People in Wales told to stay home from Friday, with pubs and restaurants ordered to close.

A decision on local rules and financial support must be made “one way or another”, a minister says.

In the earliest days of the pandemic, many immunologists, including me, assumed that patients who produced high quantities of antibodies early in infection would be free from disease. We were wrong.

Several months into studying Covid-19, like other scientists, I’ve come to realize the picture is far more complicated. A recent research study published by my colleagues and me adds more evidence to the idea that in some patients, preventing dysregulated immune system responses may be as important as treating the virus itself.

I am an immunologist at Emory University working under the direction of Dr. Ignacio Sanz, Emory’s chief of rheumatology. Immune dysregulation is our specialty.

Inflammation in Covid-19

A harrowing turn in the Covid-19 pandemic occurred with the realization that the immune system’s power in fighting infection was sometimes pyrrhic. In patients with severe Covid-19 infections, evidence emerged that the inflammatory process used to fight the SARS-CoV-2 virus were, in addition to fighting the virus, potentially responsible for harming the patient. Clinical studies described so-called cytokine storms in which the immune system produced an overwhelming quantity of inflammatory molecules, antibodies triggering dangerous blood clots and inflammation of multiple organ systems, including blood vessels, in Covid-recovered children. All these were warning signs that in some patients, immune responses to the SARS-CoV-2 virus, which causes Covid-19, may have tipped from healing to destructive.

Quick thinking and courageous decisions made by physicians on the front lines led to the use of steroids, medicines that dampen the immune response, early on in the course of infection of hospitalized patients. This approach has saved lives.

But it’s not yet clear what parts of the immune system physicians are dampening that is having the effect. Understanding the nature of immune dysregulation in Covid-19 could help identify patients in whom these treatments are most effective. It may even justify more targeted and powerful approaches for modulating the immune system currently reserved for autoimmune diseases.

The right antibodies take time

Antibodies are powerful weapons. Produced by white blood cells called B cells, they latch onto infectious agents like viruses and bacteria and prevent them from infecting your healthy cells. These antibody-virus aggregates unleash powerful inflammatory reactions and serve as homing beacons that allow the rest of your immune system to target the pathogens efficiently. In some circumstances, they can even kill.

Antibodies are so powerful that cases of mistaken identity – when a B cell produces antibodies that attack a person’s own cells – can lead to widespread organ damage and establish a perpetual cycle of immune self-targeting. We refer to this state of self-destruction as an autoimmune disease.

To avoid autoimmune disaster, and to ensure effective response against the invading pathogen, B cells undergo a training process. Those that respond to the virus refine their antibodies and mature, ensuring potent antibodies capable of disabling the invader. B cells that target your own tissue are destroyed.

But that maturation process takes time. Two weeks of B cell “training” during a severe infection can mean the difference between life and death. Faster antibody responses are needed. To bridge that gap, the immune system has an alternative form of B cell activation – called extrafollicular activation – that generates fast-acting antibodies that seem to bypass many of the known safety checks that accompany a more precise response.

Extrafollicular responses develop quickly, are short-lived by design and die back when the more targeted responses emerge onto the scene.

Except when they don’t.

Autoimmune-like responses in Covid-19

Between 2015 and 2018, our lab found that these extrafollicular immune system responses were a common characteristic of people who suffered from autoimmune diseases, such as lupus. Patients suffering from this disease show chronically active extrafollicular responses that led to high levels of self-targeted antibodies and destruction of organs such as the lungs, heart and kidneys.

The presence of specific kinds of B cells generated by extrafollicular responses in the blood can be an important indicator of disease severity in lupus, and now also Covid-19.

In a recently published paper, my colleagues and I have identified extrafollicular B cell signatures in cases of severe Covid-19 similar to those we saw in active lupus. We showed that early on in the response to infection, patients with severe disease undergo a rapid activation of this fast-track pathway for antibody production. These patients produce high levels of viral-specific antibodies, some which are capable of neutralizing the virus. However, in addition to those protective antibodies, some that we saw look suspiciously like the ones found in autoimmune disorders such lupus.

In the end, patients with these autoimmune-like B cell responses fare poorly, with high incidences of systemic organ failure and death.

Tempering immune responses in Covid-19

Let me be clear here: Covid-19 is not an autoimmune disorder. The autoimmune-like inflammatory responses my team discovered could simply reflect a “normal” response to a viral infection already out of hand.

However, even if this kind of response is “normal,” it doesn’t mean that it’s not dangerous. These prolonged extrafollicular responses have been shown to contribute to autoimmune disease severity both through the production of self-targeted antibodies and through inflammation that can damage tissue like the lung and kidney. This suggests that these early immune responses to a viral infection like Covid-19 are in tension with the later-targeted antibody response; in other words, the body’s rapid antibody production to nab the virus runs the risk of targeting not the virus, but the patient’s own organs and tissues.

