Putting science to work for the health of women

Office of Autoimmune Disease Research (OADR-ORWH)

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Approximately 8% of the U.S. population is living with an autoimmune disease, and nearly 80% of those with an autoimmune disease are women. [1]   The category of autoimmune diseases includes between 80 and 150 conditions (depending on the source) that are chronic and in many cases debilitating—with no known cures. [2]   These diseases can affect almost every organ in the body and can occur at any point across the lifespan. [3]   Despite the large burden of disease, many autoimmune diseases are understudied, and treatment options are limited. 

To accelerate progress in this area, in 2022, the U.S. Congress directed NIH to establish an Office of Autoimmune Disease Research within ORWH.

As described in the Consolidated Appropriations Acts, 2023 ( Public Law 117-328 ) for the departments of Labor, Health and Human Services, and Education, and related agencies, the Office of Autoimmune Disease Research (OADR-ORWH) will:

  • Coordinate development of a multi–institute and center (IC) strategic research plan; 
  • Identify emerging areas of innovation and research opportunity; 
  • Coordinate and foster collaborative research across ICs; 
  • Annually evaluate the NIH autoimmune disease research (ADR) portfolio; 
  • Provide resources to support planning, collaboration, and innovation; and 
  • Develop a publicly accessible central repository for ADR. 

These directives—along with the findings of the National Academies of Sciences, Engineering, and Medicine (NASEM) report titled Enhancing NIH Research on Autoimmune Disease —guide the establishment of the office. 

Currently, ADR expertise is housed across various NIH institutes, centers, and offices (ICOs) in alignment with their mission areas. Establishing OADR-ORWH within the NIH Office of the Director (OD) positions it well to amplify and integrate individual ICO efforts and create opportunities for collective innovation. 

OADR-ORWH’s mission will echo that of the overarching mission of NIH— to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability .

Dr. Shanmugam is an experienced physician-scientist, rheumatologist, and academic leader. She graduated from Oxford University with a B.A. in physiology and completed her medical degree at Imperial College School of Medicine in London, graduating with honors in medicine. She is a member of the Royal College of Physicians in London. Dr. Shanmugam completed the Internal Medicine Residency and Rheumatology Fellowship at Georgetown University and joined the faculty of Georgetown University School of Medicine in 2007. She previously served as Director of Rheumatology at the George Washington University. Learn more about Dr. Shanmugam’s extensive experience in the field of autoimmune diseases here .  

Want to learn more about OADR and the OADR Team? 

  • Join Dr. Shanmugam quarterly for virtual Updates on OADR-ORWH. Learn more here . 
  • Read Dr. Shanmugam’s guest editorial in ORWH’s publication, In Focus .   

Autoimmune diseases occur when the body’s immune system malfunctions and mistakenly attacks the body’s healthy cells, tissues, and organs.  

Autoimmune diseases include at least 80 acute and chronic illnesses that are often disabling, such as Sjögren’s disease, systemic lupus erythematosus (SLE), antiphospholipid syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD), celiac disease, primary biliary cholangitis, multiple sclerosis, type 1 diabetes, and autoimmune thyroid disease. For more information, refer to the 2022 NASEM report  Enhancing NIH Research on Autoimmune Disease  .  

Sex- and gender-specific differences in the prevalence and expression of autoimmune diseases underscore the critical importance of recognizing  sex and gender as factors in health and disease  at every stage of the research process.

The reasons underlying the higher prevalence of autoimmune diseases in women are not yet understood. [4]  In addition, not all autoimmune diseases act the same; some autoimmune diseases are many times more prevalent in women, and some affect men and women at similar rates. These diseases also affect males and females differently.  

Though the complex factors underlying these differences are not yet clear, a growing body of research has documented significant sex differences in the immune system which contribute to the sex differences observed in the symptoms, expression, treatment response, and prevalence of autoimmune diseases. For example, women tend to have a more robust immune response than men, which may contribute to improved outcomes in infectious diseases and greater vulnerability to autoimmune diseases. [5]  Psychosocial and cultural factors, as well as environmental exposures, may also contribute to the risk of developing autoimmune diseases. More research is needed to understand how these factors contribute to autoimmune disease development.

Recognizing sex and gender as factors in health and disease at every stage of the research process is a critical part of ORWH’s mission.

Learn more about the  influences of sex and gender in health and disease .

Learn more about sex differences in immunology with Module 1 of ORWH’s  Bench to Bedside  course. (Registration is free and open to the public.)  

4  Fairweather D, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective. Am J Pathol. 2008 Sep;173(3):600-9. doi: 10.2353/ajpath.2008.071008. Epub 2008 Aug 7. PMID: 18688037; PMCID: PMC2527069. 

5  vom steeg, l. g., & klein, s. l. (2016). sexx matters in infectious disease pathogenesis. plos pathogens, 12(2), e1005374.  https://doi.org/10.1371/journal.ppat.1005374    , chen, n., zhou, m., dong, x., qu, j., gong, f., han, y., et al. (2020). epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study. the lancet, 395(10223), 507–513.  https://doi.org/10.1016/s0140-6736(20)30211-7  , ngo, s. t., steyn, f. j., & mccombe, p. a. (2014). gender differences in autoimmune disease. frontiers in neuroendocrinology, 35(3), 347–369.  https://doi.org/10.1016/j.yfrne.2014.04.004   .

The direction to establish OADR-ORWH stemmed from recommendations from the NASEM report Enhancing NIH Research on Autoimmune Disease , which identified a need for greater coordination across NIH regarding autoimmune disease research. The report recommended that an Office of Autoimmune Disease Research be established within OD, and Congress selected ORWH to establish this office in because autoimmune diseases disproportionately affect women.

As one of the 14 cross-cutting offices in OD’s Division of Program Coordination, Planning, and Strategic Initiatives, ORWH is experienced and skilled at coordinating across NIH to create pathways for collaboration, foster collective innovation, and mobilize multidisciplinary efforts to advance the health of women. As a part of ORWH, OADR-ORWH will be able to leverage this existing expertise, infrastructure, and position to inform and amplify its efforts.   

ORWH is currently working to establish OADR-ORWH and lay the strategic and programmatic groundwork for future activities. In addition to meeting the immediate needs of staffing and infrastructure, OADR-ORWH is working with NIH leadership, other ICOs, researchers, clinicians, patient advocacy groups, and the general public to ensure that plans for the new office build upon congressional directives, synergize with other NIH efforts, address gaps in autoimmune disease research, and serve patients with autoimmune disorders. 

As part of this development process, OADR-ORWH is establishing the NIH-wide Coordinating Committee for Autoimmune Disease Research, which will provide a structured forum to leverage the autoimmune disease research expertise housed across different ICOs and offer a streamlined process for expanding collaboration across NIH.

OADR-ORWH has already coordinated the release of multiple funding opportunities related to autoimmune disease research. (See “Funding Opportunities” below.)

Per NIH standard practice, OADR-ORWH will develop a strategic plan for autoimmune disease research at NIH. Once preparatory efforts are complete, OADR-ORWH plans to release a request for information (RFI) to solicit public input to inform the strategic plan.

ADR is conducted by multiple ICOs at NIH, with particular focus from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Neurological Disorders and Stroke, and the National Heart, Lung, and Blood Institute. The ICOs support research on different aspects of autoimmune disease based on their mission areas and expertise. For example, the National Eye Institute supports basic, translational, and clinical studies of the causes and mechanisms of autoimmune diseases of the eye. The National Institute of Environment Health Sciences invests in research investigating environmental triggers of disease. The National Cancer Institute supports research investigating the link between cancer and the immune system. The National Human Genome Research Institute supports research that explores genetic influences on the development of autoimmune and inflammatory diseases. 

NIH-funded research across ICOs has helped advance knowledge of the basic mechanisms of the immune system, illuminate important sex differences in the immune system and immune response, and speed the development of treatments. For example, NIH-supported basic research on the immune system in the 1990s led to the development of Janus kinase (JAK) inhibitors—a class of drugs routinely used to treat a wide range of autoimmune disorders. To date, eight JAK inhibitors have been approved by the Food and Drug Administration (FDA) for treating a range of disorders. ( Learn more about the impact of NIH research .)

One example of existing ICO collaborative efforts for ADR is the Accelerating Medicines Partnership® Autoimmune and Immune-Mediated Diseases (AMP® AIM) . Launched in 2021, this program seeks to deepen our understanding of the cellular and molecular interactions that lead to inflammation and autoimmune diseases. This program is a collaboration among NIH, FDA, nonprofit organizations, and biopharmaceutical companies. Other examples of NIH-supported programs include the Autoimmunity Centers of Excellence (ACE) program and the Immune Tolerance Network .

As recommended by NASEM, an integrated NIH-wide approach will help advance progress in autoimmune disease research by amplifying the impact of the robust research already occurring within and across the ICOs. OADR-ORWH will provide the formal infrastructure and shared priorities to integrate and augment ICO efforts and create a more holistic foundation on which progress can be built.   

Future OADR-ORWH-supported research will most likely investigate genetics, environmental exposures, biomarkers, sex influences, co-occurring autoimmune diseases, mechanistic pathways as therapeutic targets, animal models, systems biology, and translational research as they relate to various autoimmune diseases.

NIH investment in autoimmune disease research has increased over the past 5 years, reaching nearly $1 billion ($946,356,182) in fiscal year (FY) 2021.

In FY 2021 and FY 2022, 1,443 new research and administrative supplement grants listed "autoimmune disease” as the spending category. However, it is important to note that progress in our understanding of autoimmune disease research may not necessarily arise from research categorized as such. At NIH, we recognize that disease does not occur in a vacuum; disease-focused research often aligns with multiple ICO mission areas, allowing for a multidisciplinary approach.

For questions about OADR-ORWH, please reach out to [email protected] . To receive updates from OADR directly to your inbox, please provide your contact information here . 

To learn more and sign up for the next virtual Updates on OADR-ORWH session on February 2nd, please visit the event page .

For media inquiries, please use  [email protected]

Funding Opportunities

1  fairweather, d., frisancho-kiss, s., & rose, n. r. (2008). sex differences in autoimmune disease from a pathological perspective. the american journal of pathology, 173(3), 600–609. https://doi.org/10.2353/ajpath.2008.071008, 2  national academies of sciences, engineering, and medicine. (2022). enhancing nih research on autoimmune disease [white paper]. the national academies press. https://doi.org/10.17226/26554, 3  fairweather, d., frisancho-kiss, s., & rose, n. r. (2008). sex differences in autoimmune disease from a pathological perspective. the american journal of pathology, 173(3), 600–609. https://doi.org/10.2353/ajpath.2008.071008  .

