Key points

Introduction

Autoinflammatory disorders are a newly described class of disorders marked predominantly by dysregulation of the innate immune system. This heterogeneous class of disorders is clinically distinct from autoimmune disorders. Autoinflammatory disorders are currently recognized as “clinical disorders marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system, with a significant host predisposition. ^” Increased levels of interleukin-1 beta (IL-1β) cause abnormal inflammatory responses and are central to these disorders. Infection has yet to be found during episodic flares and does not seem to be a precipitating factor in the disorders. High-titer antibodies and antigen-specific autoreactive T cells are also absent.

A large number of disorders are now recognized as autoinflammatory and the number continues to grow. Affected systems are diverse and include skin, joints, and the nervous system. The hereditary periodic fever (HPF) syndromes were among the first to be labeled as autoinflammatory. Gout, type 2 diabetes, obesity-induced insulin resistance, Blau syndrome, and others are now classified as autoinflammatory. Some autoinflammatory disorders, including pyogenic arthritis-pyoderma gangrenosum-acne (PAPA) syndrome and Blau syndrome, affect the skin. Other dermatologic disorders with an inflammatory component, such as rosacea or acne, may potential be autoinflammatory disorders.

Many of the autoinflammatory disorders have a strong pain component that is overlooked. Episodic flares in the HPF syndromes and gout can cause debilitating pain. Cytokines, including IL-1β, and other inflammatory mediators are known to play important roles in neuronal perception of pain. Thus abnormal innate immune responses may abnormally affect neuronal perception of pain. The nervous system plays an important role in regulating inflammation and inflammatory pain. Neural-inflammation crosstalk may be disrupted in autoinflammatory disorders and contribute to the symptoms. Although crosstalk between inflammation and perception of pain is known to occur, it has not been highlighted in autoinflammatory disorders. Highlighting the inflammatory/neural crosstalk may allow a richer understanding of autoinflammatory disorders and potentially help to broaden the current disorder classification. This article provides an overview of current autoinflammatory disorders and how inexplicable inflammation and pain may factor into classifying new autoinflammatory disorders.

Introduction

Autoinflammatory disorders are a newly described class of disorders marked predominantly by dysregulation of the innate immune system. This heterogeneous class of disorders is clinically distinct from autoimmune disorders. Autoinflammatory disorders are currently recognized as “clinical disorders marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system, with a significant host predisposition. ^” Increased levels of interleukin-1 beta (IL-1β) cause abnormal inflammatory responses and are central to these disorders. Infection has yet to be found during episodic flares and does not seem to be a precipitating factor in the disorders. High-titer antibodies and antigen-specific autoreactive T cells are also absent.

A large number of disorders are now recognized as autoinflammatory and the number continues to grow. Affected systems are diverse and include skin, joints, and the nervous system. The hereditary periodic fever (HPF) syndromes were among the first to be labeled as autoinflammatory. Gout, type 2 diabetes, obesity-induced insulin resistance, Blau syndrome, and others are now classified as autoinflammatory. Some autoinflammatory disorders, including pyogenic arthritis-pyoderma gangrenosum-acne (PAPA) syndrome and Blau syndrome, affect the skin. Other dermatologic disorders with an inflammatory component, such as rosacea or acne, may potential be autoinflammatory disorders.

Many of the autoinflammatory disorders have a strong pain component that is overlooked. Episodic flares in the HPF syndromes and gout can cause debilitating pain. Cytokines, including IL-1β, and other inflammatory mediators are known to play important roles in neuronal perception of pain. Thus abnormal innate immune responses may abnormally affect neuronal perception of pain. The nervous system plays an important role in regulating inflammation and inflammatory pain. Neural-inflammation crosstalk may be disrupted in autoinflammatory disorders and contribute to the symptoms. Although crosstalk between inflammation and perception of pain is known to occur, it has not been highlighted in autoinflammatory disorders. Highlighting the inflammatory/neural crosstalk may allow a richer understanding of autoinflammatory disorders and potentially help to broaden the current disorder classification. This article provides an overview of current autoinflammatory disorders and how inexplicable inflammation and pain may factor into classifying new autoinflammatory disorders.

