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Welcome to The Science!

Despite ongoing research into rare periodic fevers, this area of medicine is complex and not fully understood – even by scientists! In this section of the website, we present some of our 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, and HIDS/MKD. 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. This includes common viruses that cause colds or flu every winter, bacteria such as streptococcus, which can cause a very sore throat, and other germs such as those responsible for stomach flu.

The skin and mucosa (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 (the bodie'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 even without outside invaders, causing “friendly fire” that can harm people with autoinflammatory conditions.

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

  • 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: PAC-MAN!). If this is not sufficient to destroy them, the acquired immune system assists.
  • 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

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 as a response to invading germs. This autoinflammation involves the nonspecific innate immune system 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.) This causes a disease flare with typical symptoms including fever, rash, joint swelling, pain, and fatigue.

Why does this happen?

There are various causes of autoinflammatory diseases:

Genetic mutations
  • Inherited from one or both parents
  • Caused by changes in a related set of genes
  • Includes the periodic fever syndromes (CAPS, FMF, TRAPS, HIDS/MKD and others)
  • Mutational analysis may be negative in over 40% of autoinflammatory disorders
Triggers
  • These disorders may be triggered by substances released into the circulation during abnormal responses to infection
Other conditions with autoinflammatory causes
  • SJIA
  • Type II diabetes, gout, pseudogout and atherosclerosis

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, SJIA: Systemic Juvenile Idiopathic Arthritis

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 promotion of the inflammatory response. What do we mean by messenger? These are signals to immune cells to come to the site where invaders are.

IL-1β has different effects on various parts of the body

Effects of IL-1β illustration


Effects of IL-1β

Periodic fever syndromes

Periodic fever syndromes are rare diseases; they affect a very small percentage of people in the general population – for example, fewer than 5 out of 10,000 people. They are usually hereditary and may be caused by a change to the genetic recipe (DNA) of the nonspecific innate immune system that causes the system to be switched on even without invaders to fight. Periodic fever syndromes include (but are not limited to) 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).

The symptoms involve the repeated occurrence of fever lasting more than 24 hours and are often accompanied by rashes and joint pain.  They can also involve other symptoms, and sometimes further damage may occur due to the effects of continuous (chronic) inflammation.

Diagnosis

Diagnosis of CAPS, FMF, TRAPS or HIDS/MKD can be a challenge. This is because these diseases occur only rarely and have symptoms common to many other diseases. Doctors may have to rule out many possible conditions and order laboratory or genetic tests in order to make a diagnosis.

So what are autoimmune diseases?

Autoimmune conditions 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, some forms of arthritis involve the innate and acquired immune systems and can be considered both autoinflammatory and autoimmune conditions.

References

1. Lachmann HJ et al. Arth Res Ther 2009;11:212.
2. Ciccarelli F, De Martinis M, Ginaldi L. Curr Med Chem 2014; 21: 261–269.
3. NIH. Understanding Autoimmune Diseases. Available at: www.niams.nih.gov/Health_info/Autoimmune/default.asp. Accessed January 15, 2017.
4. Dinarello CA. JEM 2005; 201: 1355–1359.
5. Gattorno M et al. J Clin Immunol (2008) 28 (Suppl 1):S73–S83.
6. Shinkai K et al. Clin Experimental Derm 2007;33:1–9.
7. Lachmann HJ et al. NEJM 2009;360:2416–2425.
8. McGonagle D and McDermott MF. PLoS Med 2006;3(8):1243–1248.
9. Dall L and Standford JF. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Chapter 211. Available from: www.ncbi.nlm.nih.gov/books/NBK324/pdf/Bookshelf_NBK324.pdf. Accessed January 2017.
10. Krause K et al. Allergy 2012;67(12):1465–74.

Kids' corner

Want to help your child understand their illness? Why not visit Kids' Corner with your child and read Paula and Tim’s explanation of autoinflammatory disease and their experience of attending school and after school activities with their condition.

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Kids' Corner

NPR/ACZ885/0008E