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ScienceDaily

Possible trigger for autoimmune diseases discovered : B cells teach T cells which targets must not be attacked

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 be linked to the failure of this new mechanism as well.

In children and adolescents, the thymus gland functions as a "school for T cells." 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 a large number of molecules that occur in the body to the future T cells. If any of them reacts to one of these molecules, a self-destruction program is triggered. 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.

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Materials provided by Technical University of Munich (TUM) . Note: Content may be edited for style and length.

Journal Reference :

  • Ali Maisam Afzali, Lucy Nirschl, Christopher Sie, Monika Pfaller, Oleksii Ulianov, Tobias Hassler, Christine Federle, Elisabetta Petrozziello, Sudhakar Reddy Kalluri, Hsin Hsiang Chen, Sofia Tyystjärvi, Andreas Muschaweckh, Katja Lammens, Claire Delbridge, Andreas Büttner, Katja Steiger, Gönül Seyhan, Ole Petter Ottersen, Rupert Öllinger, Roland Rad, Sebastian Jarosch, Adrian Straub, Anton Mühlbauer, Simon Grassmann, Bernhard Hemmer, Jan P. Böttcher, Ingrid Wagner, Mario Kreutzfeldt, Doron Merkler, Irene Bonafonte Pardàs, Marc Schmidt Supprian, Veit R. Buchholz, Sylvia Heink, Dirk H. Busch, Ludger Klein, Thomas Korn. B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4 . Nature , 2024; DOI: 10.1038/s41586-024-07079-8

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“This is the first direct evidence we have that daily supplementation may reduce AD incidence, and what looks like more pronounced effect after two years of supplementation for vitamin D,” said Karen Costenbader, senior author of the study.

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Vitamin D supplements lower risk of autoimmune disease, researchers say

Haley Bridger

BWH Communications

Study of older adults is 'first direct evidence' of protection against rheumatoid arthritis, psoriasis, other conditions

In a new study, investigators from Brigham and Women’s Hospital found the people who took vitamin D, or vitamin D and omega-3 fatty acids, had a significantly lower rate of autoimmune diseases — such as rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, and psoriasis — than people who took a placebo.

With their findings published Wednesday in BMJ , the team had tested this in the large-scale vitamin D and omega-3 trial (VITAL), a randomized study which followed participants for approximately five years. Investigators found the people who took vitamin D, or vitamin D and omega-3 fatty acids had a significantly lower rate of AD than people who took a placebo.

“It is exciting to have these new and positive results for nontoxic vitamins and supplements preventing potentially highly morbid diseases,” said senior author Karen Costenbader of the  Brigham’s Division of Rheumatology, Inflammation and Immunity.  “This is the first direct evidence we have that daily supplementation may reduce AD incidence, and what looks like more pronounced effect after two years of supplementation for vitamin D. We look forward to honing and expanding our findings and encourage professional societies to consider these results and emerging data when developing future guidelines for the prevention of autoimmune diseases in midlife and older adults.”

“Now, when my patients, colleagues, or friends ask me which vitamins or supplements I’d recommend they take to reduce risk of autoimmune disease, I have new evidence-based recommendations for women age 55 years and older and men 50 years and older,” said Costenbader. “I suggest vitamin D 2000 IU a day and marine omega-3 fatty acids (fish oil), 1000 mg a day — the doses used in VITAL.”

VITAL is a randomized, double-blind, placebo-controlled research study of 25,871 men (age 50 and older) and women (age 55 and older) across the U.S., conducted to investigate whether taking daily dietary supplements of vitamin D3 (2000 IU) or omega-3 fatty acids (Omacor fish oil, 1 gram) could reduce the risk for developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses. Participants were randomized to receive either vitamin D with an omega-3 fatty acid supplement; vitamin D with a placebo; omega-3 fatty acid with a placebo; or placebo only. Prior to the launch of VITAL, investigators determined that they would also look at rates of AD among participants, as part of an ancillary study.

“Given the benefits of vitamin D and omega-3s for reducing inflammation, we were particularly interested in whether they could protect against autoimmune diseases,” said JoAnn Manson, co-author and director of the parent VITAL trial at the Brigham.

Participants answered questionnaires about new diagnoses of diseases, including rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and inflammatory bowel disease, with space to write in all other new onset ADs. Trained physicians reviewed patients’ medical records to confirm reported diagnoses.

“Autoimmune diseases are common in older adults and negatively affect health and life expectancy. Until now, we have had no proven way of preventing them, and now, for the first time, we do,” said first author, Jill Hahn, a postdoctoral fellow at the Brigham. “It would be exciting if we could go on to verify the same preventive effects in younger individuals.”

Among patients who were randomized to receive vitamin D, 123 participants in the treatment group and 155 in the placebo group were diagnosed with confirmed AD (22 percent reduction). Among those in the fatty acid arm, confirmed AD occurred in 130 participants in the treatment group and 148 in the placebo group. Supplementation with omega-3 fatty acids alone did not significantly lower incidence of AD, but the study did find evidence of an increased effect after longer duration of supplementation.

The VITAL study included a large and diverse sample of participants, but all participants were older and results may not be generalizable to younger individuals who experience AD earlier in life. The trial also only tested one dose and one formulation of each supplement. The researchers note that longer follow-up may be more informative to assess whether the effects are long-lasting.

This study was funded by the National Institutes of Health grants R01 AR059086, U01 CA138962, R01 CA138962.

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Global spread of autoimmune disease blamed on western diet

New DNA research by London-based scientists hopes to find cure for rapidly spreading conditions

More and more people around the world are suffering because their immune systems can no longer tell the difference between healthy cells and invading micro-organisms. Disease defences that once protected them are instead attacking their tissue and organs.

Major international research efforts are being made to fight this trend – including an initiative at London’s Francis Crick Institute, where two world experts, James Lee and Carola Vinuesa, have set up separate research groups to help pinpoint the precise causes of autoimmune disease, as these conditions are known.

“Numbers of autoimmune cases began to increase about 40 years ago in the west,” Lee told the Observer . “However, we are now seeing some emerge in countries that never had such diseases before.

For example, the biggest recent increase in inflammatory bowel disease cases has been in the Middle East and east Asia. Before that they had hardly seen the disease.”

Autoimmune diseases range from type 1 diabetes to rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis . In each case, the immune system gets its wires crossed and turns on healthy tissue instead of infectious agents.

In the UK alone, at least 4 million people have developed such conditions, with some individuals suffering more than one. Internationally, it is now estimated that cases of autoimmune diseases are rising by between 3% and 9% a year. Most scientists believe environmental factors play a key role in this rise.

“Human genetics hasn’t altered over the past few decades,” said Lee, who was previously based at Cambridge University. “So something must be changing in the outside world in a way that is increasing our predisposition to autoimmune disease.”

This idea was backed by Vinuesa, who was previously based at the Australian National University. She pointed to changes in diet that were occurring as more and more countries adopted western-style diets and people bought more fast food.

“ Fast-food diets lack certain important ingredients, such as fibre, and evidence suggests this alteration affects a person’s microbiome – the collection of micro-organisms that we have in our gut and which play a key role in controlling various bodily functions,” Vinuesa said.

“These changes in our microbiomes are then triggering autoimmune diseases, of which more than 100 types have now been discovered.”

Both scientists stressed that individual susceptibilities were involved in contracting such illnesses, ailments that also include celiac disease as well as lupus, which triggers inflammation and swelling and can cause damage to various organs, including the heart.

“If you don’t have a certain genetic susceptibility, you won’t necessarily get an autoimmune disease, no matter how many Big Macs you eat,” said Vinuesa. “There is not a lot we can do to halt the global spread of fast-food franchises. So instead, we are trying to understand the fundamental genetic mechanisms that underpin autoimmune diseases and make some people susceptible but others not. We want to tackle the issue at that level.”

This task is possible thanks to the development of techniques that now allow scientists to pinpoint tiny DNA differences among large numbers of individuals. In this way, it is possible to identify common genetic patterns among those suffering from an autoimmune disease.

“Until very recently, we just didn’t have the tools to do that, but now we have this incredible power to sequence DNA on a large scale and that has changed everything,” said Lee. “When I started doing research, we knew about half a dozen DNA variants that were involved in triggering inflammatory bowel disease. Now we know of more than 250.”

Such work lies at the core of Lee and Vinuesa’s efforts, which aim to find out how these different genetic pathways operate and unravel the many different types of disease doctors are now looking at. “If you look at some autoimmune diseases – for example, lupus – it has become clear recently there are many different versions of them, that may be caused by different genetic pathways,” said Vinuesa. “And that has a consequence when you are trying to find the right treatment.

“We have lots of potentially useful new therapies that are being developed all the time, but we don’t know which patients to give them to, because we now realise we don’t know exactly which version of the disease they have. And that is now a key goal for autoimmune research. We have to learn how to group and stratify patients so we can give them the right therapy.”

Lee also stressed that surging cases of autoimmune diseases across the world meant new treatments and drugs were now urgently needed more than ever before. “At present, there are no cures for autoimmune diseases, which usually develop in young people – while they are trying to complete their education, get their first job and have families,” he said.

“That means growing numbers of people face surgery or will have to have regular injections for the rest of their lives. It can be grim for patients and a massive strain on health services. Hence the urgent need to find new, effective treatments.”

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Insights into new-onset autoimmune diseases after COVID-19 vaccination

a Hebei General Hospital, Hebei Medical University, Shijiazhuang, China

Xiaoxiao Liu

b Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China

Xiangmei Chen

c Haihe Laboratory of Cell Ecosystem, China

Qinggang Li

Associated data.

Data will be made available on request.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 670 million infections and almost 7 million deaths globally. The emergence of numerous SARS-CoV-2 has heightened public concern regarding the future course of the epidemic. Currently, the SARS-CoV-2 Omicron variant has rapidly become globally dominant in the COVID-19 pandemic due to its high infectivity and immune evasion. Consequently, vaccination implementation is critically significant. However, growing evidence suggests that COVID-19 vaccination may cause new-onset autoimmune diseases, including autoimmune glomerulonephritis, autoimmune rheumatic diseases, and autoimmune hepatitis. Nevertheless, the causal relationship between COVID-19 vaccines and these autoimmune diseases remains to be demonstrated. In this review, we provide evidence that vaccination induces autoimmunity and summarize possible mechanisms of action, such as molecular mimicry, activation by bystanders, and adjuvants. Our objective is not to refute the importance of vaccines, but to raise awareness about the potential risks of COVID-19 vaccination. In fact, we believe that the benefits of vaccination far outweigh the possible risks and encourage people to get vaccinated.