The inflammasome

Identification of the inflammasome and its physiologic role helped to elucidate autoinflammatory disorders as being caused by dysregulation of the innate immune system. The inflammasome is a complex of proteins composed of a sensor protein, the adapter protein apoptosis-associated speck-like protein with CARD domain (ASC), and caspase-1. Four sensor proteins have been identified: NLRP1, NLRP3, NLRC4, and AIM2. Binding of stimuli to the sensor protein promotes assembly of the complex and activation of caspase-1. The NLRP1, NLRC4, and AIM2 inflammasomes are activated by specific microbial stimuli, whereas NLRP3 can be activated by a broad range of microbial and sterile stimuli. Once activated, the inflammasome processes proIL-1β into its active form. IL-1β is a potent regulator of inflammatory responses. Activation of IL-1β in response to inflammatory stimuli is a 2-step process. The first step involves increased production of proIL-1β. Basal expression of proIL-1β is low and is induced by nuclear factor (NF)-κB. Activation of NF-κB occurs through pathogen-associated molecular patterns (PAMPs) that stimulate phagocytic cells or through primary cytokines. The second step is activation of inflammasomes.

The NLRP3 inflammasome is the most studied inflammasome. Microbial activation can occur through bacteria, fungi, and viruses. Unlike other inflammasomes, the NLRP3 inflammasome can be activated in sterile environments by nonmicrobial stimuli; extracellular ATP, monosodium crystals, calcium pyrophosphate dehydrate crystals, cholesterol crystals, and oligomers of islet amyloid polypeptide are all capable of activating NLRP3 inflammasomes. Several of these nonmicrobial activators are also involved in the pathogenesis of other diseases with a strong inflammatory component such as gout and type 2 diabetes. Thus a broad range of stimuli or genetic defects can cause dysregulation of the innate immune system and induce an autoinflammatory response. In the established HPF syndromes and the emerging autoinflammatory disorders, dysregulation of the innate immune system, specifically the inflammasome, is at the epicenter and abnormal inflammasome activity results in increased IL-1β levels.

Inflammasome autoactivation disorders

Familial Mediterranean fever (FMF) is an HPF disorder. Patients with FMF experience episodic bouts of fever and serosal inflammation lasting up to 3 days and occurring every 10 days to once a year. During attacks, patients also experience debilitating muscle and joint pain. Defects in the MEFV gene encoding for pyrin have been found to cause FMF. Pyrin is a regulator of capsase-1 activation. The defective pyrin protein causes an overactive inflammasome, which leads to increased levels of IL-1β.

Mutations in the PSTPIP1 (proline-serine-threonine-phosphatase interacting protein 1) gene have been identified as the cause of PAPA syndrome. PAPA syndrome is an autosomal dominant hereditary syndrome that has some clinical similarities to FMF. Sterile arthritis of the knees, elbows, and ankles develops in early childhood in patients with PAPA. Symptoms also include cystic acne and pyoderma gangrenosum, which last into adulthood and may cause debilitating pain. Infection has yet to be found in cultures from skin lesions or joint fluids. PSTPIP1 interacts with pyrin to regulate inflammasome activity. Mutations result in hyperphosphorylation of PSTPIP1 disrupting regulation of the NLRP3 inflammasome, which causes increased production of IL-1β.

The cryopyrin-associated periodic syndromes (CAPSs) are a group of 3 syndromes that are also HPF syndromes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). FCAS is the least severe and is characterized by cold-induced fever and rashes. MWS is more severe and is accompanied by hearing loss and arthritis. NOMID is the most severe and is characterized by chronic fever, hives, hearing loss, overgrowth of the epiphyses of the long bones, chronic meningitis, cerebral atrophy, and delayed atrophy. All 3 are caused by inherited or de novo mutations in the NLRP3/CIAS1 gene (previously called cryopyrin). The encoded NLRP3 protein is defective in regulation and is constitutively active. Subjects afflicted with any of the CAPSs have increased levels of IL-1β. Biologic therapies for the CAPSs target IL-1β and are effective in managing the disorders. Although CAPS is caused by defects in NLRP3 , the causes of increased levels of IL-1β and the origin of the IL-1β remain unknown. It is also unknown why CAPSs only affect certain organs and not others. Mouse models of CAPS have been developed which will help to address these questions.

