link between microglia activation and motor neuron death in ALS, the ... researchers started with the most widely used mouse model of ALS, called SOD1. These mice express a mutant SOD1 protein that causes ALS in people.

They first found that many motor neurons had been eaten in the spinal cords of SOD1 mice. The levels of TAM proteins were also elevated in these mice, particularly Axl and Mer.

Looking closer at the motor neurons, the scientists noticed those “eat me” signs, which are little molecules called phosphatidylserine, were being displayed on cells when they shouldn’t be. From there, the TAM system springs into action, guiding microglia to their next meal: a live neuron.

The natural next question ... is “what happens when we eliminate Axl and Mer?” Without these two TAM family proteins, the mice got sicker faster but lived longer. ...

“When we looked at how many motor neurons mice without Axl and Mer had, compared to mice with Axl and Mer, we found losing the TAM proteins meant preserving muscle controls.” ..."

From the abstract:

"Activation of microglia is a prominent feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that leads to the death of motor neurons.

A key component of this activation is elevated expression of the TAM receptor tyrosine kinases Axl and Mer (gene name Mertk).

Here we show that germline and microglial-restricted inactivation of the Axl and Mertk genes in the SOD1G93A mouse model of ALS leads to an extension of lifespan, which is tied to the preservation of cholinergic motor neurons and neuromuscular synapses.

Also elevated on SOD1G93A neuronal surfaces is the essential TAM co-ligand phosphatidylserine, a potent ‘eat-me’ signal through which apoptotic cells are engulfed by microglia.

Correspondingly, we find that microglial lysosomes are filled with the remains of cholinergic neurons in the SOD1G93A spinal cord, whereas this accumulation is markedly reduced in the SOD1G93AAxl-/-Mertk-/- cord.

Together, these results suggest that microglia phagocytically kill living neurons, and thereby hasten death in ALS."

Are predatory brain immune cells eating nerve cells in ALS? – Salk Institute "Salk Institute scientists discover central nervous system immune cells find and kill specific nerve cells in the spinal cords of mice with late-stage ALS, exacerbating the condition; findings could be harnessed in cancer and autoimmune therapy innovation efforts"

Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis (open access, but still in press)

Microglia (green) contain the remnants of motor neurons (purple) inside microglial lysosomes (yellow).

Cell therapy substantially reduces severe rheumatoid arthritis in first clinical trial

Good news, but a very small sample size! Impressive!

"Immunotherapies such as CAR T-cell therapy are used primarily to treat cancer. In the future, these patient-specific therapies, manufactured from patients’ own immune cells, could also help cure autoimmune diseases.

Six patients with particularly severe rheumatoid arthritis have now received this treatment at Charité – Universitätsmedizin Berlin. In the journal Nature Medicine*, the researchers report the results from the world’s first clinical trial of its kind: Disease activity decreased substantially in all participants. By the end of the observation period, three of the patients no longer required any medication for rheumatoid arthritis. ...

Currently available treatments can usually keep the inflammation under control, but do not cure the disease. Patients therefore require lifelong medication ...

For the world’s first clinical trial to evaluate the safety and efficacy of a CD19 CAR T-cell therapy in rheumatoid arthritis, the research team ... initially enrolled six patients with particularly severe disease. The three women and three men, aged 31 to 69, had received up to eight targeted or biologic therapies over the previous ten years, none of which had been sufficiently effective. ...

For the researchers, the results from the first part of the COMPARE trial are highly encouraging: “Disease activity decreased markedly in all six patients. During follow-up of up to one year, three patients were in sustained remission without any medication for rheumatoid arthritis,” ..."

From the abstract:

"Chimeric antigen receptor (CAR) T cell-mediated B cell depletion has demonstrated efficacy in several autoimmune diseases.

Here we report clinical and molecular data obtained during the nonrandomized phase 1 part of the phase 1/2 COMPARE trial, evaluating safety and efficacy of mivocabtagene autoleucel (miv-cel), an autologous fully human CD19 CAR T cell therapy, in rheumatoid arthritis (RA).

Six patients (three men, three women) with severe, treatment-refractory, anti-citrullinated protein antibody (ACPA)-positive RA received a single infusion of miv-cel after stopping all disease-modifying antirheumatic drug treatments and after standard lymphodepletion therapy.

Patients were followed for 36–52 weeks for safety and efficacy.

Primary endpoints were the incidence and severity of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and adverse events (AEs) within the first 4 weeks after treatment.

Secondary and explorative endpoints assessed clinical efficacy and cellular and humoral immune responses.

CRS occurred in all patients and was limited to grade 1 and 2 events. No ICANSs or serious AEs occurred; one dose-limiting toxicity was recorded (grade 3 transaminase elevation, resolved without sequelae).

The primary endpoint was met with acceptable safety findings, allowing advancement to phase 2.

CAR T cell therapy resulted in depletion of CD19+ B cells across blood and tissue, coinciding with a continuous decline of autoantibodies with seroconversion in four of the six patients for ACPAs against mutated citrullinated vimentin and five of six for rheumatoid factor immunoglobulin M.

Despite cessation of immunosuppressive treatments, disease activity improved in all patients (median 34% DAS28-CRP reduction at the latest follow-up with DAS28-CRP remission and American College of Rheumatology 70% response in 3 of 6 patients).

CD19 CAR T cells showed acceptable short-term tolerability in patients with treatment-refractory RA, justifying further evaluation. ..."

Cell therapy substantially reduces severe rheumatoid arthritis in first clinical trial

Charité study demonstrates efficacy of CD19 CAR T cells in first patients  (original news release)

CD19 CAR T cell therapy for treatment-refractory seropositive rheumatoid arthritis: a phase 1 trial (no public access)

Patients own immune cells genetically modified in the laboratory, track down the disease driving B cells, even deep within tissues. Inflammatory foci such as those seen here around the knee joints of a study participant (magenta) are no longer detectable even several months after CD19-CAR T-cell therapy (right in the PET-MRI image). Swelling and pain have subsided, with improved mobility.

Scientists uncover hidden sex differences in the human immune system

Amazing stuff!