1. Introduction

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In March 2020, the World Health Organization declared COVID-19 a global pandemic [ 1 ]. As of 31 January 2023, the Johns Hopkins University Center for Systems Science and Engineering reported that the worldwide number of confirmed infections has exceeded 670 million worldwide, resulting in nearly 7 million deaths [ 2 ]. Since the outbreak began, national governments have adopted various strategies to manage the pandemic, including strict quarantine, complete lockdowns, and mask-wearing, which have effectively reduced the spread of SARS-CoV-2. However, given the tradeoff between infection control measures and socioeconomic development, the development and production of vaccines will now take precedence over other actions [ 3 ].

Vaccines are indispensable in preventing and controlling over 20 life-threatening diseases, such as diphtheria, tetanus, pertussis, influenza, and measles [ 4 ]. Moreover, vaccines are critical tools in the fight against the COVID-19 pandemic. The World Health Organization reports that there are currently 176 vaccine candidates in clinical development, including Protein subunit (PS), Viral Vector (non-replicating) (VVnr), DNA, Inactivated Virus (IV), RNA, Viral Vector (replicating) (VVr), Virus Like Particle (VLP), VVr + Antigen Presenting Cell (VVr + APC), Live Attenuated Virus (LAV), VVnr + Antigen Presenting Cell (VVnr + APC), and Bacterial antigen-spore expression vector (BacAg-SpV) [ 5 ]. Most vaccines developed by researchers worldwide are currently administered by intramuscular (IM) injection. However, COVID-19 intranasal (IN) vaccines are being developed to provide protective mucosal immunity in addition to eliciting antibody-mediated and cell-mediated immunity [ 6 ]. Unfortunately, several SARS-CoV-2 variants have emerged globally, including Alpha (B.1.1.7) [ 7 ], Beta (B.1.351) [ 8 ], Gamma (P.1) [ 9 ], Delta(B.1.617.2) [ 10 ] and Omicron (B.1.1.529) [ 11 ], and others. Undoubtedly, the emergence of variants poses a huge challenge to vaccine development.

Although vaccination against COVID-19 has proven to be effective in reducing disease severity and mortality, some people are hesitant to get vaccinated due to concerns about side effects [ 12 ]. Recently, reports have emerged suggesting that COVID-19 vaccines may cause rare autoimmune diseases, including autoimmune glomerulonephritis [ 13 ], autoimmune rheumatic diseases [ 14 ], and autoimmune hepatitis [ 15 ]. These adverse events have increased public skepticism about vaccination. However, the causal relationship between COVID-19 vaccination and these autoimmune phenomena needs further investigation. Previous studies have suggested that vaccines can trigger autoimmunity through mechanisms such as molecular mimicry, bystander activation, anti-idiotypic network, and epitope spreading [ 16 ]. Based on current evidence, we provide a summary of the rare autoimmune diseases that may be induced by COVID-19 vaccines and discuss possible underlying mechanisms.

This review aims to provide a comprehensive analysis of the emergence of rare autoimmune diseases following COVID-19 vaccination. A systematic PubMed search was conducted to identify relevant literature on COVID-19 vaccination and new-onset autoimmune phenomena published up to 1st February 2023. Inclusion criteria encompassed case reports, case series, original articles, letters to the editor, and reviews. Additionally, the references and related citations for the resulting articles were examined for potential inclusion. Search terms utilized included: “COVID-19 Vaccine”, “SARS-CoV-2 vaccine”, “autoimmune diseases”, “IgA glomerulo-nephritis”, “membranous nephropathy”, “membranous nephropathy”, “lupus nephritis”, “systemic lupus erythematosus”, “focal segmental glomerulosclerosis”, ”ANCA-associated nephritis”, “thrombotic microangiopathy”, “autoimmune rheumatic diseases”, “Rheumatoid arthritis”, “antiphospholipid syndrome”, “adult-onset Still’s disease”, “ANCA associated vasculitis”, “giant cell arteritis”, “Sjogren’s syndrome”, “Behcet disease”, “autoimmune hepatitis”, “type 1 diabetes mellitus”, “autoimmune hemolytic anemia”, “vaccine-induced immune thrombocytopenia and thrombosis”, “myocarditis”, “alopecia areata”, “autoimmune thyroid diseases”, “Guillain-barre syndrome”, “molecular mimicry”, “adjuvants”, “Bystander Activation”, “epitope diffusion”, and “polyclonal activation”.

To facilitate comprehension, we organized our findings into distinct categories. Specifically, these categories comprise Immune-mediated nephropathy, autoimmune rheumatic diseases, autoimmune hepatitis, type 1 diabetes mellitus, autoimmune hemolytic anemia, as well as additional autoimmune conditions.

3.1. Immune-mediated nephropathy

3.1.1. iga nephropathy(igan).

IgA nephropathy (IgAN) is the most prevalent primary form of glomerulonephritis worldwide, and its clinical presentation ranges from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis [ 17 ]. Reports have emerged on the potential of COVID-19 vaccination to induce IgAN, as well as relapse of previously treated cases. Among the published cases, 39 individuals experienced new-onset IgAN following vaccination, with a male predominance of 61.5% (24/39) [ [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] ].( Table 1 ). The vast majority of these cases (approximately 90%) involved mRNA vaccines, while only three were associated with Viral vector vaccines, and one with an inactivated vaccine. The mRNA vaccine’s lipid nanoparticle formulation may activate CD4 + and CD8 T + cells at a higher rate. In most instances (14/39), patients reported experiencing symptoms within 1 to 2 days after receiving the second dose, with gross hematuria being the most common initial symptom following vaccination (excluding cases with missing data), followed by albuminuria. Notably, the majority of these individuals had a history of microscopic hematuria or occult blood before vaccination and developed macroscopic hematuria shortly after receiving the vaccine. This suggests that these individuals may have had a pre-existing, undiagnosed IgAN and that the vaccine may have hastened disease progression as a predisposing factor.

Reported cases of de novo IgAN following COVID-19 vaccination.

F, female; M, male; IgAN, IgA nephropathy; F, female; M, male; HTP, hypertension; MH, microscopic hematuria; AH, asymptomatic hematuria; GH, gross hematuria; AKI, acute kidney injury; CKD, Chronic Kidney Disease; NS, nephrotic syndrome;RF, renal failure; KT, kidney transplantation; AAN, aristolochic acid nephropath; APS,antiphospholipid syndrome;UC, ulcerative colitis; MPGN type 1;membranous proliferative glomerulonephritis type 1; RF;rheumatoid arthritis; GDM, gestational diabetes mellitus; Scr, Serum creatinine; ALB, serum albumin; RBC, red blood cell; UTP,24-hurine protein;UPCR, urine protein-to-creatinine ratio; HD, hemodialysis; RASi,renin-angiotensin-aldosterone system inhibition;TPE, Therapeutic plasma exchange;N,none; CR, complete remission; PR, partial remission; NA, non-applicable; NR, no response;R, response.

Among this group of patients, we also observed several noteworthy phenomena. For instance, Mokos et al. reported the first instance of IgAN in a renal transplant recipient following the administration of the adenovirus vector SARS-CoV-2 vaccine, which suggests a heightened possibility of adverse reactions in immunocompromised solid organ recipients [ 37 ]. Additionally, Nakatani et al. reported the first case of new-onset IgA vasculitis with IgAN soon after receiving the mRNA vaccine, which highlights the need for careful follow-up to prevent new glomerulonephritis in the presence of significant purpura following vaccination [ 41 ].

The majority of the reported cases recover spontaneously within a short period of time with conservative treatment, although some cases may necessitate steroids, immunosuppressants, and dialysis to achieve remission. Fortunately, patients who did not exhibit obvious symptoms before vaccination or only had asymptomatic microscopic hematuria may be less likely to require additional treatment. Therefore, individuals in this group need not worry excessively about receiving the COVID-19 vaccine.

3.1.2. Membranous nephropathy(MN)

Membranous nephropathy (MN) is a glomerular disease characterized by the thickening of the glomerular capillary walls and accounts for approximately 30% of cases of nephrotic syndrome in adults [ 42 ]. This review identified 18 cases of de novo MN after COVID-19 vaccination [ 13 , 25 , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] ]( Table 2 ), with a male-to-female ratio of 17:5. The first reported case of new-onset MN following COVID-19 vaccination was by Gueguen et al. [ 46 ] Of these 18 cases, 14 cases (9 after the second dose) occurred following mRNA vaccines, 3 cases after viral vector vaccines, and 1 case after the first dose of the inactivated vaccine. Interestingly, mRNA vaccines appear to induce new-onset MN more frequently than viral vector vaccines and inactivated vaccines, which may be attributed to the higher immunogenicity of mRNA [ 54 ]. Most patients did not have a history of autoimmune or other glomerulonephritis and only developed nephrotic syndrome after vaccination. Immunotherapy was administered to all cases (except for those without a stated treatment regimen or effect), leading to clinical remission. M-type phospholipase A2 receptor (PLA2R) is a major target antigen involved in idiopathic membranous nephropathy in adults [ 55 ]. Of the patients in this group, three were PLA2R antibody-positive, suggesting a possible loss of tolerance to PLAR2 antigen following COVID-19 vaccination [ 47 , 48 , 50 ]. However, further studies are needed to elucidate the underlying mechanisms of COVID-19 vaccination and new-onset MN.

Reported cases of de novo MN after COVID-19 vaccination.

F, female; M, male;membranous nephropathy,MN; HTP, hypertension; AKI, acute kidney injury; CKD, Chronic Kidney Disease; NS, nephrotic syndrome;Scr, Serum creatinine; ALB, serum albumin; RBC, red blood cell; UTP,24-hurine protein;UPCR,urine protein-to-creatinine ratio; HD, hemodialysis; RASi, renin-angiotensin-aldosterone system inhibition;N,none; CR, complete remission; PR, partial remission; NA, non-applicable; NR, no response;R, response.