Metabolite autoinflammatory diseases

Gout is an autoinflammatory disorder marked by severe swelling and pain of the joints. Attacks are recurring and acute, and, if left untreated, can progress into chronic tophaceous gout. Gout is caused by an accumulation of monosodium urate (MSU) crystals. However, MSU crystals are not the sole causative agent in gout. One study investigated what effect MSU crystals or free fatty acids (FFAs) had on human peripheral blood mononuclear cells (PBMCs) and murine macrophages in vitro. Neither produced IL-1β when exposed to MSU crystals or FFAs alone. When PBMCs or murine macrophages were simultaneously exposed to both, large amounts of IL-1β were produced. Thus accumulation of MSU crystals and FFAs activate the NLRP3 inflammasome, resulting in increased levels of IL-1β. This finding is consistent with the clinical manifestation of gout frequently occurring during night. Released IL-1β then binds IL-1 receptors on macrophages, which leads to additional production of proinflammatory cytokines and chemokines.

Mevalonate kinase deficiency (MKD; formerly called hyperimmunoglobulinemia D syndrome [HIDS]) is an HPF syndrome caused by a recessively inherited defect in the mevalonate kinase gene. Mevalonate kinase is the second enzyme in the mevalonate pathway of cholesterol synthesis. Deficiencies result in reduced levels of downstream metabolites. Episodic attacks last longer than those associated with FMF. Symptoms can include abdominal pain, headache, cervical lymphadenopathy, arthritis, and diarrhea. Dysregulation of the inflammasome in HIDS has also been identified. Experiments that inhibited mevalonate kinase by alendronate in human PBMCs treated with lipopolysaccharide (LPS) resulted in a 20-fold increase in NLRP3 expression and increased levels of secreted IL-1β. When treated with alendronate or LPS alone, NLRP3 expression was only increased approximately 2.5-fold. Basal levels of NLRP3 in PBMCs isolated from 2 subjects with MKD were also increased. When these PBMCs were stimulated with just LPS, levels of IL-1β increased. Thus a functioning mevalonate kinase gene and downstream metabolites are necessary for proper inflammasome regulation. Similar to gout, it also seems that multiple stimuli are required to elicit an autoinflammatory response in MKD.

Type 2 diabetes is now recognized as an autoinflammatory disease. High levels of glucose stimulate beta cells to produce IL-1β, indicating a direct role for IL-1β in the disease. Glucose, FFAs, and leptin all induce production of IL-1β from human islets. Adipocyte differentiation and insulin resistance are controlled by caspase-1 activation and production of IL-1β. Inhibition of IL-1β improves insulin sensitivity. Taken together, these results highlight the central role of IL-1β in type 2 diabetes and confirm its classification as autoinflammatory.

NF-κB diseases

Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS) was the first disorder to be recognized as autoinflammatory. TRAPS is a dominantly inherited disorder characterized by episodic periods of fever, abdominal pain, migratory erythema, myalgia, and periorbital edema. Molecular cloning identified a missense mutation in the TNFRSF1A gene, which encodes for a TNF receptor. Mutations result in increased activity of NF-κB and, ultimately, increased production of IL-1β.

Blau syndrome is an autosomal dominant hereditary disease with a childhood onset. Symptoms include iritis, skin rash, granulomatous arthritis, and periarticular synovial cysts. Blau syndrome is caused by mutations in the NOD2 gene. NOD2 is a cytosolic protein that recognizes muramyl dipeptide (MDP), the minimal active peptidoglycan motif common to bacteria. On MDP recognition, NOD2 activates and interacts with RIP2 activating NF-κB. Mutations in NOD2 cause excessive activation and signaling of NF-κB, resulting in increased IL-1β levels.