Immunologists like me need to learn more. Why are only some patients turning on such strong extrafollicular B cell responses? Are the antibodies that result from this response particularly prone to attacking and destroying the host’s organs? Would an ongoing autoreactive response help explain instances of “lingering” Covid-19 even after the viral infection has cleared?

Despite these uncertainties, the medical community needs to recognize that, in the appropriate patients, dampening immune responses through steroid treatment (or perhaps even more powerful autoimmune-focused therapies) is a critical weapon in combating Covid-19. Physicians and scientists must continue to build our arsenal of therapeutics around the idea that in some cases of Covid-19, controlling your response to the virus might be as important as controlling the virus itself.

Matthew Woodruff, Instructor, Lowance Center for Human Immunology, Emory University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Image credit: Getty Images

Matthew Woodruff, Emory University

Just over 20 years ago, people from three generations of an American family were referred to the National Institutes of Health (NIH) in Washington DC with an unknown disease.

They were ten to 82 years old and had symptoms including monthly episodes of unexplained high fevers (up to 41 degrees celsius), lasting two to seven days.

They also had painful swollen lymph nodes, enlarged spleens and livers, abdominal pain, mouth ulcers, joint pain, and a patchwork of other symptoms.

The symptoms, which they’d had since shortly after birth, seemed like an inflammatory reaction. However, doctors could not trace the episodes to an infection.

We now know these symptoms are typical of autoinflammatory diseases – rare conditions with seemingly unprovoked episodes of fever and inflammation.

Because the inflammatory episodes occur regularly, the diseases are also known as “periodic fever syndromes”. In addition to being painful and debilitating, some of the conditions can damage vital organs, such as the heart and lungs.

What causes autoinflammatory disease?

Autoinflammatory diseases are caused by abnormal activation of the innate immune system, the body’s first-line defence against invading pathogens.

The innate immune system is a hard-wired response that can quickly mobilise to fight foreign invaders. Among its many roles is the release of cytokines.

These are immune messengers critical for alerting and recruiting other cells to the fight, increasing blood circulation and inducing fever. More about cytokines later.

However, in autoinflammatory diseases, invading microbes don’t cause the fever and inflammation. Instead, genetic changes (mutations) lead to the innate immune system being activated for what appears to be no reason, causing uncontrolled inflammation.Autoinflammatory diseases typically begin in childhood, often from birth, and are lifelong conditions. The genetic mutations can be passed from parents to their children, leading to multiple cases of disease in an extended family.

Autoinflammatory diseases are different from autoimmune diseases, such as multiple sclerosis, which are caused by defects in the adaptive immune system, a different arm of the immune response.

There are a number of different autoinflammatory diseases, often caused by different genetic mutations.

How do we treat autoinflammatory disease?

Autoinflammatory diseases cannot be cured, and treatment is usually to relieve symptoms during an attack. Patients are often treated with high doses of corticosteroids, a broad-brush approach to suppress the immune system.

Autoinflammatory diseases are also quite rare, which in the past has made it difficult to develop specific treatments.

Because autoinflammatory diseases are typically associated with excess production of cytokines, they are sometimes treated with so-called biologics – antibodies that mop up these excess cytokines.

These are usually antibodies to the cytokines tumour necrosis factor (TNF) or interleukin-1.

However biologics are expensive, and can have significant side-effects.

Without knowing the cause of an inflammatory disease, treatment is a trial and error process; a drug that works for one person may not work for another.

Can genetic testing help?

The discovery of mutations in genes causing autoinflammatory diseases has led to the development of genetic tests to help diagnosis.

However, some people with autoinflammatory disease do not have a change in one of the known disease-causing genes.

So our researchers have established the Australian Autoinflammatory Disease Registry to help identify other genetic causes of autoinflammatory diseases.

How we found out about the underlying mechanism

While the NIH researchers were looking for a cause of the American family’s disease, another strand of the story was playing out in Australia.

We were looking at the role of the master cytokine TNF, which controls many aspects of the body’s inflammatory response, and its partner RIPK1.

Usually, the body has many checks and balances to ensure these molecules are tightly controlled.

But we worked with the US scientists who found a critical mutation in the gene coding for RIPK1. We found this mutation, leading to changes in just one amino acid, was enough to supercharge its partner TNF into an elite killer.

This is what triggered the uncontrolled inflammation behind the American family’s disease.

Our team named this condition CRIA syndrome (cleavage-resistant RIPK1-induced autoinflammatory syndrome).

So what does this mean?

Understanding the molecular mechanism by which CRIA syndrome causes inflammation gives us an opportunity to get to the root of the problem, and to offer an alternative to existing treatments.