3.1.3. Lupus nephritis (LN)

Systemic lupus erythematosus (SLE) is an autoimmune disease with a range of variable features, yet its pathogenesis and precise mechanism remain unclear. Lupus nephritis(LN), one of the most severe organ complications of SLE, is a form of glomerulonephritis that is histologically classified into six distinct classes [ 56 ]. To date, at least 12 cases of new-onset SLE induced by COVID-19 vaccination have been reported in the literature, of which two were male and the rest were female [ [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] ] ( Table 3 ). Most cases developed two to three weeks after vaccination ( Table 3 ). Although the exact evidence to elucidate the relationship between SLE and COVID-19 vaccine is not available, there are some potential mechanisms between COVID-19 vaccination and SLE, including molecular mimicry [ 69 ], type 1 interferons and inflammatory mediators production via stimulation of toll-like receptors(TLR) [ 70 ] and vaccine adjuvants triggering autoimmune events [ 71 ], among others. Previous studies have reported flares of SLE triggered by other vaccines such as hepatitis-B, and HPV [ 72 , 73 ]. Therefore, the possibility of a similar effect cannot be denied.

Reported cases of SLE after COVID-19 vaccination.

F, female; M, male; ANA,anti-nuclear antibody; anti-dsDNA,antibody recognizing double-strandded DNA; anti-SSA,anti-Sjgren syndrome A antibody; anti-SSB,anti-Sjgren syndrome B antibody; anti-RNP,anti-ribonuclear protein antibody;anti-Sm,anti-Smith antibody; anti-Rib-P, anti-ribosomal P protein antibody; C3, complement 3; C4,complement 4; SLE, systemic lupus Erythematosus; AA,alopecia areata;APS, antiphospholipid syndrome; PMH, past medical history. Scoring of SLE is based on the 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria.

To date, only three cases of new-onset LN following COVID-19 vaccination have been reported [ [74] , [75] , [76] ]( Table 4 ), with two cases following viral vector vaccination and one case following mRNA vaccination. The age range of the cases varied widely (14 to 60 years), and initial symptoms were diverse. Nevertheless, the serological profiles were generally similar, showing elevated ANA titers, positive anti-dsDNA antibody, and low complement levels. All three patients received immunosuppressive therapy, resulting in varying degrees of remission.

Reported cases of LN after COVID-19 vaccination.

F, female; M, male; ANA,anti-nuclear antibody; anti-dsDNA,antibody recognizing double-strandded DNA; anti-RNP,anti-ribonuclear protein antibody;anti-Sm,anti-Smith antibody; N,none;NA, non-applicable; R, response.

While these findings suggest that the COVID-19 vaccine may trigger the onset of LN in susceptible populations, a definitive cause-effect relationship between COVID-19 vaccination and LN has not yet been established.

3.1.4. Focal segmental glomerulosclerosis(FSGS)

Focal segmental glomerulosclerosis (FSGS) is a heterogenous syndrome that arises from podocyte injury caused by various factors, and it represents a major cause of kidney disease worldwide [ 77 ]. Recently, five cases of de novo FSGS after COVID-19 vaccination have been reported [ 13 , [78] , [79] , [80] , [81] ] ( Table 5 ), with four of the cases following mRNA vaccine and one following the viral vector vaccine. The majority of patients were women (3/5, 60%) and below 30 years of age (4/5,80%). Nephrotic syndromes characterized by edema and proteinuria developed in almost all patients after vaccination, and renal biopsy confirmed FSGS. In addition to conservative treatment, all five patients received steroid therapy, and three also received immunosuppressive therapy. Most cases responded well to regular immunosuppression.However, Jha et al. reported a case of a 21-year-old male patient who developed de novo FSGS after ChAdOx1 nCoV-19 vaccination and did not respond to steroid + tacrolimus + rituximab therapy, unlike the other four patients [ 78 ]. It is difficult to establish a definite causal relationship between COVID-19 vaccination and FSGS, due to the small number of reported cases. Nevertheless, previous studies have suggested that mRNA vaccines may elicit T cell responses, and T-cell-mediated immune response could potentially trigger podocyte damage [ 82 ].

Reported cases of FSGS after COVID-19 vaccination.

F, female; M, male; focal segmental glomerulosclerosis, FSGS; IHD,ischemic heart disease;TTP, thrombotic thrombocytopenic purpura; HT, hypothyroidism;HTP, hypertension;MH,Microscopic hematuria;NS, nephrotic syndrome; PLA2R,phospholipase A2 receptor; Scr, Serum creatinine; ALB, serum albumin; UPCR,urine protein-to-creatinine ratio;C3, complement C3; C4, complement C4; N,none; R,remission; PR, partial remission; NA, non-applicable; NR, no response.

Overall, these findings suggest that COVID-19 vaccination may induce FSGS in some susceptible individuals. Further studies are needed to determine the underlying mechanisms and to identify risk factors associated with FSGS after COVID-19 vaccination.

3.1.5. Others

In addition to the aforementioned adverse events induced by COVID-19 vaccination, other autoimmune manifestations have also been reported in some cases, including ANCA-associated nephritis, thrombotic microangiopathy (TMA), and others.

Kim et al. reported a case of a 72-year-old woman who presented with anorexia, abdominal pain, and fever after receiving the mRNA vaccine. Laboratory tests showed occult blood (2+), proteinuria (2+), microscopic hematuria, and elevated serum creatinine levels (1.25 mg/dL). Serological tests revealed positive ANCA titers and antibodies against MPO. Based on renal biopsy results, ANCA-associated pauci-immune crescentic glomerulonephritis was diagnosed. After high-dose steroid treatment and plasmapheresis, the patient’s symptoms and renal function improved [ 83 ].

Fabritiis et al. reported a case of a 35-year-old previously healthy man who developed moderate fatigue one day after receiving the first dose of mRNA vaccine, coupled with dysgeusia, myalgia, pharyngodynia, and foamy urine. Laboratory tests showed nephrotic proteinuria, microhematuria. Kidney biopsy showed some ultrastructural alterations suggestive of an initial phase of renal TMA and complete remission of proteinuria and microhematuria was achieved in four weeks after high-dose steroid treatment [ 84 ]. However, Bitzan et al. reported five cases of TMA after influenza vaccination before [ 85 ]. To date, there are few reports of thrombotic microangiopathy following COVID-19 vaccination, suggesting that the underlying pathogenic relationship remains to be explored.

3.2. Autoimmune rheumatic diseases (ARDs)

3.2.1. rheumatoid arthritis (ra).

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) that cause inflammation [ 86 ]. Seven cases of de novo RA following COVID-19 vaccination have been reported, with a higher incidence in women (4/7, 57%) [ 14 , [87] , [88] , [89] , [90] , [91] ]. Four of these were reported after the mRNA vaccine and one after the Viral vector vaccine. Yonezawa et al. reported the first case of de novo seropositive RA after COVID-19 mRNA vaccination [ 87 ]. In most cases, patients presented with early symptoms of arthritis, such as morning stiffness, swelling, and pain. Serological tests showed positive RF and ACPA. Treatment included steroids, with four cases treated with methotrexate, two with hydroxychloroquine, and one with tocilizumab. Most patients responded well to the treatment and achieved varying degrees of clinical remission. However, Nahra et al. reported that symptoms recurred in patients after the prednisone dosage was reduced to less than 10mg per day [ 88 ].

3.2.2. Antiphospholipid syndrome(APS)

Antiphospholipid syndrome(APS)is a unique form of autoantibody-induced thrombophilia characterized by recurrent thrombosis and pregnancy complications. Lupus anticoagulant is the most significant predictor of APS-related features [ 92 ]. Moreno-Torres et al. recently reported a case of APS following an mRNA COVID-19 vaccine. The patient, a 27-year-old woman with a previous history of selective immunoglobulin A deficiency and paucisymptomatic COVID-19, presented with fever, digital ischemia, and abdominal pain 36 hours after receiving the first dose of BNT162b2 mRNA vaccine. Laboratory tests showed the presence of lupus anticoagulant. The patient was treated with low-dose prednisone, hydroxychloroquine, adjusted low-molecular-weight-heparin (LMWH) and thrice-weekly hemodialysis [ 93 ].

In another case, Molina-Rios et al. reported a 42-year-old woman with a history of three pregnancies, two of which resulted in spontaneous abortions. She presented with inflammatory polyarthralgia, bilateral synovitis, and bilateral Achilles tendon enthesopathy two weeks after receiving the first dose of the mRNA vaccine. Combined with laboratory data and imaging findings, SLE and secondary APS were considered [ 94 ].

3.2.3. Adult-onset Still’s disease (AOSD)

Adult-onset Still’s disease (AOSD) is a rare auto-inflammatory disorder of unknown etiology characterized by a high spiking fever, arthralgia, evanescent rash, and striking leucocytosis with neutrophilia [ 95 ]. A total of twenty-two cases of new-onset AOSD were reported in patients presenting with macroscopic hematuria following COVID-19 vaccination, with a male-to-female ratio of 4:7 [ [96] , [97] , [98] , [99] , [100] , [101] , [102] , [103] , [104] , [105] , [106] , [107] , [108] , [109] , [110] ]. Ten cases were reported following the mRNA vaccine, with five after the second dose, and the remainder following the viral vector vaccination, with one case reported after the second dose. Fever was the first symptom in all patients after vaccination, which was sometimes accompanied by other symptoms, such as sore throat, arthritis, headache, and others. As the disease progressed, most patients developed skin rashes. Laboratory tests showed elevated leukocytosis and CRP in most patients, while some patients showed an increase in liver enzymes. The vast majority of patients respond to steroid therapy, with a few requiring tocilizumab therapy. However, Gasparotto et al. reported a case of a 50-year-old female who did not go into remission after steroid and anti-IL1 treatment [ 101 ].

The exact pathogenesis of AOSD is not fully understood, but previous studies have shown that innate immune system activation is involved, with Toll-like receptors (TLRs) possibly activating the innate immune system with subsequent cytokine overproduction, especially ongoing aberrant IL-1, IL-18, IL-6, and TNF-α [ 95 ].