Autoinflammatory disorders downstream of IL-1β

Deficiency of the IL-1 receptor agonist (DIRA) is a recently described autoinflammatory disorder. Symptoms present within 2.5 weeks of birth and include fetal distress, pustular rash, joint swelling, oral mucosal lesions, pain with movement, and cutaneous pustulosis. The pathogenesis of DIRA is caused by deletion or truncation of the IL1RN gene. Patients with DIRA fail to produce a functioning IL-1 receptor agonist (IL1RA), which plays a crucial role in modulating the effects of IL-1β at the receptor level. Other autoinflammatory disorders can be traced to mutations or changes to stimuli upstream of IL-1β production or activation, but DIRA is unique because the disorder is caused by defects downstream of IL-1β.

Autoinflammatory pain

There are 3 types of recognized pain: nociceptive, neuropathic, and inflammatory. Nociceptive pain is the result of noxious stimuli activating sensory neurons. Nociceptors respond to temperature, chemical, and mechanical stimuli. Neuropathic pain arises from damage or dysfunction to the nervous system. Normal sensory cells generate action potentials from the end of the nerve at the receptive field. Damaged nerve cells can generate pathologic ectopic discharges from the site of injury, and healthy nerve fibers near damaged nerves can also spontaneously generate pain. Ectopic and spontaneous pain are examples of neuropathic pain. Inflammatory pain results from damaged tissue, cancer cells, and other inflamed tissues, which release inflammatory mediators known as an inflammatory soup that modulates nociceptors to perceive pain. Posttranslational modification to nociceptors alters their response, making them more sensitive to pain. Peripheral nociceptors are normally dormant in the absence of stimuli. When activated, they produce an acute response that provides a warning of eminent danger and plays an essential function in an organism’s survival.

In particular, IL-1β hypersensitizes nociceptors and proinflammatory cytokines play an important role in hyperalgesia and inflammatory pain. Part of this response is alterations of periphery nociceptors that reduce their threshold and increase their sensitivity. The goal of hyperalgesia is to heighten pain awareness to prevent further injury to the afflicted area. Dysregulation of IL-1β can result in increased nociceptor sensitization and eventually neuropathic pain. Attacks and increased levels of IL-1β are episodic in the HPF syndromes; associated pain is acute and does not progress into neuropathic pain. Other autoinflammatory disorders that are not episodic may have associated chronic pain.

The symptoms of gout are extremely painful. Gout initially presents as acute flares, but can progress into a chronic state. Activation of IL-1β produces increased levels of inflammatory mediators and chemokines, which create an influx of neutrophils into the joint. In addition to the direct role that IL-1β has in modulating pain, neutrophils may also have hyperalgesic properties. Chemokines are also important in modulating pain. Thus IL-1β may not only increase pain in gout but also amplify it. Treatment of gout with anakinra, a recombinant IL-1 receptor antagonist, or canakinumab, an anti–IL-1β monoclonal antibody, improves symptoms of acute and chronic tophaceous gout. Blocking or inhibiting the effects of IL-1β in treating gout reinforces the central role IL-1β has in autoinflammation as well as pain.

Given the important role that IL-1β plays in pain modulation, subjects with type 2 diabetes frequently experience peripheral neuropathic pain. However, only 3% to 25% of subjects experience peripheral neuropathic pain. Why only a small portion of subjects with type 2 diabetes experience peripheral neuropathic pain is unclear. Clinical trials with anakinra in subjects with type 2 diabetes showed improvements in beta-cell function and inflammation. Current pain management therapies for type 2 diabetes do not target IL-1β function. Treatments include lipoic acid, tricyclic antidepressants, gabapentin, pregabalin, duloxetine, and oxycodone. Because of the central role IL-1β plays in pain, IL-1β antagonists and blockers could be potential therapeutic agents for pain relief as well as for helping to manage symptoms in subjects with type 2 diabetes.

The link between autoinflammation and pain is further underscored in animal models. One study screened N -ethyl- N -nitrosourea (ENU)–mutated mice to identify a mouse model for pain. This line showed abnormal nociceptor responses and was hypersensitive to pain. The line also showed symptoms of autoinflammation. These mice showed normal behavior and were otherwise healthy. A mutation in the PSTPIP2 gene, the same gene implicated in PAPA syndrome, was identified as the causative factor. A successful screen for a pain model in mice yielded a mutation known to cause an autoinflammatory disorder. The identification of this mouse model highlights the importance of pain in autoinflammatory disorder and how the two are interconnected.