For this American family, treatment with an agent that inhibits the faulty RIPK1 might be a tailored option.

Lastly, the discovery of CRIA syndrome now confirms RIPK1 can play an important role in regulating inflammation in humans. So it may also play a role in far more common human illnesses, such as colitis (inflammation of the colon), rheumatoid arthritis and the skin condition psoriasis.

John Silke, Leader, Infection, Inflammation and Immunity theme, Walter and Eliza Hall Institute and Najoua Lalaoui, Postdoctoral research fellow, Inflammation Division, Walter and Eliza Hall Institute

This article is republished from The Conversation under a Creative Commons license. Read the original article.

John Silke, Walter and Eliza Hall Institute and Najoua Lalaoui, Walter and Eliza Hall Institute

Fourteen new donation centres are to open around the country in November and December.

• Musically trained kids had more activity in certain brain regions, a study found
• These children may enjoy improved reading, higher resilience, greater creativity and a better quality of life
• The researchers want to evaluate musical training intervention for kids with attention-deficit/hyperactivity disorder

Learning to play a musical instrument helps fine-tune kids’ brains, researchers say.

In a new study, 40 children (aged 10 to 13) performed memory and attention tasks while their brain activity was monitored with functional MRI. This type of imaging scan detects small changes in blood flow within the brain.

Twenty of the children played an instrument, had completed at least two years of lessons, practised at least two hours a week and regularly played in an orchestra or ensemble.

The other 20 children had no musical training other than in the school curriculum.

More brain activation

The two groups had no differences in reaction time. But the musically trained children did better on the memory task, according to the report published online in the journal Frontiers in Neuroscience.

And along with better memory recall, the musically trained kids had more activation in brain regions associated with attention control and auditory encoding – functions associated with improved reading, higher resilience, greater creativity and a better quality of life.

“Our most important finding is that two different mechanisms seem to underlie the better performance of musically trained children in the attention and … memory task,” said team leader Leonie Kausel, a violinist and neuroscientist at the Pontifical Catholic University of Chile, in Santiago.

Music training may increase the functional activity of certain brain networks, Kausel explained in a journal news release.

Learning a universal language

The researchers’ next step is to dig into the mechanisms they found for improving attention and working memory. They also plan to study musical training with children and possibly to evaluate a musical training intervention for kids with attention-deficit/hyperactivity disorder, Kausel said.

Do the findings mean it’s a good idea to put your kids in music classes?

“Of course, I would recommend that,” Kausel said. “However, I think parents should not only enrol their children because they expect that this will help them boost their cognitive [mental] functions, but because it is also an activity that, even when very demanding, will provide them with joy and the possibility to learn a universal language.”

^{Image credit: iStock}

• Problems during pregnancy could increase women’s risk of heart failure at a later stage
• A study found that preeclampsia was associated with a fourfold risk of heart failure
• Factors like breastfeeding were, however, associated with a lower risk of heart disease

Pregnancy complications, including preeclampsia and miscarriage, may be linked to an increased risk of heart disease later in life, a new study suggests.

For the study, the researchers analysed 32 reviews that assessed women of childbearing age and their subsequent risk of heart disease. The women in those papers were followed for an average of seven to 10 years.

Several reproductive factors were linked with an up to twofold risk of heart disease later in life: starting periods early; use of combined oral contraceptives; polycystic ovary syndrome; miscarriage; stillbirth; preeclampsia; diabetes during pregnancy; preterm birth; low birth weight; and early menopause.

In addition, preeclampsia was associated with a fourfold risk of heart failure.

Reproductive risk factors

Family medical history, genetics, weight, high blood pressure and cholesterol levels, and chemical imbalances from use of hormonal contraceptives are among the possible explanations for these associations, according to study author Krishnarajah Nirantharakumar, a senior clinical lecturer at the University of Birmingham in the United Kingdom, and colleagues.

There was no association between heart disease risk and current use of progesterone-only contraceptives, use of non-oral hormonal contraceptive agents or fertility treatment, the study authors noted.

More time breastfeeding was associated with a lower risk of heart disease, according to the report published online in the BMJ.

Previous research has suggested that women may have specific risk factors for heart disease and stroke, but there were questions about the quality of evidence, the study authors said in a journal news release.

The new report doesn’t prove cause and effect, but the findings indicate that reproductive factors do influence women’s future risk of heart disease. The researchers suggest that women’s healthcare guidelines be updated to include reproductive risk factors as part of the risk assessment for heart disease.

^{Image credit: iStock}

Nagoya University researchers have synthesized a unique molecule with a surprising property: it can absorb near infrared light. The molecule is made only of hydrogen and carbon atoms and offers insights for making organic conductors and batteries. The details were published in the journal Nature Communications.

Why does the divergence between science and politics appear to be wider than it has ever been?