"... Now, researchers have discovered over 1,000 genetic switches that operate differently in female and male immune cells, driving higher overall activity of inflammatory pathways in females. ...

Advances in single-cell technologies now allow researchers to study individual immune cells in great detail. This study is the first to examine immunity differences between males and females at single-cell resolution on this scale.

The team sequenced over 1.25 million peripheral blood mononuclear cells – immune cells circulating in the blood – from nearly 1,000 healthy individuals. ... These participants were part of the OneK1K cohort, a major Australian project designed to map how genetics influence individual immune cells at a population scale.

The analysis revealed distinct cellular profiles between the sexes.

Males had higher proportions of monocytes, cells that act as first immune responders, and their genetic activity was more concentrated on basic cellular maintenance and protein-building functions.

In contrast, females possessed higher levels of immune cells called B cells and regulatory T cells, with genetic activity heavily skewed towards inflammatory pathways.

“While this highly reactive immune profile gives females an advantage in fighting viral infections, it comes with a biological trade-off: a greater predisposition to autoimmune diseases. On the other hand, male immune cells are less primed for inflammation, making men generally more susceptible to infections and non-reproductive cancers,” ..."

From the abstract:

"Sex has a key role in disease susceptibility (in particular, autoimmunity).

Sex differences in the immune system originate from genes and their interactions with both intrinsic and extrinsic factors.

However, the cellular-level factors influencing sexual dimorphism are not fully understood.

We thus examined immune sex differences at single-cell resolution to dissect the genetic impacts.

Female-biased sex-differentially expressed genes (sex-DEGs) in multiple immune cells were involved in tumor necrosis factor alpha (TNF-α) signaling, whereas 

male DEGs were enriched for ribosomal-related functions.

While cis-expression trait quantitative loci (eQTLs) were less common on sex chromosomes, we identified over 1,000 sex-specific eQTLs and 51 sex-interacting eQTLs on autosomes.

When we examined the effect of genetic control on sex-DEGs, we found genetic variants affecting the female-biased expression of FCGR3A in natural killer (NK) cells (rs2099684) and ITGB2 in monocytes (rs760462), both of which are associated with systemic lupus erythematosus.

Our work reveals biases masked in bulk analyses and highlights sexually dimorphic genes and pathways at baseline."

Scientists uncover hidden sex differences in the human immune system | Garvan Institute of Medical Research "The study maps over a million cells to help explain why women are more prone to autoimmune diseases like lupus."

The impact of sex on the immune system explored at the single-cell level (open access)

Figure 1 Overview of study

Figure 2 Distributions of cell-type proportions across sex

Figure 3 Sex-differential expression

Scientists uncover hidden sex differences in the human immune system or e.g. why women are more prone to autoimmune diseases

Good news!

"... Now, researchers have discovered over 1,000 genetic switches that operate differently in female and male immune cells, driving higher overall activity of inflammatory pathways in females. ...

Until recently, technological limitations meant that immune differences between the sexes were studied using bulk blood analysis, which measures the average activity across a whole mixture of cells, masking specific cell behaviours. Advances in single-cell technologies now allow researchers to study individual immune cells in great detail. This study is the first to examine immunity differences between males and females at single-cell resolution on this scale.

The team sequenced over 1.25 million peripheral blood mononuclear cells – immune cells circulating in the blood – from nearly 1,000 healthy individuals. ...

The analysis revealed distinct cellular profiles between the sexes.

Males had higher proportions of monocytes, cells that act as first immune responders, and their genetic activity was more concentrated on basic cellular maintenance and protein-building functions.

In contrast, females possessed higher levels of immune cells called B cells and regulatory T cells, with genetic activity heavily skewed towards inflammatory pathways. ...

they discovered that the vast majority of these variations reside on autosomes – the shared non-sex chromosomes – identifying over 1,000 sex-specific genetic switches in these regions.

Importantly, these genetic controls were linked directly to autoimmune conditions. The team found specific variants affecting the female-biased expression of two genes associated with systemic lupus erythematosus, potentially helping to explain why lupus is nine times higher in women compared to men. ..."

From the abstract:

"Sex has a key role in disease susceptibility (in particular, autoimmunity). Sex differences in the immune system originate from genes and their interactions with both intrinsic and extrinsic factors. However, the cellular-level factors influencing sexual dimorphism are not fully understood.

We thus examined immune sex differences at single-cell resolution to dissect the genetic impacts. Female-biased sex-differentially expressed genes (sex-DEGs) in multiple immune cells were involved in tumor necrosis factor alpha (TNF-α) signaling, whereas male DEGs were enriched for ribosomal-related functions. While cis-expression trait quantitative loci (eQTLs) were less common on sex chromosomes, we identified over 1,000 sex-specific eQTLs and 51 sex-interacting eQTLs on autosomes.

When we examined the effect of genetic control on sex-DEGs, we found genetic variants affecting the female-biased expression of FCGR3A in natural killer (NK) cells (rs2099684) and ITGB2 in monocytes (rs760462), both of which are associated with systemic lupus erythematosus.

Our work reveals biases masked in bulk analyses and highlights sexually dimorphic genes and pathways at baseline."

Scientists uncover hidden sex differences in the human immune system | Garvan Institute of Medical Research "The study maps over a million cells to help explain why women are more prone to autoimmune diseases like lupus."

The impact of sex on the immune system explored at the single-cell level (open access)

Graphical abstract

Figure 1 Overview of study

Figure 3 Sex-differential expression

Hidden mutations in immune cells linked to autoimmune disease

Good news! This could be a breakthrough!

"New research suggests that autoimmune diseases may be driven by DNA mutations in immune cells that remove the natural brakes on the immune system. It reveals a previously hidden role for somatic mutations — DNA changes acquired throughout life — in diseases beyond cancer.

Researchers ... used a series of cutting-edge techniques to identify previously unseen changes in DNA that may contribute to thyroid autoimmunity, where the immune system attacks the thyroid gland. ...

The researchers used several advanced DNA analysis techniques.
Firstly, they used a method called NanoSeq, which they recently developed and allows detection of rare mutations invisible to traditional DNA sequencing methods, to look for genetic changes that may drive the disease. They found that many B cells had developed inactivating mutations in key genes that normally control the immune system.

