Clinical Development in Rare Diseases: Autoinflammatory Syndrome ”Autoinflammatory” is a term used to describe a group of diseases that cannot be classified as immunological disorders [auto-immune, allergic, or immunodeficient]1. The term was first mentioned by Michael McDermott and Daniel Kastner and colleagues, coined to describe the monogenic periodic fever syndromes when it was first proposed in 19992,3. Today, it has become an encompassing term to include diverse conditions that involve not only the disorders of the innate immune system but also polygenic, metabolic and storage disorders4. Autoinflammatory syndromes are a set of genetically diverse but clinically similar conditions caused by an exaggerated innate immune system response resulting in repeated episodes of spontaneous inflammation affecting multiple organs and manifesting as recurrent fever, mucocutaneous lesions, serositis and osteoarticular symptoms5,6,7. It is characterised by absence of pathogens, autoantibodies or antigen specific T cells and with no evidence of adaptive immune dysregulation2. It is genetically driven with resultant activation of the inflammasome and cytokine excess. Affected individuals often have first- or second-degree relatives with similar features5. In 2013, a study estimated the incidence to be 2.83 patients per million people in Sweden. The prevalence of a given disease can vary from 1:1000 people (Sweet's syndrome) to 1:1,000,000 (Marshall’s syndrome) and vary between populations. Owing to their relatively recent identification and their low incidence rates, it is believed that clinical cases are currently underdiagnosed and increased clinical awareness is required8. Concept of Autoinflammatory The innate immune response acts with immediacy to danger or pathogen signals, termed pathogen-associated molecule patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs)5. Inflammasome pathway can lead to its constitutive activation, producing inflammation in the absence of a trigger. In fact, inflammasomes are so critical to the pathogenesis of autoinflammatory syndromes that these are also referred to as inflammasomopathies. Inflammasomes belong to the family of pattern recognition receptors and are an integral part of the innate immune system. These multiprotein complexes can sense not only pathogen-associated molecular patterns but also intracellular molecules released from injured host cells7. PAMPs and DAMPs activate intracellular inflammasomes to set forth an inflammatory cascade of effector molecules. For example, as depicted in Figure 1, Nod like receptor protein3 (NLRP3) inflammasome is a cytosolic scaffold of proteins triggered by multiple signals including microbial products, endogenous substances such as cholesterol and uric acid, or by proinflammatory cytokines and chemokines leading to the activation of NLRP3 gene and the inflammasome. NLRP3 inflammasone complex consists of a protein component which is NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD) is the binding component and pro-caspase1. The pro-caspase1 gets activated to caspase1 with resultant unopposed cytokine activation such as IL-1, IL-18, TNF-α, IL-6, IL-17, type 1 interferons (IFN-α and IFN-β), and the complement system5. 38 Journal for Clinical Studies
Activation of inflammasomes produces an inflammatory response by activating caspase. Caspase activation also leads to pyroptosis, a specific form of programmed cell death, which also releases pro‑inflammatory molecules and further potentiates the inflammatory cascade. Activating mutations in genes coding for any component of the inflammasome pathway can lead to its constitutive activation, producing inflammation in the absence of a trigger7.
Figure 1: Illustrated above is the formation of an inflammasome complex. NLRP3 inflammasone complex consists of a protein component which is NLRP3, ASC (apoptosisassociated speck-like protein containing a CARD) is binding component and procaspase1 and it gets activated to caspase1, which in turn activates the pro-cytokines and chemokines to their active form.
Genetics of Autoinflammatory Disorders The spectrum of systemic autoinflammatory disorders has been evolving continually over the last decade9. The initial classifications were based on the clinical phenotypes. However, with increasing understanding of the pathogenesis, new classification systems are being based on the underlying molecular defects7. Today, 30 genes have been linked to autoinflammatory diseases8, and comprise both hereditary and multifactorial disorders7. As genetic testing is used more regularly and increasing numbers of patients are screened, there is widening of clinical phenotypes. Numerous attempts to classify autoinflammatory disorders have been made. However, until we understand the inheritance patterns as well as the influence of the environment, epigenetic factors and their interactions, any classification modality will remain arbitrary4. McGonagle and McDermott proposed a ‘continuum model’ for immunological Volume 11 Issue 6
Journal for Clinical Studies