PRIMER ON THE INNATE IMMUNE SYSTEM

The innate immune system represents the first-line response to immunologic challenges and is composed of cellular defenses (neutrophils, dendritic cells, macrophages, and natural killer cells), proinflammatory signaling proteins known as cytokines, and the complement system. IL-1, IL-6, and TNF-α represent the critical proinflammatory cytokines of the innate immune system. Nearly all mutations found in the autoinflammatory syndromes disrupt normal control of inflammatory signaling and result in generation of a proinflammatory state and inflammatory symptoms.

FAMILIAL MEDITERRANEAN FEVER

Familial Mediterranean fever (FMF) is the most common and best characterized autoinflammatory syndrome. A mutation in the MEFV gene disrupts the conformation of pyrin, a protein critical to control of IL-1 production, leading to increased IL-1 levels. Although classically described as autosomal recessive, many patients with FMF have only one abnormal allele. The carrier rate in certain ethnic groups (e.g., Sephardic Jews, Turks, Arabs, Armenians) is very high.

Brief episodes of fever accompanied by intense serositis are the hallmarks of FMF attacks. Approximately 80% of patients will suffer their first attack before age 20 years. Patients have a body temperature that is typically greater than 102°F, with the fever lasting less than 72 hours. Arthritis of predominantly the lower extremities is found in 70% of FMF patients during attacks. Erysipeloid erythema, an intensely erythematous warm, tender, plaquelike lesion on the lower extremities, can be noted in up to 40% of patients. Orchitis also frequently occurs during attacks. Over time, these recurrent episodes of inflammation may result in amyloidosis of the kidneys or liver.

Colchicine is the mainstay of therapy for patients with FMF. Seventy percent of FMF patients treated with colchicine have complete cessation of their symptoms, whereas 25% of patients have a reduction in the severity and frequency of attacks. Only 5% to 10% of FMF patients will not respond to colchicine, usually owing to the gastrointestinal side effects of the drug. In these patients, drugs that inhibit IL-1 activity offer great promise.

The prognosis of FMF is mainly related to genotype and development of amyloidosis. Those patients with genotypes resulting in mild disease have a lower probability of developing amyloidosis, and thus prognosis is favorable. In general, FMF attacks become less frequent and severe over time.

HYPERIMMUNOGLOBULIN D SYNDROME

The underlying genetic abnormality underlying hyperimmunoglobulin D syndrome (HIDS) has been localized to the gene encoding the enzyme mevalonate kinase. Most of these mutations are missense mutations in highly conserved areas of protein resulting in a partial decrease in mevalonate kinase activity. Although classically described as autosomal recessive, many patients with HIDS have only one abnormal allele.

More than 70% of patients will suffer their first HIDS attack before age 2, and the average age at onset is 6 months. Parents may report that routine vaccinations during infancy trigger attacks. Attacks typically last 4 days, and this longer duration can assist in differentiating attacks from FMF. More than 90% of patients will exhibit significant cervical lymphadenopathy, and 80% will develop a nonspecific erythematous rash. Headache, arthritis, and abdominal pain also are found in 70% of patients. As the name implies, serum levels of IgD are elevated in patients with HIDS. However, the specificity of this finding is questionable because elevated IgD levels are found in many children with chronic inflammatory conditions and levels fluctuate throughout childhood. Assessment of urinary mevalonic acid levels during febrile attacks offers a more reliable method of diagnostic investigation in patients presumed to have HIDS. Genetic sequencing is an alternative method of diagnostic testing in patients with symptoms suggestive of HIDS. However, roughly 30% of patients meeting clinical criteria for HIDS have no definable mutation.