Next, using additional methods that look at the DNA of individual cells and microscopic areas of tissue, the researchers found that many B cells in each patient carried several mutations in key genes.

Two critical immune-checkpoint genes, TNFRSF14 and CD274 (or PDL1), were often lost independently in multiple clones of mutated B cells in each patient. Some of these clones had even acquired as many as six driver mutations over many years, silently building up changes in DNA before symptoms appeared, a highly unexpected observation outside of cancer.

Importantly, artificial inactivation of these genes, in experimental studies or during cancer immunotherapy, is known to cause thyroid autoimmunity. The researchers have now found frequent mutations in these genes occurring in autoimmune patients. ..."

From the abstract:

"Our immune system contains multiple checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis posits that somatic mutations in immune-regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints1–3, but testing this has been challenging due to technical limitations.

Here, we use whole-exome and targeted NanoSeq, an accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed many B cell clones convergently acquiring loss-of-function mutations in the key immune checkpoint genes TNFRSF14 (HVEM) and CD274 (PD-L1), as well as less frequent mutations in other immune genes.

In highly inflamed biopsies, we detected tens to hundreds of independent immune checkpoint mutant clones. Laser microdissection, methylation sequencing, spatial transcriptomics, immunostaining, single-nucleus DNA sequencing, and antibody synthesis localised these mutations to B cells, confirmed some to be self-reactive, and identified clones carrying multiple hits.

We found widespread TNFRSF14 biallelic loss, and clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small fraction of cells (typically <1%), the myriad mutant clones in each donor amounted to a substantial fraction of B cells harbouring driver mutations.

Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution, providing new insights into the molecular basis of autoimmune disease."

Hidden mutations in immune cells linked to autoimmune disease "Mutations in immune cells may be the missing piece in the autoimmune disease puzzle."

Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity (no public access)

New Study Reveals Mechanism Behind Persistent Autoimmune Joint Destruction

Good news!

"Nearly 1.5 million Americans and nearly 5% of women over the age of 55 have rheumatoid arthritis (RA), an incurable autoimmune disease marked by joint inflammation and subsequent damage. ...

T lymphocytes ... the study found that some of these lymphocytes have a receptor for the immune hormone macrophage migration inhibitory factor, or MIF, on their surface.

Previous research has shown that many individuals with autoimmunity have overactive forms of the MIF gene ...

The researchers discovered that these T lymphocytes are expanded in mouse models of joint inflammation and that simply transferring these particular cells to healthy mice caused RA-like joint inflammation. The research team went on to identify these novel MIF-sensitive T lymphocytes in joint tissue from patients with RA who needed joint replacement.

“These T lymphocytes persist in the joints and have the characteristic of memory cells, meaning they retain their autoimmune properties long after the initial inflammatory response dies down, either spontaneously or after drug treatment,” ...

During a relapse of RA, joint inflammation often redevelops first in the same joints that were previously affected by disease. These particular memory T lymphocytes may explain this phenomenon ... The findings also suggest that the persistence of these memory lymphocytes is responsible for the continued, gradual joint destruction in many patients with RA who are in remission and feel well. ..."

From the significance and abstract:

"Significance

The significance of our presented work supports the notion that MIF-dependent, CD74+ memory T cells mediate the chronicity of rheumatoid synovitis and the preferential relapse of disease in previously involved joints. Targeting of the MIF/CD74 signaling pathway in T cells may be therapeutically beneficial, particularly in those individuals with high expression MIF alleles, which occur in approximately 20% of individuals.

Abstract

High expression alleles of the innate cytokine, macrophage migration inhibitory factor (MIF), are associated with the development or the severity of autoimmune inflammatory diseases, including rheumatoid arthritis.

Numerous studies support MIF’s role in activating inflammatory pathways and MIF inhibition reduces joint pathology in different experimental models of arthritis.

We examined the impact of gene deletion of MIF or its cognate receptor CD74 in the T cell–dependent model of collagen-induced arthritis (CIA) and observed the complete absence of arthritis development, suggesting an unforeseen role for MIF/CD74 signaling in the development of arthritogenic T cells.

While MIF has been shown in model systems to contribute to T cell activation by augmenting innate responses, fewer than 1% of T lineage cells express CD74 in naive spleens and lymph nodes, and its functional consequences in pathogenic T cell subpopulations have not been studied.

We found CD74+ T cells to expand during CIA and to increase in number within joint synovium, where they express an effector memory phenotype and recapitulate CIA development upon transfer into naive mice.

We further found evidence for the presence of CD74+ T cells in the circulation and joint synovium of patients with rheumatoid arthritis.

MIF-dependent, CD74+ T cells may contribute to the chronicity of rheumatoid synovitis and to disease relapse in previously inflamed joints."

New Yale Study Reveals Mechanism Behind Persistent Autoimmune Joint Destruction | Internal Medicine

Pathogenic role of MIF receptor (CD74) expressing T cells in inflammatory arthritis (no public access)

Apparently, Google is able to show some of the images from this PNAS research article, but only blurred (see below). This is not very nice! I have noticed this many times before with other research articles.

Study uncovers immune switch for cancer and autoimmunity

Good news! This could be a breakthrough. Cancer is history (soon)!

"... A single signaling pathway controls whether immune cells attack or befriend cells they encounter while patrolling our bodies, researchers ... have found. Manipulating this pathway could allow researchers to toggle the immune response to treat many types of diseases, including cancers, autoimmune disorders, and those that require organ transplants. ...

The critically important building of immune tolerance to “self” is a two-step process.
The first, called central immune tolerance, occurs in the bone marrow and the thymus where B cells and T cells undergo a first round of selection to eliminate or reprogram self-reactive cells before they are released into the bloodstream.
The second, peripheral immune tolerance, serves as a backup to screen circulating cells that escape the first culling. ...

The immune system’s response – threatening or welcoming – is governed by the Tregs, which tamp down inappropriate attack impulses of other immune cells called T and B cells. ... “We not only discovered this mechanism, but we also learned how it can be turned on and off.” ...

