Autoinflammation, once an unknown term, describes a variety of diseases, including periodic fever syndromes and various rheumatic diseases. An important molecule in these diseases is the "cytokine interleukin-1 (IL-1)", which is activated by the "inflammasome" at the cellular and molecular level. Mutations in the genes that code for the components of the inflammasome are associated with autoinflammatory diseases.
The most important things at a glance
- Introduction to autoinflammation
- The role of interleukin-1 (IL-1) in autoinflammatory diseases
- Diseases that are part of auto-inflammation
Introduction to autoinflammation
Normally, inflammation is triggered by the innate, non-specific immune system as a reaction to harmful microorganisms, foreign substances, toxins or cancer cells. Such an inflammatory reaction is usually self-limiting.
However, some chronic diseases with inflammatory symptoms lack both a clearly recognizable trigger and self-regulation. McGonagle and McDermott have introduced the concept of autoimmune and autoinflammatory diseases as interlocking patterns. On the one hand, there are rare monogenic diseases and classic polygenic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and ANCA-associated vasculitis. On the other side are the autoinflammatory diseases, which include rare monogenic diseases such as FMF, TRAPS, CAPS, HIDS, PAPA, blue syndrome and polygenic autoinflammatory diseases such as gout, pseudogout, Still's disease and sarcoidosis. In between, there are diseases with mixed patterns that indicate acquired (MHC class I association) and autoinflammatory components (Behçet's disease, reactive and psoriatic arthritis, ankylosing spondylitis, HLA-B27-associated uveitis).
The role of interleukin-1 (IL-1)
An important molecule in autoinflammatory processes is the cytokine interleukin-1beta (IL-1β). IL-1β plays a key role in the response to microbial inflammation and tissue damage. It acts on various cells and tissues and induces the synthesis of other inflammatory mediators such as IL-6 and CSF. These mediators cause the observable symptoms of inflammation such as fever, increased white blood cell count, increased platelet count, increased sensitivity to pain, local tissue damage and others.
At the cellular and molecular level, the inflammasome is the central hub for IL-1β activation and plays a critical role in innate immunity by recognizing intracellular pathogens and metabolic danger signals. Mutations in the genes encoding the components of the inflammasome (either loss of function or gain of function) are associated with autoinflammatory diseases.
Diseases that are part of auto-inflammation
Periodic fever syndromes (PFS)
Periodic fever syndromes are diseases in which people have repeated episodes of fever that last longer than six months without an identifiable infection or autoimmune disease as the cause. These diseases affect otherwise healthy patients who have elevated levels of inflammation in the blood during fever episodes. Between episodes, patients usually feel completely healthy. Periodic fever syndromes can be caused by inherited genetic changes that cause the immune system to overreact and lead to inflammation. Some examples of periodic fever syndromes are familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic syndromes (TRAPS) and hyper-IgD syndrome (HIDS).
Cryopyrin-associated periodic fever syndromes (CAPS)
Cryopyrin-associated periodic fever syndromes are a group of diseases with varying degrees of severity, including FCAS (familial cold autoinflammatory syndrome), MWS (Muckle-Wells syndrome) and NOMID (neonatal onset multisystemic inflammatory syndrome) or CINCA (chronic infantile neurologic, cutaneous and articular syndrome). What these syndromes have in common is that they are caused by a specific genetic change in the CIAS1/NALP3 gene, which codes for the protein cryopyrin. Cryopyrin is an important protein in the inflammasome and its defective function leads to excessive production of IL-1β, an inflammatory factor. These syndromes are rare and their incidence is about 0.1 per 100,000 in the USA.
Symptoms range from mild to severe inflammation, depending on the particular syndrome. Treatment is often with drugs that block IL-1, such as anakinra or canakinumab.
Idiopathic/multifactorial diseases
Juvenile idiopathic arthritis (JIA) is a type of arthritis that occurs in children and whose cause is unknown. There are different subgroups of JIA and treatment depends on the symptoms and severity of the disease. IL-1 plays a role in the systemic form of JIA and drugs such as anakinra or tocilizumab can be effective.
Adult onset Still's disease (adult M. Still)
The adult form of Still's disease is a rare inflammatory disease whose cause is unclear. It is similar to the juvenile form but affects adults. Again, IL-1 and other inflammatory factors play a role, and treatment may include drugs that block IL-1.
Gout
Gout is a type of arthritis caused by an accumulation of uric acid crystals in the joints. These crystals activate the inflammasome and lead to the release of IL-1β, which causes inflammation. Treatment includes medication to lower uric acid levels and for acute attacks, drugs such as colchicine or IL-1 blockers such as anakinra can be effective.
