Welcome to ‘The Science ’!

Rare periodic fevers can be a minefield. A good amount of research has been dedicated to understanding these conditions, and the genetics behind them; yet, there is still so much more to fully understand about these diseases – even by scientists! A lot of it comes down to differences in the genetic recipe (DNA) between people. DNA differences between people are natural - individuals are rarely identical - but every once in a while a tiny change (1 change in 3 billion base pairs of DNA) has big downstream effects (like pushing over the first card in a long line of branching cards). In this science section of the website, we describe highlights of the current understanding of the science behind the tiny DNA change(s) that lead to rare periodic fevers, and we describe some of the diseases themselves – CAPS, SJIA, FMF, TRAPS, HIDS/MKD and Gout. Explore to find out more.

Autoinflammatory Diseases

Body invaders: How the body protects us

A healthy immune system: Your body’s defence against germs

We all know that a healthy immune system is essential to fight off invading germs that can cause illnesses or disease. These include common viruses (causing colds or the flu) that seem to plague us every winter, or bacteria (such as streptococcus, which can cause a bad sore throat).

The skin and mucosa (e.g. inner lining of the nose) act as frontline barriers to prevent germs from entering the body. They are coupled with our saliva, sweat and tears (which are the body’s ‘chemical’ defences), which contain substances (such as enzymes) that can kill germs.

If germs manage to enter the body, the immune system forms the next line of defence to prevent them from growing and multiplying. The immune defence system consists of patrolling cells and messenger substances (cytokines) that circulate in the blood, which detect and fight invading germs.

Infection: When germs invade

Find out now how some immune system defences become active in patients with autoinflammatory diseases, even when the body has not been exposed to invaders, causing “friendly fire” and inflammation inside the body.

When germs invade the body causing an infection, two parts of the immune system work together to fight the invaders:

1. A typical infection is first fought by the built-in response to invaders (innate immune system) through the process of inflammation, which attracts cells to “eat” the invaders (think: Pacman^TM!). If this is not sufficient to destroy them, the acquired immune system assists.
2. The acquired immune system “learns” about the germ and then develops antibodies specifically targeted to that germ. The antibodies bind to and clump the germs together so they can be destroyed. The acquired system also “remembers” the germ and can produce the germ-specific antibodies very rapidly from the “immune memory” if the same germ invades the body again. We take advantage of the body’s ability to remember previous invasions by germs when we get vaccinated against diseases.

Development of a healthy immune response to germs

Friendly fire: Autoinflammatory diseases

What are autoinflammatory diseases?

Autoinflammatory diseases are conditions where the inflammatory response appears to occur automatically or “on its own”, instead of in response to invading germs. This auto-inflammation involves the nonspecific innate immune system^[1] and occurs periodically in some people or continuously (chronically) in others.

During an autoinflammatory response, the innate immune system is activated even though no germs are present in the body. (This means that the immune cells act as if they were fighting germs, resulting in an inflammatory response that affects the entire body.^[1]) This causes a disease flare with typical symptoms including fever, rash, joint swelling, pain, and fatigue.^[1]

Why does this happen?

There are various causes of autoinflammatory diseases:^[1]

CAPS: Cryopyrin-associated periodic syndromes, FMF: Familial mediterranean fever, TRAPS: Tumour necrosis factor receptor associated periodic syndrome, HIDS/MKD: Hyperimmunoglobulinemia D syndrome / Mevalonate kinase deficiency

The culprit: IL-1β

Interleukin-1 beta (IL-1β) is a messenger of the nonspecific innate immune system that can play a special role in many autoinflammatory diseases, including the promotion of the inflammatory response.^[2] What do we mean by messenger? These are signals that communicate to the immune cells to come to the site where invaders are.

Effects of IL-1β (modified according to ^[2])

IL-1β has different effects on various parts of the body: ^[2-6]

Periodic fever syndromes

Periodic fever syndromes are rare diseases meaning they affect fewer than 5 out of 10,000 people.^[6] They are usually hereditary ^[1] and may be caused by a change to the genetic recipe (DNA ) of the non-specific innate immune system that causes the system to be switched on even without invaders to fight. Periodic fever syndromes include cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour necrosis factor receptor associated periodic syndrome (TRAPS) and hyperimmunoglobulinemia D syndrome/Mevalonate kinase deficiency (HIDS/MKD).^[1]

The symptoms

involve the repeated occurrence of fever lasting more than 24-hours and are often accompanied by rashes and joint pain.^[1] Other symptoms can be present and sometimes further damage may occur due to the effects of continuous (chronic) inflammation.^[1]

Diagnosis

Diagnosis of CAPS, FMF, TRAPS or HIDS/MKD can be a complicated process. This is because these diseases occur only rarely, and have symptoms common to many other diseases. Thus, a diagnosis may involve several diagnostic tests before the true cause or condition is identified. It’s also important to know that, in order to arrive at the diagnosis, the clinical specialist must rule out many other possible conditions.^[7] Some patients may have relatives, parents, or even sibling with the same autoinflammatory disease.

So what are autoimmune diseases?

Autoimmune diseases involve the acquired immune system . The acquired immune system includes immune cells that following initial contact, fight only a specific type of germ. Autoimmune diseases often involve the formation of antibodies that are mistakenly directed against parts of the body. Well-known autoimmune diseases include Crohn’s disease, psoriasis, and rheumatoid arthritis.

But there is some overlap

Some diseases of the immune system cannot be strictly categorized as either autoinflammatory or autoimmune. For example, rheumatoid arthritis and SJIA involve the innate and acquired immune systems and can be considered both autoinflammatory and autoimmune conditions.^[1]