Type 1 conventional dendritic cells, or cDC1s, specialize in engulfing dead or dying cells or pathogens and displaying bits of those cells like immunological fishing lures for T cells.

To learn how cDC1s are involved in the development of immune tolerance, ... to investigate whether and how the genes they express change in mice after total lymphoid irradiation. They found that the gene encoding the receptor for erythropoietin – EPOR, is expressed at much higher levels in the cDC1s of irradiated animals, and that the levels of EPO are elevated in the animals’ blood circulation. ...

Normally, this would have been a huge surprise. Erythropoietin is well known as the primary instigator of red blood cell production, and it was named for this function (erythro meaning “red” and poietin meaning “to produce”). But [researchers] now show that signaling through EPOR in cDC1s – the antigen-presenting cells that orchestrate T-cell responses to cell-associated antigens – acts as a central switch controlling immune tolerance.
In earlier work, the same researchers demonstrated that EPO produced by immunologically “cold” tumors can suppress antitumor immunity by acting on macrophages. Together, these discoveries establish the EPO-EPOR axis as a fundamental regulator of immune balance, extending its influence from dendritic cell-mediated T-cell programming to broader immune regulation.

When ... genetically manipulated the mice to remove the ability of the cDC1s to express the EPOR, the animals rejected transplants of unmatched tissue after total lymphoid irradiation, showing conclusively that the EPO signaling pathway is necessary for the development of immune tolerance. But there was another intriguing finding.

“What was quite a surprise to me is that when you remove or block the EPO receptor on the cDC1s, you don’t just block the development of tolerance,” ... “Instead, you have now converted these cDC1s into super stimulators, or powerful activators of immune response. There is a dual opportunity to not just induce tolerance to treat autoimmune diseases, but also to trigger a strong immune response to cancer cells or to life-threatening infections.” ..."

From the abstract:

"Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis and cross-presenting abilities, resulting in antigen-specific T cell immunity or tolerance. However, the mechanisms that underlie cDC1 tolerogenic function remain largely unknown.

Here we show that the erythropoietin receptor (EPOR) acts as a critical switch that determines the tolerogenic function of cDC1s and the threshold of antigen-specific T cell responses.

In total lymphoid irradiation-induced allograft tolerance, cDC1s upregulate EPOR expression, and conditional knockout of EPOR in cDC1s diminishes antigen-specific induction and expansion of FOXP3+ regulatory T (Treg) cells, resulting in allograft rejection.

Mechanistically, EPOR promotes efferocytosis-induced tolerogenic maturation of splenic cDC1s towards late-stage CCR7+ cDC1s characterized by increased expression of the integrin β8 gene (Itgb8), and conditional knockout of Itgb8 in cDC1s impairs tolerance induced by total lymphoid irradiation plus anti-thymocyte serum.

Migratory cDC1s in peripheral lymph nodes preferentially express EPOR, and their FOXP3+ Treg cell-inducing capacity is enhanced by erythropoietin. Reciprocally, loss of EPOR enables immunogenic maturation of peripheral lymph node migratory and splenic CCR7+ cDC1s by upregulating genes involved in MHC class II- and class I-mediated antigen presentation, cross-presentation and costimulation.

EPOR deficiency in cDC1s reduces tumour growth by enhancing anti-tumour T cell immunity, particularly increasing the generation of precursor exhausted tumour antigen-specific CD8+ T cells in tumour-draining lymph nodes and supporting their maintenance within tumours, while concurrently reducing intratumoural Treg cells. Targeting EPOR on cDC1s to induce or inhibit T cell immune tolerance could have potential for treating a variety of diseases."

Study uncovers immune switch for cancer and autoimmunity | Stanford Report "Researchers found that a key molecule involved in red blood cell production governs whether the immune system attacks or tolerates cells, revealing potential treatments for autoimmune diseases and cancer."

Erythropoietin receptor on cDC1s dictates immune tolerance (no public access)

Scientists tie lupus to a virus nearly all of us carry, the Epstein-Barr virus

Good news!

"One of humanity’s most ubiquitous infectious pathogens bears the blame for the chronic autoimmune condition called systemic lupus erythematosus or, colloquially, lupus, Stanford Medicine investigators and their colleagues have found.

The Epstein-Barr virus (EBV), which resides silently inside the bodies of 19 out of 20 Americans, is directly responsible for commandeering what starts out as a minuscule number of immune cells to go rogue and persuade far more of their fellow immune cells to launch a widespread assault on the body’s tissues, the scientists have shown. ..."

"... Transmitted in saliva, EBV infection typically occurs in childhood, from sharing a spoon with or drinking from the same glass as a sibling or a friend, or maybe during our teen years, from exchanging a kiss. EBV can cause mononucleosis, “the kissing disease,” which begins with a fever that subsides but lapses into a profound fatigue that can persist for months. ..."

From the editor's summary and abstract:

"Editor’s Summary

Epstein-Barr virus (EBV) has been making waves as a candidate driver of diseases like multiple sclerosis and Long Covid. It has also long been linked to systemic lupus erythematosus (SLE), although the “why” behind this link has not been defined. Here, Younis et al. provide evidence for a link between EBV infection and disease development. The authors found, using a new strategy to identify EBV-infected cells by RNA sequencing, that infected B cells were transcriptionally distinct from their uninfected counterparts.

EBV-infected B cells exhibited features associated with antigen presentation, and this programming seemed likely to be directly driven by the EBV protein EBNA2. These EBV-infected B cells with antigen-presenting abilities had the capacity to activate autoreactive helper T cells, setting off a chain reaction where those T cells could activate other autoreactive B cells, including uninfected ones. In vitro studies in B cell lines provided functional support for this hypothesis. These data suggest that EBV infects and reprograms autoreactive B cells that, in turn, drive the systemic autoimmune response in SLE.  ...

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by antinuclear antibodies (ANAs). Epstein-Barr virus (EBV) infection has been epidemiologically associated with SLE, yet its role in pathogenesis remains incompletely defined.

Here, we developed an EBV-specific single-cell RNA-sequencing platform and used it to demonstrate that EBV infection reprograms autoreactive antinuclear antigen B cells to drive autoimmunity in SLE. We demonstrated that, in SLE, EBV+ B cells are predominantly CD27+CD21low memory B cells that are present at increased frequencies and express ZEB2, TBX21 (T-bet), and antigen-presenting cell transcriptional pathways.

Integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and RNA polymerase II occupancy data revealed EBV nuclear antigen 2 (EBNA2) binding at the transcriptional start sites and regulatory regions of CD27, ZEB2, and TBX21, as well as the antigen-presenting cell genes demonstrated to be up-regulated in SLE EBV+ B cells.

We expressed recombinant antibodies from SLE EBV+ B cells and demonstrated that they bind prototypical SLE nuclear autoantigens, whereas those from healthy individuals do not.

We further found that SLE EBV+ B cells can serve as antigen-presenting cells to drive activation of T peripheral helper cells with concomitant activation of related EBV− antinuclear double-negative 2 B cells and plasmablasts.

Our results provide a mechanistic basis for EBV being a driver of SLE through infecting and reprogramming nuclear antigen-reactive B cells to become activated antigen-presenting cells with the potential to promote systemic disease–driving autoimmune responses."

Stanford Medicine scientists tie lupus to a virus nearly all of us carry "The Epstein-Barr virus can convert B cells it’s infected into diabolical overlords that reprogram myriad other immune cells to attack our tissues, Stanford Medicine scientists have found."

Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus (no public access)

‘Disease in a dish’ study of progressive MS finds critical role for unusual type of brain cell

Good news!

"... To model what is happening in the disease, researchers ... took skin cells from patients with progressive MS and reprogrammed them into induced neural stem cells (iNSCs), an immature type of cell capable of dividing and differentiating into various types of brain cells.

Using this ‘disease in a dish’ approach, the team observed that a subset of the cultured brain cells was somehow reverting to an earlier developmental stage, transforming into an unusual cell type known as radial glia-like (RG-like) cells. Notably, these cells were highly specific and appeared approximately six times more frequently in iNSC lines derived from individuals with progressive MS compared to controls. As a result, they were designated as disease-associated RG-like cells (DARGs). ...

Unexpectedly, DARGs not only revert to an ‘infant’ state but also display hallmark features of premature aging, or senescence.

These newly identified DARGs possess a distinctive epigenetic profile—patterns of chemical modifications that regulate gene activity—although the factors influencing this epigenetic landscape remain unclear. These modifications contribute to an exaggerated response to interferons, the immune system’s ‘alarm signals,’ which may help explain the high levels of inflammation observed in MS. ..."

From the highlights and abstract:

"Highlights

• Human iNSCs maintain epigenetic age with high fidelity

• PMS fibroblasts and iNSCs share hypomethylated genes driving IFN signaling

• PMS iNSCs harbor senescent, IFN-responsive RG-like cells that promote inflammation

• Non-neurogenic senescent DARGs are found in lesions of people with PMS

Summary

Progressive multiple sclerosis (PMS) involves a persistent, maladaptive inflammatory process with numerous cellular drivers.

We generated induced neural stem cells (iNSCs) from patient fibroblasts through a direct reprogramming protocol that preserved their epigenome, which revealed a PMS-specific hypomethylation of lipid metabolism and interferon (IFN) signaling genes.

Single-cell multi-omics uncovered a novel, disease-associated radial glia-like cell (DARG) subpopulation in PMS cell lines exhibiting senescence and potent IFN responsiveness driven by specific transcription factors.

Functionally, PMS iNSCs induced paracrine senescence and inflammation onto control cells, which was inhibited upon senolytic treatment.

We identified in PMS brains a distinct population of senescent, IFN-responsive DARGs that developmentally aligned with the trajectories of iNSCs in vitro and spatially associated with inflammatory glia in chronically active lesions.

DARGs may sustain smoldering inflammation, unveiling a previously unrecognized cellular axis that could underpin mechanisms in neurodegeneration. This discovery offers novel insights into disease mechanisms and highlights potential therapeutic targets."

‘Disease in a dish’ study of progressive MS finds critical role for unusual type of brain cell | University of Cambridge "Scientists have identified an unusual type of brain cell that may play a vital role in progressive multiple sclerosis (MS), likely contributing to the persistent inflammation characteristic of the disease."

Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis (open access)

Graphical abstract

New study reveals rheumatoid arthritis begins long before symptoms, opening door to prevention

Good news!

"... It silently starts years earlier. RA is a debilitating autoimmune disease that causes painful joint inflammation and damage. The new research reveals that people at risk for RA experience dramatic immune system changes long before they feel symptoms. During this early phase, their bodies fight an autoimmune battle invisibly. ..."

From the editor's summary and abstract:

"Editor’s summary

Individuals who go on to develop rheumatoid arthritis (RA) experience a stage of disease development before clinical onset where they develop anticitrullinated protein antibodies (ACPAs). However, not all ACPA+ individuals go on to develop clinical RA. Here, He et al. investigated what distinguished those individuals who are ACPA+ and go on to develop disease. They found that systemic inflammation and dysregulation of the B and T cell pools during the at-risk stage were associated with subsequent RA development. These data offer insights into the immune system in individuals who go on to develop RA and may enable the development of treatments to prevent RA before clinical disease. ...

Abstract

Rheumatoid arthritis (RA) is preceded by an at-risk stage of disease that can be marked by the presence of anticitrullinated protein antibodies (ACPAs) but the absence of clinically apparent synovitis (clinical RA). Preemptive intervention in at-risk individuals could prevent or delay future tissue damage; however, the immunobiology of this stage is unclear.

Using integrative multiomics, we longitudinally profiled at-risk individuals, where one-third of participants developed clinical RA on study. We found evidence of systemic inflammation and signatures of activation in naïve T and B cells of at-risk individuals.

During progression to clinical RA, proinflammatory skewing of atypical B cells and expansion of memory CD4 T cells with signatures of activation and B cell help were present without elevations in circulating ACPA titers. Epigenetic changes in naïve CD4 T cells suggested a predisposition to differentiate into effector cells capable of B cell help.

These findings characterize pathogenesis of the ACPA+ at-risk stage and support the concept that the disease begins much earlier than clinical RA. Additionally, an extensive immune resource of the at-risk stage and progression to clinical RA with interactive tools was developed to enable further investigation."