3.2.4. ANCA-associated vasculitis (AAV) and Giant cellarteritis(GCA)

Antineutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) is a rare autoimmune disorder that involves severe small-vessel vasculitis and is characterized by a loss of tolerance to neutrophil primary granule proteins such as leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). AAV is classified into three types based on clinical features, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA) [ 111 ]. A total of 17 new-onset AAV cases have been reported, including 5 cases of PR3-ANCA vasculitis, 9 cases of MPO-ANCA vasculitis, and 3 cases of dual-positive MPO- and PR3-ANCA vasculitis [ [112] , [113] , [114] , [115] , [116] , [117] , [118] , [119] , [120] , [121] , [122] , [123] , [124] , [125] , [126] , [127] , [128] ]. The majority of cases were women (11/17, 64.7%). Of these 17 cases, 13 cases were reported following the mRNA vaccines, 3 were reported following viral vector vaccines, and 1 was reported following inactivated vaccines. All patients received steroid therapy, while some also received hemodialysis (2/17,11.8%), plasmapheresis (7/17,41.2%), cyclophosphamide (11/17,64.7%), and rituximab(6/17,35.3%). Christodoulou et al. reported the first case of a healthy patient who developed de novo MPO-ANCA vasculitis shortly after COVID-19 vaccination and responded to steroids and cyclophosphamide but relapsed immediately after COVID-19 infection [ 121 ]. This finding suggests that both SARS-CoV-2 infection and vaccination may induce vasculitis and involve similar immune mechanisms.

Furthermore, So et al. have reported a new case of new-onset MPA following COVID-19 vaccination. A 42-year-old healthy male presented with general weakness, shortness of breath, edema, gross hematuria, and significant weight loss after receiving a second dose of mRNA vaccine. Elevated MPO antibodies and histological findings lead to the diagnosis of MPA. After receiving glucocorticoid therapy, rituximab, and plasma exchange, the patient’s symptoms improved [ 129 ]. However, the exact mechanism by which COVID-19 vaccines induce AAV is not yet well understood.

Giant cell arteritis (GCA) is a rare inflammatory disease affecting medium and large blood vessels, with clinical manifestations including headache, scalp tenderness, jaw and tongue pain, and visual disturbances [ 130 ]. There were five new-onset cases of GCA reported, with three patients developing symptoms after the mRNA vaccine and one patient after the first dose of the viral vector vaccine [ [131] , [132] , [133] , [134] , [135] ]. Four (80%) patients presented with headaches, while two (40 %) patients presented with jaw claudication. Scalp tenderness was observed in two (40%) cases. Most patients responded to steroid therapy. Mungmungpuntipantip et al. suggest that COVID-19 vaccination may increase blood viscosity, which may lead to inflammation resulting in arteritis [ 136 ]. However, the underlying pathogenesis of GCA remains unclear and may be associated with COVID-19 vaccines.

3.2.5. Sjogren’s syndrome (SS) and Behçet's disease (BD)

Ramos-Casals et al. documented the first case of subclinical Sjogren’s syndrome (SS) occurring 10 days after the first dose of the ChAdOx1 nCoV-19 vaccine (Oxford/AstraZeneca). A 55-year-old male with a history of colon carcinoma presented with widespread petechiae, bleeding gums, and hematuria following vaccination. Laboratory tests revealed a platelet count of 3 x 10 9 /L, positive IgG antibodies, ANA, and anti-Ro52 antibodies [ 137 ].

Tagini et al. described the first case of a new-onset Behçet's disease (BD) developing 15 days after the second dose of the SARS-CoV-2 mRNA-1273 vaccine. A woman in her late 20s with a medical history of polycystic ovary syndrome presented with a 1-week history of general malaise and her first episode of painful oral and genital ulcers after vaccination. BD was suspected based on clinical presentation, and the patient rapidly recovered after receiving prednisone 1 mg/kg/day [ 138 ].

3.3. Autoimmune hepatitis (AIH)

Autoimmune hepatitis (AIH) is a chronic liver disease characterized by elevated serum transaminase levels, elevated immunoglobulin G levels, the presence of autoantibodies, and interface hepatitis on liver histology [ 139 ]. The first case of AIH following COVID-19 vaccination was reported by Bril et al. in a 35-year-old female who developed AIH one week after receiving the first dose of COVID-19 vaccine (Pfizer-BioNTech) in her third month postpartum [ 140 ]. Although immunoglobulin G levels were not elevated as typically seen in AIH, histology showed the presence of eosinophils, which are also observed in liver damage caused by drugs or toxins. However, both conditions have also been reported in AIH [ 141 , 142 ]. To date, COVID-19 vaccines that induce AIH include mRNA vaccines, viral vector vaccines, and inactivated vaccines, with mRNA vaccines accounting for the majority and inactivated vaccines accounting for the least [ 15 , 140 , [143] , [144] , [145] , [146] , [147] , [148] , [149] , [150] , [151] , [152] , [153] , [154] , [155] , [156] , [157] , [158] , [159] , [160] , [161] , [162] , [163] , [164] , [165] , [166] , [167] , [168] ]. Clayton-Chubb et al. reported for the first time a case of adenovirus-based vaccine eliciting AIH. A 36-year-old male physician with a history of hypertension but no history of liver disease developed AIH following the first dose of the ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca) [ 152 ]. Mekritthikrai et al. reported the first case of AIH flare-up after receiving an inactivated COVID-19 vaccine. A 52-year-old woman without previous liver disease was diagnosed with AIH after receiving 2 doses of inactivated COVID-19 vaccine (CoronaVac) [ 157 ].

Although an increasing number of reports have linked COVID-19 vaccination to the development of AIH, the mechanisms remain unclear. Vojdani et al. found that antibodies to the SARS-CoV-2 spike protein cross-reacted with transglutaminase 3 (TTG3), transglutaminase 2(TTG2), and other proteins, suggesting that SARS-CoV-2 may trigger autoimmunity [ 169 ]. Furthermore, previous reports described a relationship between vaccination and the development of AIH, including influenza vaccines [ 170 ], which suggest that COVID-19 vaccines may also induce AIH. The cases presented above indicate that different types of vaccines have different potentials for inducing autoimmunity, and the mechanisms by which they promote autoimmunity may also differ slightly. For mRNA vaccines, adjuvant activity and binding to pattern recognition receptors (PRRs), such as Toll-like receptors, may trigger T and B cell immune responses [ 171 , 172 ]. For viral vector vaccines, adjuvants or binding to model receptors, particularly TLR9, may be involved [ 173 ]. Inactivated vaccines may exert immune effects through adjuvants and molecular mimicry [ 157 ].

3.4. Type 1 diabetes mellitus (T1DM)

Type 1 diabetes mellitus (T1DM) is an autoimmune endocrine disorder characterized by symptoms such as polyuria, nocturia, enuresis, lethargy, polydipsia, weight loss, and abdominal pain [ 174 ]. Out of the 13 cases analyzed (6 men and 7 women), approximately 54% did not have any medical history of autoimmune diseases, while 15% of patients had a history of vitiligo, type 2 diabetes mellitus, and Hashimoto’s thyroiditis [ [175] , [176] , [177] , [178] , [179] , [180] , [181] , [182] , [183] ]. While 10 patients received the mRNA vaccine, 2 received the inactivated vaccine. Almost all of the patients exhibited classic symptoms of diabetes, such as thirst, polyuria, polydipsia, and fatigue, and showed remission after insulin treatment, with one patient getting worse after medical nutrition therapy.

Tang et al. reported the first case of a 50-year-old healthy male who developed fulminant type 1 diabetes mellitus (FT1DM) after receiving an inactivated COVID-19 vaccine. The patient experienced fever and an abrupt onset of polydipsia and polyuria 5 days after vaccination. Laboratory tests at presentation revealed hyperglycemia, ketosis, metabolic acidosis, and a positive result for susceptibility human leukocyte antigen (HLA) alleles for FT1DM (DQB1*02:03/03:03 and DRB1*09:01/09:01). However, the patient’s islet function was almost completely lost 4 weeks after initial presentation. Tang et al. suggested that genetic susceptibility and autoimmunity might be involved in the pathogenesis of FT1DM, indicating that vaccination might trigger autoimmunity in individuals with susceptible genetic backgrounds and cause FT1DM [ 176 ]. Additionally, Sasaki et al. proposed that there might not be a single mechanism responsible for the loss of islet function and the development of hyperglycemia associated with Covid-19 vaccination, as new-onset T1DM patients with positive autoantibodies developed symptoms 4-7 weeks after vaccination, while patients with negative autoantibodies showed symptoms within a week after vaccination. The type of vaccine may also be a contributing factor to the difference in onset times [ 181 ].

MDA5 is a crucial innate pathogen recognition protein that has been shown to play a role in the immune response to COVID-19 mRNA vaccines. According to Sakurai et al., MDA5 recognizes RNA from these vaccines and triggers the synthesis of type I interferons. This immune response may interfere with insulin production, proinsulin conversion, and mitochondrial function in pancreatic β-cells, leading to the development of diabetes [ 180 ].

3.5. Autoimmune hemolytic anemia(AIHA)

To date, studies on vaccine-induced autoimmune hematologic disorders have been focused on cases of vaccine-associated thrombosis with thrombocytopenia (VITT), while reports of other vaccine-related hematologic diseases are uncommon. Autoimmune hemolytic anemia (AIHA) is one such rare disorder characterized by the accelerated destruction of autologous red blood cells (RBCs) due to autoantibodies [ 184 ].

Of the 9 new-onset cases of AIHA reported, of which 6 patients developed symptoms following the mRNA vaccine, and 3 patients developed symptoms after the viral vector vaccine [ [185] , [186] , [187] , [188] , [189] , [190] ]. In laboratory tests, all the patients showed decreased levels of Hb and haptoglobin, increased levels of LDH and bilirubin, and a positive direct antiglobulin test (DAT). Treatment involved steroid therapy for all patients, while 4 (44%) patients were treated with rituximab or immune globulin, and 2 (22%) patients received supportive RBC transfusions. One patient received plasmapheresis or mycophenolate mofetil.

The mechanism by which COVID-19 vaccines induce AIHA remains unclear. Angileri et al. proposed that molecular mimicry may be involved. Ankyrin-1 (ANK-1) is an erythrocyte membrane protein that is essential for erythrocyte differentiation and function. They found that ANK-1 shares a putative immunogenic antigenic epitope (amino acids LLLQY) with 100% identity with Spike’s predicted immunogenic epitope 750-SNLLLQYGSFCTQL-763 for B cells. Thus, the viral spike glycoprotein encoded by mRNA vaccines could induce the production of antibodies against spike protein, which may cross-react with ANK-1 RBC protein through molecular mimicry, leading to AIHA [ 191 ].

