What is autoinflammatory disease, the rare immune condition with waves of fever?



from www.shutterstock.com

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

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℃), 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.




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Explainer: what is inflammation and how does it cause disease?


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.




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Explainer: what is the immune system?


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.




Read more:
Explainer: what are autoimmune diseases?


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.

Antibodies against the molecule TNF (above) can be used to treat excess inflammation.
from www.shutterstock.com/StudioMolekuul

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.




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The Conversation


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.

Coptic Blogger in Egypt Threatens Hunger Strike


Authorities deny Christian’s application for release.

ISTANBUL, November 9 (CDN) — A Coptic Christian blogger in Egypt held in prison for more than a year without charge said today he will go on a hunger strike unless authorities grant his next application for release.

Hani Nazeer, a 28-year-old high school social worker from Qena, Egypt and author of the blog “Karz El Hob,” received word today that his latest application for release, sent to the Ministry of the Interior a week ago, was denied. His attorneys said they would re-apply for his release tomorrow.

The interior ministry did not “supply the grounds for refusal” according to Rawda Ahamad, Nazeer’s lead defense attorney.

“He has no charges against him,” Ahamad said. “He is not a criminal. He must be released immediately. He’s an innocent man – anyone exposed to this severe injustice would do the same.”

On Oct. 3, 2008, Nazeer was arrested by Egypt’s State Security Investigations (SSI) and sent to Burj Al-Arab prison. Although police never charged him with any crime, Nazeer has been detained for more than a year under Egypt’s administrative imprisonment law.

Nazeer ran afoul of SSI officers a few days before his arrest when a group of local teenagers visited his website and clicked on a link to an online copy of “Azazil’s Goat in Mecca,” a novel written under the pseudonym “Father Utah.” The book is a response to “Azazil,” a novel by Yusuf Zidane, critical of Christianity.

Insulting religion is illegal in Egypt, but the law is enforced unequally. Zidane’s critique of Christianity garnered him fame and awards throughout the Arab world. Nazeer’s website link cost him his freedom, despite the fact that police have never publicly produced any evidence linking Nazeer to Utah’s work. After Nazeer was arrested, posts continued on Utah’s website.

Nazeer has reported to his attorneys that he has been placed in prison with felons, some of them violent. He also claims that prison authorities have pressured him to convert to Islam.

Gamel Eid, executive director of the Arabic Network for Human Rights Information, the group representing Nazeer, stood by his client’s accusations, saying police have urged inmates to suggest to Nazeer that officers would work to free him if he were to convert to Islam.

Nazeer’s situation is complicated by the fact that his writings upset both Islamic authorities and the hierarchy of the Coptic Orthodox Church. On one hand, he criticized the increasing Islamization of Egyptian civil society. On the other, he lamented the political involvement of the Coptic Orthodox Church. In one post, Nazeer wrote that a gathering of activists at a Coptic church was inappropriate because churches were meant to be venues for prayer, not for politics.

According to Eid, Nazeer was arrested with the complicity of leaders in the Coptic Orthodox Church. In October of 2008, police detained Nazeer’s relatives at a police station and threatened to hold them until he came out of hiding. Nazeer turned himself into the police station on the advice of Bishop Kirollos of Nag Hammadi, Nazeer reported to his attorneys. Kirollos assured Nazeer he would be detained no more than four days and then be released.

Kirollos had denounced Nazeer to security, Nazeer told his attorneys.

All attempts to reach Kirollos about his alleged involvement in Nazeer’s arrest were unsuccessful. Several attempts to reach Bishop Anba Yoannes, authorized to speak about the case on behalf of the Coptic Orthodox Church’s Pope Shenouda III, were also unsuccessful. Egypt’s SSI, a political police force run by the Interior minister, routinely declines to comment on cases.

This week’s application will be sent to a court within the Ministry of the Interior. But under the emergency law, police officials have the power to ignore court orders. When local police execute a court order to release prisoners held under Egypt’s emergency law, security police commonly re-arrest them minutes later.

The law, enacted after the 1981 assassination of President Anwar Sadat, allows authorities to hold people without charge. Eid estimated that there are approximately 14,000 people imprisoned under this law. In 2005, while running for re-election, Egyptian President Hosni Mubarak promised to replace the contested law. But in May of 2008, the Egyptian government extended the law for two more years.

Mamdouh Nakhla, an attorney and civil rights activist in Egypt, said oppression of Coptic Christians is common and that many police officers in Egypt are the “agents of persecution.” At best, he said, they are complicit in acts of persecution. At worst, he added, police collude with others hostile to Christianity.

“They give green lights to Islamists, and protect them, and give them the feeling that they are immune from prosecution,” he said.

Report from Compass Direct News