New study reveals rheumatoid arthritis begins long before symptoms, opening door to prevention  - Allen Institute "The seven-year study reveals early-warning signs that could help doctors catch the disease before it starts, potentially saving patients years of pain and disability"

Systemic Inflammation in At-Risk Individuals Advancing to Clinical Rheumatoid Arthritis

Progression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation (no public access)

Novel narrow-spectrum antibiotic targets inflammatory bowel diseases (IBD) and AI predicted how it works

Good news!

"Researchers ... have made two scientific breakthroughs at once: they not only discovered a brand-new antibiotic that targets inflammatory bowel diseases (IBD), but also successfully used a new type of AI to predict exactly how the drug works. To their knowledge, this is a global first for the AI. ...

Most antibiotics used in clinics today are "broad-spectrum" drugs, meaning they wipe out good bacteria in addition to those that cause disease ...

But enterololin, the new antibiotic discovered ... is a "narrow-spectrum" drug, meaning it spares the microbiome and attacks only a specific group of disease-causing bugs—in this case, a family of bacteria called Enterobacteriaceae, which happens to include E. coli. ...

thorough MOA [mechanism of action] study can take up to two years and cost around $2 million; however, using AI, his group did enterololin's in just six months and for just $60,000. ...

In just 100 seconds, he was given a prediction: his new drug attacked a microscopic protein complex called LolCDE, which is essential to the survival of certain bacteria. ..."

"... DiffDock, a generative AI model ...

DiffDock was designed to predict how small molecules fit into the binding pockets of proteins, a notoriously difficult problem in structural biology. Traditional docking algorithms search through possible orientations using scoring rules, often producing noisy results. DiffDock instead frames docking as a probabilistic reasoning problem: a diffusion model iteratively refines guesses until it converges on the most likely binding mode.

“In just a couple of minutes, the model predicted that enterololin binds to a protein complex called LolCDE, which is essential for transporting lipoproteins in certain bacteria,” ...

put that prediction to the test. Using DiffDock predictions as an experimental GPS, they first evolved enterololin-resistant mutants of E. coli in the lab, which revealed that changes in the mutant’s DNA mapped to lolCDE, precisely where DiffDock had predicted enterololin to bind.

They also performed RNA sequencing to see which bacterial genes switched on or off when exposed to the drug, 

as well as used CRISPR to selectively knock down expression of the expected target. These laboratory experiments all revealed disruptions in pathways tied to lipoprotein transport, exactly what DiffDock had predicted. ..."

From the abstract:

"Current clinical antibiotics are largely broad-spectrum agents that can alter the gut microbiome and promote colonization by Enterobacteriaceae, which are often drug resistant. This includes adherent-invasive Escherichia coli (AIEC), particularly in patients with inflammatory bowel disease, in which dysbiosis creates a niche for this pathogen to colonize. There is an urgent and unmet need for novel narrow-spectrum and microbiome-sparing antibiotics.

Here we screened 10,747 bioactive small molecules for antibacterial activity against AIEC and discovered enterololin, an antibacterial compound with targeted activity against Enterobacteriaceae species. Enterololin could overcome intrinsic and acquired resistance mechanisms in clinical isolates when combined with a subinhibitory concentration of SPR741, a polymyxin B analogue used here to increase outer membrane permeability in Gram-negative bacteria.

Molecular substructure- and deep learning-guided mechanism-of-action investigations revealed that enterololin perturbs lipoprotein trafficking through a mechanism involving the LolCDE complex, laboratory-evolved resistant mutants predominantly mapped to lolC and lolE, with an in vitro frequency of resistance of ~10−8 to 10−7.

Enterololin showed low mammalian cytotoxicity (HEK293 half-maximal inhibitory concentration ~100 µg ml−1) and suppressed AIEC infection in mouse models when administered in combination with SPR741, while largely preserving the overall microbiome composition.

This study highlights the utility of deep learning methods for predicting molecular interactions and identifies a promising Enterobacteriaceae-specific antibacterial candidate for further development."

Novel antibiotic targets IBD—and AI predicted how it would work before scientists could prove it

Researchers discover new antibiotic for IBD — and AI correctly predicts how it works (original news release) "McMaster researchers have discovered an antibiotic that targets inflammatory bowel diseases like Crohn’s. Then, in a first, they used cutting-edge AI to determine how it would work."

AI maps how a new antibiotic targets gut bacteria (original news release) "MIT CSAIL and McMaster researchers used a generative AI model to reveal how a narrow-spectrum antibiotic attacks disease-causing bacteria, speeding up a process that normally takes years."

Discovery and artificial intelligence-guided mechanistic elucidation of a narrow-spectrum antibiotic (no public access)

How fast mRNA degrades linked to autoimmune disease risk

Good news! This is early, but promising research!

"Key takeaways

• Messenger RNA copies and carries instructions from the DNA in the cell’s nucleus to where protein is made. More mRNA usually means more protein — unless the mRNA is unstable and breaks down too quickly.
• Mutations in the DNA can affect the production and stability of mRNA, which influences how much protein a cell produces and a person’s risk of disease. 
• UCLA researchers have identified genetic mutations that influence mRNA stability. Many of these genes are involved in immune system function.

... [mRNA] is produced, it does its job, and then it’s destroyed. But most research has focused on how mRNA is made. Much less attention has been paid towards how fast it’s degraded — and that’s just as important.”

Both the production and stability of mRNA can be affected by mutations in the DNA, which are commonly referred to as genetic variants. These variants can affect how much protein a cell makes, and in turn, influence a person’s risk of disease. But figuring out whether a variant affects how much mRNA is made — or how long it survives — has been a major challenge. ...

The team also found that several of the genetic variants linked to unstable mRNA had already been associated with autoimmune diseases in large-scale genetic studies. ...

Using additional modeling, the researchers linked expression levels of these stability-regulated genes to diseases including allergic rhinitis, lupus, diabetes mellitus and multiple sclerosis. The findings suggest that mRNA stability — long overlooked — may be a key mechanism behind many immune-related diseases. ..."