3.6. Others

In addition to the adverse events previously described, COVID-19 vaccination has also been associated with various autoimmune manifestations. These include vaccine-induced immune thrombocytopenia and thrombosis (VITT), myocarditis, alopecia areata(AA), autoimmune thyroid diseases, and Guillain-barre syndrome (GBS). Pavord et al. conducted a prospective cohort study involving 294 patients with suspected VITT. The syndrome is characterized by thrombosis, thrombocytopenia, elevated D-dimer, and positive platelet factor 4 (PF4) antibodies, which were observed 5 to 30 days after SARS-CoV-2 vaccination [ 192 ]. Myocarditis is another rare complication reported after COVID-19 vaccination. Fichadiya et al. reported a case of a 60-year-old healthy male with no past medical history who developed heart failure (NHYA class 4) symptoms and suspected myocarditis four weeks after receiving the first dose of COVID-19 vaccine (mRNA1273, Moderna) [ 193 ]. Alopecia Areata(AA), classified as an autoimmune disease with an unknown cause, has also been linked to COVID-19 vaccination. Lee et al. reported a case of an 80-year-old man who developed AA after the first dose of the COVID-19 vaccine(BNT162b2) [ 194 ]. Additionally, several thyroid disorders such as Graves’ disease, subacute thyroiditis, and others, have been reported following COVID-19 vaccination [ 195 ]. Guillain-Barré syndrome (GBS) is an acute disorder of the nervous system and is one of the autoimmune neurological diseases. McKean and Chircop reported a case of a 48- year- old man with dyslipidemia who developed GBS following the first dose of the COVID-19 vaccine (Vaxzevria) [ 196 ].

Recent findings suggest that the incidence of autoimmune diseases triggered by COVID-19 vaccines is on the rise, highlighting the pressing need to identify high-risk and vulnerable populations. Furthermore, it is essential to gather more evidence to confirm the link between COVID-19 vaccines and autoimmunity. To this end, several mechanisms have been proposed to elucidate the causal relationship, which will be detailed in the subsequent section ( Fig. 1 ).

Fig. 1

Schematic illustration of mechanisms inducing autoimmune diseases following COVID-19 vaccination. A. Following vaccination, vaccine antigens can trigger an immune response in the body. However, due to the presence of a heptapeptide that is shared between the SARS-CoV-2 spike glycoprotein and human proteins, vaccine antigens may also attack human proteins with similar structures via the molecular mimicry pathway. B. Adjuvants in vaccines can act as ligands for pattern recognition receptors (PRRs), such as toll-like receptors (TLR), bind to them to mobilize innate immune cells and secrete massive cytokines, and induce an innate immune response. Additionally, adjuvants also enhance the induction of adaptive immune responses to vaccine antigens. Upon binding to T-cell receptors (TCRs), antigens activate naive T-cells, which differentiate into Th1 or Th2 cells under the influence of different cytokines. Th1 cells primarily stimulate cellular responses, including the production of cytotoxic T lymphocytes (CTLs) that can eliminate infected cells, while Th2 cells promote humoral responses, such as B-cell proliferation, differentiation, and secretion of neutralizing antibodies. C. During the innate immune response following vaccination, the immune system produces a large number of cytokines, which may induce autoimmunity through the bystander activation pathway. This includes the activation of bystander CD8 + T cells primarily under the action of IL-15 and the activation of CD4 + T cells primarily under the influence of IL-2. PRRs, pattern recognition receptors; TLR, Toll-like receptor; TCR, T cell receptor; CTL, Cytotoxic T lymphocyte.

4. Mechanisms of COVID-19 vaccine-induced autoimmune diseases

4.1. molecular mimicry and immune cross-reaction.

The term molecular mimicry refers to the structural similarity between specific human proteins and certain disease-causing elements contained in vaccines. This similarity may result in immune cross-reaction, where the immune system mistakes human proteins for pathogens and attacks them, leading to autoimmune diseases [ 69 ]. Segal et al. have suggested several examples of vaccine-induced autoimmune diseases associated with molecular mimicry and immunological cross-reaction. These include influenza (H1N1) vaccines and Guillain-Barre syndrome(GBS), hepatitis B virus vaccines and multiple sclerosis (MS), and human papillomaviruses (HPV) and systemic lupus erythematosus (SLE) [ 69 ]. The mechanisms of molecular mimicry and immune cross-reaction may also play an important role in inducing autoimmune diseases following post-SARS-CoV-2 vaccination. Kanduc et al. have analyzed abundant heptapeptide sharing between SARS-CoV-2 spike glycoprotein and human proteins [ 197 ]. Therefore, antibodies produced by the body against the SARS-CoV-2 spike protein after vaccination may cross-react with the host and cause autoimmune diseases.

4.2. Adjuvants

Adjuvants are substances that accelerate, prolong, or enhance antigen-specific immune responses without having any specific antigenicity. They stimulate the immune system and increase the response to vaccines [ 198 ]. Toll-like receptors (TLRs) are a group of PRRs present on the innate immune system cells that recognize pathogens and initiate a response to infection. Adjuvants act as TLR ligands, binding to TLRs and leading to the initiation of innate immune responses, followed by adaptive immune responses [ 199 ]. However, adaptive antibody responses can also occur even in the absence of TLR ligands, as noted by Gavin et al. [ 200 ]. The concept of ”ASIA-Autoimmune/inflammatory Syndrome Induced by Adjuvants” has been proposed by Shoenfeld and Agmon-Levin, suggesting that adjuvants can trigger immune-mediated diseases [ 201 ]. Nevertheless, more studies are needed to confirm the role of adjuvants in the development of COVID-19 vaccine-mediated autoimmune diseases.

4.3. Bystander activation

Bystander activation refers to the cytokine-dependent, T and B cell receptor-independent activation of T and B cells [ 202 , 203 ]. In viral infections, Tough et al. reported for the first time that T-cell proliferation is driven by cytokines instead of TCRs and that memory cells may require minimal TCR ligation or be completely independent of TCRs. They require only intermittent exposure to IFN I released during viral infection to promote the long-term memory carried by CD8+ cells [ 204 ]. Additionally, Boyman suggested that bystander activation of CD4+ T cells may involve IL-2 and other cytokines [ 205 ]. In adjuvant-containing vaccines or adjuvants alone, T cells can be activated via bystander pathways; however, the migration of these activated auto-reactive cells to the site of inflammation and the mass secretion of cytokines may be sufficient to induce autoimmune pathologies, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and type 1 diabetes [ 202 ]. Therefore, it is highly probable that bystander activation is involved in the autoimmunity phenomena that occur following COVID-19 vaccination.

4.4. Others

In addition to the mechanisms discussed above, two other mechanisms involved in the development of vaccine-induced autoimmune diseases are epitope diffusion and polyclonal activation of B cells. Epitope spreading(ES) refers to an immune response to an epitope that is different from the dominant epitope and has no cross-reaction. This immune response can spread to different epitopes on the same protein (intramolecular ES) or to epitopes on other proteins (intermolecular ES) [ 206 ]. Studies by Cornaby et al. have shown that intermolecular and intramolecular B cell ES contribute to the development of numerous autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Graves’ disease, and Multiple sclerosis [ 207 ].

Polyclonal activation and proliferation of B cells are induced by long-lasting or constant immune system activation [ 208 ]. In some cases, this activation leads to the formation of circulating immune complexes, which can eventually cause damage to self-tissues.

5. Conclusion

Since the outbreak of COVID-19, its impact on the global economy, politics, and other aspects has been significant. In December 2021, the SARS-CoV-2 Omicron variant quickly became the dominant strain in the COVID-19 pandemic. Notably, Omicron contains numerous mutations in the spike protein that confer high immune evasion, and Shen’s research suggests that a booster dose of the COVID-19 vaccine is critical for generating neutralizing antibody responses against Omicron [ 209 ]. Given Omicron’s high infectivity, although it is less pathogenic than previous strains, a large number of cases would still overwhelm healthcare systems [ 210 ]. In this case, further optimization of the COVID-19 vaccine, such as changing the route of administration or adjusting vaccination strategies (e.g., adopting sequential immunization), is of great significance for controlling infections and alleviating public health pressure [ 211 ]. However, it is important not to ignore the potential side effects of vaccination.

In this comprehensive review, we have discussed rare autoimmune diseases that may potentially arise following COVID-19 vaccination, such as autoimmune glomerulonephritis, autoimmune rheumatic diseases, and autoimmune hepatitis, among others. However, the true incidence of these diseases after vaccination remains difficult to determine, as not all cases are or will be reported. Further exploration is necessary to establish a causal relationship between COVID-19 vaccines and the aforementioned autoimmune diseases.

It is important to emphasize that vaccines are generally safe and necessary for disease prevention. The benefits of COVID-19 vaccination significantly outweigh the theoretical risks, and we strongly encourage worldwide vaccination to build immune protection in the population. Nevertheless, it is our responsibility to remain vigilant and actively understand the serious adverse events associated with COVID-19 vaccines, critically evaluate vaccine safety, and increase public and healthcare worker awareness regarding vaccination. This will enable prompt identification, diagnosis, and treatment of these autoimmune diseases following vaccination through the recognition of their clinical and laboratory features.

Authors' contributions

Study concept and design: Q.G.L. and X.X.L. Literature search and data collection: M.G. Drafting of the manuscript: M.G., X.X.L. and Q.G.L. X.M.C. and Q.G.L. made critical revisions of the review. All authors read and approved the final manuscript. Q.G.L. takes responsibility for the integrity of the content and and the accuracy of analysis.

This study was supported by National Natural Science Foundation of China (81830019), Beijing Natural Science Foundation (7202188) and Haihe Laboratory of Cell Ecosystem Innovation Fund (22HHXBSS00002).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Researchers identify new choice of therapy for rare autoimmune disease EGPA

by McMaster University

autoimmune

An international team has identified a new therapeutic for patients with a rare autoimmune disease called eosinophilic granulomatosis with polyangiitis (EGPA). A biologic drug called benralizumab has been shown to be non-inferior to mepolizumab in the treatment of EGPA.

In a clinical trial involving 140 patients with the rare disease , researchers directly compared two biologic drugs, mepolizumab and benralizumab. Patients received monthly subcutaneous injections of either 300 mg of mepolizumab or 30 mg of benralizumab for one year. The findings of the trial were published on Feb. 23, 2024, in the New England Journal of Medicine .

"Our findings show that benralizumab was just as effective as mepolizumab at reducing exacerbations and providing disease remission during the 52 weeks of the study," says Parameswaran Nair, a professor with McMaster's Department of Medicine and a respirologist at St. Joe's Firestone Institute for Respiratory Health.