From the abstract:

"Gene expression is modulated jointly by transcriptional regulation and messenger RNA stability, yet the latter is often overlooked in studies on genetic variants. Here, leveraging metabolic labeling data (Bru/BruChase-seq) and a new computational pipeline, RNAtracker, we categorize genes as allele-specific RNA stability (asRS) or allele-specific RNA transcription events.

We identify more than 5,000 asRS variants among 665 genes across a panel of 11 human cell lines.

These variants directly overlap conserved microRNA target regions and allele-specific RNA-binding protein sites, illuminating mechanisms through which stability is mediated.

Furthermore, we identified causal asRS variants using a massively parallel screen (MapUTR) for variants that affect post-transcriptional mRNA abundance, as well as through CRISPR prime editing approaches.

Notably, asRS genes were enriched significantly among a multitude of immune-related pathways and contribute to the risk of several immune system diseases. This work highlights RNA stability as a critical, yet understudied mechanism linking genetic variation and disease."

How fast mRNA degrades linked to autoimmune disease risk | UCLA "A UCLA study showed genes affecting mRNA stability are also related to disorders such as lupus, diabetes and multiple sclerosis"

Genetic variants affecting RNA stability influence complex traits and disease risk (no public access)

Natural killer cells could reset immune system to fight autoimmune diseases

Good news!

"Immune cells called ‘natural killer’ (NK) cells could be supercharged to attack cells that fuel autoimmune diseases such as lupus and systemic sclerosis. Two small clinical trials suggest that researchers can genetically engineer NK cells to assassinate the renegade cells that produce antibodies against the body’s own tissues. NK cells can be taken from donor blood, making the treatment potentially much cheaper than another, similar approach called CAR-T-cell therapy, which must be manufactured from a person’s own T cells."

From the highlights and abstract:

"Highlights

• QN-139b is an iPSC-derived CD19/BCMA dual-targeting CAR-NK product

• QN-139b showed minimal toxicity in a patient with severe refractory systemic sclerosis

• QN-139b reversed fibrosis and restored skin and vascular structure in the patient

• QN-139b reduced autoantibodies, depleted pathogenic B cells, and induced immune rest

Summary

This study reports the first-in-human application of iPSC-derived CD19/BCMA dual-targeting chimeric antigen receptor-natural killer (CAR-NK) cells (QN-139b) in a patient with severe, diffuse cutaneous systemic sclerosis. The allogeneic product was genetically edited for reduced alloreactivity and improved in vivo performance, with no structural chromosomal abnormalities detected. The treatment led to significant B cell depletion with minimal toxicity, similar to CAR T cell therapy.

The patient showed marked clinical improvements during the 6-month follow-up, including reduced autoantibodies and reversed fibrosis, which are resistant to conventional treatments.

Single-cell analysis of peripheral blood revealed that the treatment shifted B cells toward more naive phenotypes and eliminated pathogenic B cells.

Proteomic studies demonstrated suppression of inflammation and fibrosis, enhanced tissue regeneration, and improved angiogenesis.

Pathological evaluation confirmed the elimination of infiltrated lymphocytes from affected skin along with restored skin and microvascular structure.

These findings suggest QN-139b is a promising immune-modulatory treatment for severe autoimmune diseases."

Nature Briefing: Translational Research

Turbocharged ‘killer’ cells show promise for autoimmune disease "Experimental treatment could offer a safer, cheaper alternative to CAR-T-cell therapies for disorders such as lupus."

An iPSC-derived CD19/BCMA CAR-NK therapy in a patient with systemic sclerosis

Graphical abstract

Discover New ‘Molecular Glues’ as a Possible Therapeutic Approach for Autoimmune Conditions

Good news! Amazing stuff!

"“Molecular glues are an exciting new area of research that allows us to fight disease by working with the body’s systems rather than against them.”  ... “By gluing together an inactive form of the BRISC complex with our system, we’re able to reduce the continuous inflammatory signaling due to dysregulated BRISC complex activity in autoimmune diseases.”

Deubiquitylases, or DUBs, are enzymes that regulate protein stability; A DUB removes the “ubiquitin mark” on a protein, normally targeting it for degradation, thereby stabilizing the protein resulting in aberrant signaling.

Certain diseases, such as lupus, are due to aberrant inflammatory signaling. Approaches targeting this dysregulated DUB activity are expected to balance protein homeostasis and lead to pathogenic outcomes. Scientists are interested in methods that could therapeutically intervene to reduce DUB dysregulation and its pathogenic effects; however, until now, targeting DUB dysregulation has been challenging with small-molecule approaches due to lack of specificity and side effects. ...

a different approach to overcoming the challenge with a new technology termed Molecular Glue. Unlike inhibitory small molecules, which block the active processing site of an enzyme, molecular glues facilitate the formation of protein complexes. In this paper, the research team applied the molecular glue approach, for the first time, to form an inactive complex against pathological inflammatory signaling due to aberrant DUB activity.

A DUB in humans called BRISC complex regulates inflammatory signaling. When BRISC becomes dysregulated, excessive inflammation can flare up, and research suggests that BRISC dysregulation contributes to the persistent inflammation in autoimmune conditions like lupus.

After an initial high-throughput screen, ... identified compounds that functioned as molecular glues that selectively stabilize BRISC in a biologically inactive complex, which they confirmed with high-resolution cryo-electron microscopy and mass spectrometry. The BRISC molecular glues, or BLUEs, bind to BRISC in a way that causes it to form an inactive complex. The BLUE-induced inactive BRISC complex can no longer stabilize inflammatory signaling, caused by aberrant BRISC activity. The deactivated complex allows the ubiquitinated inflammatory signaling protein to be degraded under normal protein homeostasis conditions.

In preclinical testing, the researchers confirmed that the BLUEs were successful in reducing interferon signaling (a potent inflammatory response). This finding was particularly notable for reducing interferon signaling in blood samples from patients with scleroderma, an autoimmune disease in which interferon responses are abnormally elevated. ..."

From the abstract:

"Deubiquitylases (DUBs) are crucial in cell signaling and are often regulated by interactions within protein complexes.

The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signaling by cleaving K63-linked polyubiquitin chains on type I interferon receptors (IFNAR1).