Nair was one of the study's principal investigators who led the Canadian team. He worked closely with Nader Khalidi, a professor with McMaster's Department of Medicine and a rheumatologist with St. Joe's, to design the study and recruit patients.

"The single 30 mg subcutaneous dosing of benralizumab offers an advantage to patients over the three 100 mg subcutaneous dosing of mepolizumab," says Nair.

EGPA, also known as Churg-Strauss Syndrome, is a rare autoimmune disease caused by inflammation of small and medium sized blood vessels and is associated with very high blood and tissue eosinophil counts. This can lead to damage of the lungs, skin, heart, gastrointestinal tract, and nerves. Most patients with EGPA experience breathing and lung issues.

The researchers noted that approximately 16 percent more patients in the benralizumab group were able to abstain from using oral corticosteroids compared to the mepolizumab group. Typically, patients with EGPA use oral corticosteroids like prednisone for symptom control despite the adverse effects.

"Without biologics, we're relying predominantly on oral corticosteroids to control EGPA symptoms. Prolonged treatment with prednisone reduces the risk of a relapse of EGPA symptoms, but it comes with progressive toxic effects," says Khalidi. "In our study, treatment with benralizumab allowed more patients to discontinue prednisone over a 52-week period compared to mepolizumab."

Mepolizumab and benralizumab are biologic drugs. Biologics are a class of drugs that come from living organisms or from their cells, often made using biotechnology.

The two biologics used in this study work by targeting either the signals or the receptors of eosinophils, a type of immune cell that is found in high concentrations in the blood and tissue of EGPA patients. By blocking the signals or receptors that draw eosinophils into various tissues, such as the lungs, mepolizumab and benralizumab effectively decrease eosinophils, reducing symptoms.

"Benralizumab was associated with greater blood eosinophil depletion than mepolizumab from week one onwards," says Nair. "Both drugs were well tolerated without any new adverse events."

The study builds on a long history of research on eosinophilic conditions from the Firestone Institute for Respiratory Health at St. Joe's. Pioneering work into the study of severe eosinophilic asthma by Freddy Hargreave led to a method for enumerating eosinophils in sputum samples for accurate asthma diagnoses.

For patients with severe prednisone-dependent asthma, Hargreave, Nair, and their colleagues were the first to demonstrate the efficacy of mepolizumab in 2009 . By 2017 , Nair had further demonstrated the efficacy of benralizumab for the same condition. Both landmark studies were published in the New England Journal of Medicine .

"It is very gratifying that our research program at the Firestone Institute at St. Joe's has led to the development of these new treatment options for patients with severe eosinophilic diseases," Nair says.

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Study Offers New Clues to Why Most People with Autoimmune Diseases Are Women

Posted on February 15th, 2024 by Dr. Monica M. Bertagnolli

Purple chromosomes fill the scene but a greyed-out chromosome locked up with chains labeled "Xist" is in the foreground. One of the Xist chains is covered with sharp thorns.

As many as 50 million Americans have one of more than 100 known autoimmune diseases , making it the third most prevalent disease category, surpassed only by cancer and heart disease. 1,2 This category of disease has also long held a mystery: Why are most people with a chronic autoimmune condition—as many as four out of every five—women? This sex-biased trend includes autoimmune diseases such as rheumatoid arthritis , multiple sclerosis , scleroderma , lupus , Sjögren’s syndrome , and many others.

Now, exciting findings from a study supported in part by NIH provide a clue to why this may be the case, with potentially important implications for the early detection, treatment, and prevention of autoimmune diseases. The new evidence, reported in the journal Cell , suggests that more women develop autoimmune diseases than men due in part to the most fundamental difference between the biological sexes: that females have two X chromosomes, while males have an X and a Y. More specifically, it has to do with molecules called Xist (pronounced “exist”), which are encoded on the X chromosome and transcribed into long non-coding stretches of RNA, only when there are two X chromosomes.

Those long Xist molecules wind themselves around sections of just one of a female’s two X chromosomes, shutting down the extra X chromosome in a process known as X-chromosome inactivation. It’s an essential process to ensure those cells won’t produce too many proteins encoded on X chromosomes, which would be a deadly mistake. It’s also something that males, with a single X chromosome and much smaller Y chromosome carrying almost no working genes, don’t have to worry about.

The new findings come from a team at Stanford University School of Medicine, Stanford, CA, led by Howard Chang and Diana Dou . What they suggest is that while Xist molecules play an essential role in X-chromosome inactivation, they also have a more nefarious ability to encourage the formation of odd clumps of RNA, DNA, and proteins that can in turn trigger strong autoimmune responses.

In earlier research, the team identified about 80 different proteins that bind to Xist either directly or indirectly. After taking a close look at the list, the researchers realized that many of the proteins had been shown to play some role in autoimmune conditions. This raised an intriguing question: Could the reason women develop autoimmune diseases so much more often than men be explained by those Xist-containing clumps?

To test the idea, the researchers first decided to study it in male mice. They made two different strains of male mice produce Xist to see if it would increase their risk for autoimmunity in ways they could measure. And it did. The researchers found that once Xist was activated in male mice that were genetically prone to autoimmunity, they became more susceptible to developing a lupus-like condition. It didn’t happen in every individual, which suggests, not surprisingly, that the development of autoimmune disease requires additional triggers as well.

In addition, in a different mouse strain that was resistant to developing autoimmunity, the addition of Xist in males wasn’t enough to cause autoimmunity, the researchers found. That also makes sense in that, while women are much more prone to developing autoimmune disease, most people don’t. Xist complexes likely lead to autoimmunity only when certain genetic and other factors are met.

The researchers also examined blood samples from 100 people with autoimmune conditions and found they had antibodies to many of their own Xist complexes. Some of those antibodies also appeared specific to a certain autoimmune disorder, suggesting that they might be useful for tests that could detect autoimmunity or particular autoimmune conditions even before symptoms arise.

There are still many questions to explore in future research, including why men sometimes do get autoimmune conditions, and what other key triggers drive the development of autoimmunity. But this fundamentally important discovery points to potentially new ways to think about the causes for the autoimmune conditions that affect so many people in communities here and around the world.

References:

[1] The American Autoimmune Related Diseases Association. Autoimmune Facts .

[2] Dou DR, et al . Xist ribonucleoproteins promote female sex-biased autoimmunity . Cell . DOI: 10.1016/j.cell.2023.12.037. (2024).

NIH Support: National Institute of Arthritis and Musculoskeletal and Skin Diseases

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Tags: autoimmune disease , autoimmune disorders , chromosomes , lupus , multiple sclerosis , rheumatoid arthritis , scleroderma , Sjogren's syndrome , women's health , Xist

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Stanford Medicine-led study shows why women are at greater risk of autoimmune disease

Research throws light on the mystery of why women are much more prone to autoimmune disorders: A molecule made by one X chromosome in every female cell can generate antibodies to a woman’s own tissues.

February 1, 2024 - By Bruce Goldman

X chromosomes and autoimmunity

In every cell in a woman’s body, one X chromosome is disabled to ensure that the right levels of proteins are produced from that chromosome pair. But the way the second chromosome is shut down generates unfamiliar molecular structures that can trigger antibodies (shown in red) targeting those structures. Emily Moskal

Somewhere 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 fostering a better way to predict autoimmune disorders before they develop.

“As a practicing physician, I see a lot of lupus and scleroderma patients, because those autoimmune disorders manifest in skin,” said  Howard Chang , MD, PhD, professor of dermatology and of genetics 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 , 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, in every female cell, of two X chromosomes. 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 cell, male or female, 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 makes an independent decision 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. 

Howard Chang

Howard Chang

As the researchers discovered, X-chromosome inactivation can lead to autoimmune disorders, although 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 member of that pair.

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. 

Every cell in a woman’s body produces Xist. But for several decades, we’ve used a male cell line as the standard of reference. 

Merely inserting that modified Xist gene had no noticeable effect on the mice. But the Xistproduced 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. 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.”

Researchers from the Johns Hopkins University School of Medicine; the KTH Royal Institute of Technology, in Stockholm; and the Swiss Federal Institute of Technology, in Zurich, contributed to the work.

The study was funded by the National Institutes of Health (grants T32AR007422, K99/R00 and T32AR050942), the Scleroderma Research Foundation and the Howard Hughes Medical Institute.

Bruce Goldman

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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Novel CMV Vaccine Generates Stronger Response in Key Immune Cells Than Previous Candidate

NIAID Now | February 21, 2024

Scattered burgundy spheres against a light green background with dark green markings throughout.

Transmission electron micrograph of cytomegalovirus (CMV) particles (burgundy) found within intracellular vesicles of an infected macrophage (green). Image captured at the NIAID Integrated Research Facility in Fort Detrick, Maryland.

A messenger RNA (mRNA) vaccine designed to prevent human cytomegalovirus (CMV) elicited long-lasting CMV-specific responses from several types of immune cells, outperforming a previous vaccine concept in multiple measures in a NIAID-supported laboratory study. The findings were published in the Journal of Infectious Diseases .

CMV has been present in much of the global population for centuries. Most people with CMV experience no symptoms and are unaware that they are living with the virus, but CMV is dangerous for people with compromised immune systems and for babies. It is the most common infectious cause of birth defects in the United States. When babies acquire CMV through birth it is called congenital CMV, and it affects about 1 out of every 200 children. Of babies with CMV, about 1 in 5 will experience long-term health effects, including hearing or vision loss, developmental and motor delays, seizures, or microcephaly (a small head). Infants born before 30 weeks’ gestational age or with low weight for age that have CMV may be susceptible to additional complications.

There is no preventive vaccine for CMV, and treatment options are limited. An effective CMV vaccine could present needless suffering for millions of babies, and research has been progressing for decades. A recent vaccine candidate was designed to use a laboratory-developed protein from CMV’s surface called glycoprotein B (gB)—known to assist CMV in fusing with and entering human cells—to safely teach the immune system how to respond to CMV exposure without causing disease. The vaccine provided about 50% protection from CMV in Phase 2 trials, but that effect was insufficient for the concept to advance to large efficacy studies. 

A different, mRNA-based, vaccine is now in a Phase 3 efficacy study in cisgender women with no existing CMV infection. The vaccine was designed to instruct cells to produce the gB protein while also producing a combination of five other glycoproteins on CMV’s surface, which like gB are involved in human cell entry.

To better understand how the mRNA vaccine might perform in comparison to gB-based vaccine, researchers examined the immune cells present in blood samples provided by people when they participated in previous studies of each vaccine. The study team performed several assays—laboratory tests—and made the following key observations:

  • The mRNA vaccine generated higher levels of antibodies to the five glycoproteins unique to the that vaccine in the form of immunoglobulin G (IgG) antibodies, which are associated with long-term immunity.
  • The mRNA vaccine generated more potent signals that the immune system was prepared to deploy antibodies to surround and neutralize—destroy—CMV.
  • The gB-based vaccine generated higher levels of IgG antibodies to gB.
  • Immune responses to both vaccines were greater in study participants with no existing CMV, but the vaccines still amplified immune system activity in people already living with the virus. 

The authors concluded that the mRNA vaccine concept showed promise for better performance than its predecessor in ongoing clinical studies, of which results are expected soon. These results also highlight an opportunity to reformulate the mRNA vaccine to increase the amount of gB proteins it generates, which in tun could improve gB-specific immune responses.

This work was led by Weill Cornell Medicine in collaboration with the Duke Human Vaccine Institute at Duke University Medical Center, Vanderbilt University, Cincinnati Children’s Hospital Medical Center, and Moderna, Inc. in Cambridge, Mass. Moderna co-funded the research with NIAID.

Reference: X Hu, et al . Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine . Journal of Infectious Diseases DOI: 10.1093/infdis/jiad593 (2024). 

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Types of encephalitis: A Mayo Clinic expert explains

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Editor's note: February 22 is World Encephalitis Day.

Encephalitis  is a disease referring to the inflammation or swelling of the brain. Broadly, it can happen because of infections, including viral infections, or the immune system acting up. 

That's why  Dr. Sarosh Irani , a Mayo Clinic neurologist and  researcher , says it's essential to recognize World Encephalitis Day.

"A number of physicians, and certainly the public, are not aware of encephalitis as an entity. Yet, it is a medical emergency, where we know that early treatment makes a major difference to our patients, both with infectious forms of the disease and the growing — and perhaps now more common — autoimmune forms of the disease," Dr. Irani says.

Watch: Dr. Sarosh Irani discusses types of encephalitis

Journalists: Broadcast-quality sound bites and video broll with Dr. Irani are available in the downloads at the end of the post. Please courtesy: "Mayo Clinic News Network." Name super/CG: Sarosh R. Irani, B.M.B.Ch., D.Phil./Neurology/Mayo Clinic.

Types of encephalitis

The two main types or divisions of encephalitis are infectious and autoimmune. In some cases, the exact cause of encephalitis remains unidentified.

Important things to know about infectious encephalitis :

  • It's caused by viruses invading the brain, such as herpes and enteroviruses.
  • Mosquitoes and ticks can also transmit viruses which can cause encephalitis.
  • Symptoms develop quickly, over days to weeks. 

Most people with infectious encephalitis start with symptoms such as headache and fever. These can progress to more severe symptoms within hours to days, such as confusion, personality changes, seizures, and loss of sensation or movement in specific body areas.

Important things to know about autoimmune encephalitis:

  • The immune system mistakenly attacks the brain.
  • It primarily targets people from their first year of life to late 80s, both women and men. Some forms preferentially affect young or old; males or females.
  • It can be triggered by an infection elsewhere in the body (post-infectious autoimmune encephalitis) or a tumor (paraneoplastic autoimmune encephalitis). But in about 90% of cases, the cause is not found.
  • Symptoms can develop quickly, as per infectious encephalitis, or more slowly, over weeks to months, and may not include fever.
  • Those symptoms of autoimmune encephalitis may include changes in personality, memory loss, problems understanding reality (psychosis), hallucinations (seeing or hearing things that aren't there), seizures and unusual movements.

Preventing encephalitis

Prevention is a significant challenge, says Dr. Irani. 

"We do not have consistent preventive measures for these illnesses. Only a few infectious causes may be prevented with vaccinations. There are also a few causes of infectious encephalitis which we can prevent through limiting person-to-person spread or by trying to stop, for example, vectors like mosquitoes infecting some patients. But for autoimmune causes, we don't know of ways to prevent this illness, yet this is a major question from all of our patients," he says.

Dr.Sarosh R. Irani with researcher in his laboratory

Dr. Irani leads a research team studying autoimmune neurological diseases. 

"One of our principal goals is to figure out how we can educate other neurologists and physicians around the world to identify patients earlier and give them early treatment," says Dr. Irani.

He says the research is about using science to create personalized treatments that make a difference for patients.

"I see ourselves as a translational research group. We see patients, care for them clinically, and obtain samples from our patients to understand their disease more closely," he says. "We then correlate clinical findings with those we obtain in our laboratory."

As for the laboratory work, he's interested in learning more about how these diseases occur.

"We want to know how the cells of the immune system that caused the illness appeared, how they perpetuate, which bodily compartments they go to, which parts of the body they reside in, and then, of course, fundamentally, how we can accurately delete them without giving the patients many side effects," says Dr. Irani.

Dr.Sarosh R. Irani talking with research team in his lab

Present and future research

"In the short term, I hope this research will help patients by giving physicians a better understanding of when we should treat patients, how we should recognize them and which treatments might be most effective in which scenarios," he says.  

"In the longer term, I hope we'll be able to build a platform by which we can interrogate each disease in turn and, as they all are slightly different to each other, try and ask how they cross compare to one another. And how can we offer the right patient the right treatment at the right time," says Dr. Irani.

Learn more about encephalitis research at Mayo Clinic:

  • Autoimmune encephalitis: Paving the way to better outcomes
  • Avoiding misdiagnosis of autoimmune encephalitis

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  • 12 December 2023

‘It’s all gone’: CAR-T therapy forces autoimmune diseases into remission

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Engineered immune cells have given 15 people with once-debilitating autoimmune disorders a new lease on life, free from fresh symptoms or treatments. The results raise hopes that the approach — called CAR-T-cell therapy — might one day be extended to a variety of other conditions fuelled by rogue immune cells that produce antibodies against the body’s own tissues.

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Nature 624 , 483-484 (2023)

doi: https://doi.org/10.1038/d41586-023-03968-6

Kansal, R. et al. Sci. Transl. Med. 11 , eaav1648 (2019).

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Haghikia, A. et al. Lancet Neurol. 22 , 1104–1105 (2023).

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Chip Chick

New Research Suggests The X Chromosome May Be The Reason Why Women Are Four Times More Likely Than Men To Develop Autoimmune Diseases

W omen are actually up to four times as likely as men to develop autoimmune diseases, where the immune system erroneously targets the body’s own cells.

Researchers believe they’ve found the reason behind this higher susceptibility in women, too. It could be linked to the way the body manages its X chromosomes.

Humans possess two kinds of chromosomes, labeled X and Y. Typically, females have a pair of X chromosomes in every cell, whereas males usually have one X and one Y chromosome.

The X chromosome is not only bigger than the Y but also houses a significantly larger number of genes responsible for protein synthesis.

However, in individuals with two X chromosomes, only one is required for the production of proteins to avoid an overload of proteins in the cells.

To manage this, one of the X chromosomes in each cell undergoes a process known as “silencing” during the embryonic development stage in females.

A lengthy RNA molecule, known as Xist, which is closely related to DNA, plays a key role in this silencing process by attaching itself to one of the X chromosomes.

Interestingly, it has been observed that Xist tends to attract many proteins, forming large complexes of RNA and proteins.

This propensity for proteins to bind to Xist could make females more susceptible to autoimmune diseases.

Sign up for Chip Chick’s newsletter and get stories like this delivered to your inbox.

According to a recent study involving both mice and humans, this occurs because these complexes can trigger an immune response, leading the body to produce antibodies targeting the proteins contained within them.

“So besides Xist’s job in controlling gene activity, there’s really a major immunological imprint that maybe hadn’t been previously recognized,” said Dr. Howard Chang, the study’s co-senior author.

Thus, Chang believes this discovery may pave the way for exploring new treatment options for autoimmune diseases.

Autoimmune diseases impact over 23.5 million people in the United States and result from a mix of genetic factors and environmental influences.

Although researchers have suggested various hypotheses to understand why women are more prone to these disorders, citing factors such as hormones and the microorganisms living in and on their bodies, none of these theories have been definitively proven.

Previous studies conducted by Chang and his team indicated that the Xist complex might contribute to the gender differences observed in autoimmunity, given its ability to bind with numerous proteins linked to autoimmune diseases.

However, to accurately assess Xist’s role, it was necessary to examine it separately, eliminating the influence of other variables like hormones that could obscure its effects.

That’s why the researchers created two genetically modified male mouse strains capable of producing Xist: one predisposed to autoimmune symptoms akin to lupus and another that was resistant, serving as the control group.

After observing that female mice in the lupus-like strain were more susceptible to symptoms than their male counterparts, the team hypothesized that introducing Xist would elevate the disease incidence in males to match that of females.

So, during the study, the team integrated a modified version of the Xist gene into the DNA of male mice, which could be activated without silencing their sole X chromosome.

To induce autoimmune conditions, it was necessary to expose the mice predisposed to lupus to a particular chemical.

After activating Xist and triggering lupus, the researchers observed that male mice expressing Xist exhibited the disease at rates comparable to females and experienced more severe symptoms than those mice not expressing Xist.

However, Chang noted that the necessity for both an environmental chemical trigger and a genetic susceptibility to lupus served as a crucial control measure. This approach enhanced the relevance of the mouse experiments to human conditions.

“If someone is born with a genetic susceptibility, then the presence of Xist has some impact, but also, very importantly, this environmental trigger is necessary,” Chang explained.

Having Xist does not ensure that an individual will develop an autoimmune disease. Rather, the Xist complex might simply explain the differences in disease prevalence between genders.

To support their findings from the mouse studies, the researchers examined blood samples from over 100 individuals with autoimmune diseases, such as lupus, alongside 20 healthy controls without autoimmune conditions.

They found that those with autoimmune diseases had higher levels of Xist autoantibodies in their blood compared to those without autoimmune diseases.

Chang said that the variety and quantity of autoantibodies varied among individuals based on the specific disease, which could aid in diagnosing and treating these conditions in the future.

For instance, analyzing these autoantibody profiles might eventually enable physicians to identify the particular disease affecting a patient or foresee the progression of their illness.

To read the study’s complete findings, which have since been published in Cell , visit the link here .

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