As a Zn2+-dependent JAMM/MPN (JAB1, MOV34, MPR1, Pad1 N-terminal) DUB, BRCC36 is challenging to target with selective inhibitors.

Here, we discover first-in-class inhibitors, termed BRISC molecular glues (BLUEs), which stabilize a 16-subunit human BRISC dimer in an autoinhibited conformation, blocking active sites and interactions with the targeting subunit, serine hydroxymethyltransferase 2.

This unique mode of action results in selective inhibition of BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs.

BLUE treatment reduced interferon-stimulated gene expression in cells containing wild-type BRISC and this effect was abolished when using structure-guided, inhibitor-resistant BRISC mutants.

Additionally, BLUEs increase IFNAR1 ubiquitylation and decrease IFNAR1 surface levels, offering a potential strategy to mitigate type I interferon-mediated diseases.

Our approach also provides a template for designing selective inhibitors of large protein complexes by promoting rather than blocking protein–protein interactions."

The Wistar Institute, The University of Leeds, and the Perelman School of Medicine Discover New ‘Molecular Glues’ as a Possible Therapeutic Approach for Autoimmune Conditions - The Wistar Institute "The Collaborative Discovery Could Help Mitigate Inflammation in Autoimmune Diseases"

Molecular glues that inhibit deubiquitylase activity and inflammatory signaling (open access)

Fig. 7: Proposed model of BLUE compound mode of action.

Out-of-balance bacteria is linked to multiple sclerosis − the ratio can predict severity of disease

Good news!

"... Scientists have long suspected that gut bacteria may influence a person’s risk of developing multiple sclerosis. But studies so far have had inconsistent findings.

To address these inconsistencies, my colleagues and I used what researchers call a bedside-to-bench-to-bedside approach: starting with samples from patients with multiple sclerosis, conducting lab experiments on these samples, then confirming our findings in patients.

In our newly published research, we found that the ratio of two bacteria in the gut can predict multiple sclerosis severity in patients, highlighting the importance of the microbiome and gut health in this disease. ..."

From the significance and abstract:

"Significance

We demonstrate the heterogeneity of the gut microbiome in multiple sclerosis (MS) patients, characterized by the enrichment of Blautia and Akkermansia species. Using a mouse model of MS, we identified that a reduced Bifidobacterium to Akkermansia ratio served as a gut microbial marker of disease severity. Administering MS-associated Blautia species in mice altered this ratio and strongly correlated with disease scores, underscoring its potential in predicting severity. The lower Bifidobacterium to Akkermansia ratio at the species level, Bifidobacterium adolescentis to Akkermansia muciniphila (BA:AM), was validated in our human cohort and the larger International Multiple Sclerosis Microbiome Study (iMSMS). These findings highlight the BA:AM ratio’s promise as a microbial marker for microbiome-based diagnostics and therapeutic interventions in MS.

Abstract

Gut microbiota dysbiosis is associated with multiple sclerosis (MS), but the causal relationship between specific gut bacteria and MS pathogenesis remains poorly understood. Therefore, we profiled the stool microbiome of people with MS (PwMS) and healthy controls (HC) using shotgun metagenomic sequencing. 

PwMS showed a distinct microbiome compared to HC, with Prevotella copri (PC) and Blautia species as drivers of microbial communities in HC and PwMS, respectively.

Administration of MS-driving Blautia species (Blautia wexlerae; BW) to mice resulted in increased levels of gut inflammatory markers and altered microbiota with increased capacity to induce proinflammatory cytokines. 

Utilizing experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we identified a lower gut Bifidobacterium to Akkermansia ratio as a hallmark of the disease. BW-administered mice also showed a lower Bifidobacterium to Akkermansia ratio pre-EAE induction which correlated with increased disease severity post-EAE induction.

The importance of the Bifidobacterium to Akkermansia ratio at the species level, lower Bifidobacterium adolescentis to Akkermansia muciniphila (BA:AM), was validated in our MS cohort and a large International Multiple Sclerosis Microbiome Study. Thus, our findings highlight the BA:AM ratio as a potential gut microbial marker in PwMS, opening avenues for microbiome-based diagnosis, prognosis, and therapy in MS."

Out-of-balance bacteria is linked to multiple sclerosis − the ratio can predict severity of disease

Specific microbial ratio in the gut microbiome is associated with multiple sclerosis (no public access)

Bioengineered CAR T quashes severe autoimmune diseases

Good news! If these great results are confirmed by more trials, this could be a breakthrough! The cost for such treatments could be significantly lowered!

"Three people with severe autoimmune diseases are in remission after being treated with bioengineered and CRISPR-modified immune cells called chimeric antigen receptor (CAR) T cells. They are the first to be treated with engineered immune cells from donors. The advance could represent the first step towards mass production of CAR-T therapies for conditions such as lupus and multiple sclerosis. The ongoing success and safety of the therapy need to be demonstrated in more people before it can be considered for wider use, but it “could prove paradigm shifting” ..."

"... The three individuals from China are the first people with autoimmune disorders to be treated with engineered immune cells created from donor cells, rather than ones collected from their own bodies. This advance is the first step towards mass production of such therapies. ...

If successful, they would allow pharmaceutical companies to scale up manufacturing, potentially slashing costs and production times. Instead of making one treatment for one person, therapies for more than a hundred people could be made from one donor’s cells ..."

From the highlights and abstract:

"Highlights

• TyU19 is a genetically engineered, healthy donor-derived CD19-targeting CAR-T product

• TyU19 caused B cell depletion in three patients with refractory autoimmune diseases

• TyU19 alleviated severe skeletal muscle damage in a patient with refractory IMNM

• TyU19 reversed extensive fibrotic damage to critical organs in two patients with dcSSc

Summary

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases."

Nature Briefing: Translational Research

World-first therapy using donor cells sends autoimmune diseases into remission "The treatment’s success in three people raises hopes for mass production of cutting-edge CAR T therapies."

Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis (no public access)

Graphical abstract

Engineered immune cells, called CAR T cells (yellow), have revolutionized treatment for some tumours (pink) and show promise for treating autoimmune conditions.