Understanding autoinflammation

By Kai Yee Eng

Our immune system detects, identifies, and removes pathogens or any potential threats. One of the characteristics of the immune system which allows its function is the ability to differentiate between  foreign molecules and healthy cells. However, when the immune system fails to distinguish between the two and is erroneously activated, the immune system will attack own cells and in severe cases lead to death. This can be separated into two general categories based on the arm of immune system involved: autoimmunity pertains to the adaptive immune system and involves production of autoantibodies or self-reactive T cells that attack our own tissues, autoinflammation on the other hand activates only the innate immune system, which is manifested clinically with symptoms such as recurrent fever and localized inflammation. (Arakelyan et al., 2017)

Before we discuss autoinflammation in-depth, let us first consider inflammation. Inflammation occurs when the receptors received a stimulus, namely DAMPs (danger-associated molecular patterns) or PAMPs (pathogen-associated molecular patterns). (Chen et al., 2018) The stimulus will trigger the pattern recognition receptors, initiating a cascade of reactions that ultimately lead to inflammasome formation and a state of inflammation. These reactions result in the release of pro-inflammatory cytokines and the increase of blood flow to recruit more white blood cells, among which are monocytes, which later mature to form macrophages. Both cells are cytokine producers at the site of inflammation. These pro-inflammatory cytokines help to combat infections by facilitating infiltration of white blood cells and acting as cell signalling molecules to white blood cells to relay information about the severity of the infection or if the threat has been removed. 

However, when inflammation is uncontrolled, the white blood cells and the excess pro-inflammatory cytokines can cause damage to healthy cells. Inflammation-related proteins such as C-reactive protein contribute to cardiovascular diseases by promoting platelet activation and thrombus formation. (Badimon et al., 2018) Serum amyloid A protein accumulation due to inflammation can cause a condition known as amyloidosis. (Obici and Merlini, 2012) Patients with amyloidosis are at risk of organ failure. These highlights the importance of regulation of inflammation. Other forms of damage include that incurred by pyroptosis, a form of programmed cell death mediated by Gasdermin D. Gasdermin D is activated by caspase-1, the downstream effector of the inflammasome, and forms a pore on the cell membrane that leads to cell lysis.(Swanson et al., 2019)

Now, we can look into the first step to formation of inflammasome: the receptors or sensors. A gain-of-function mutation in the receptor produces hypersensitive receptors. This means the receptor can now respond to stimulus at lower levels which are not harmful to healthy cells. One such receptor is the NLRP3 inflammasome. NLRP3 can recognise a wide range of molecules and plays a critical role in infections. (Kelley et al., 2019) The activation of NLRP3 inflammasome involves two steps, the first of which is priming or licensing, followed by the formation of inflammasomes. The NLRP3 inflammasome has three main structures: the sensor, NLRP3, the adaptor, ASC (apoptosis-associated speck-like protein with a CARD) and the effector pro-caspase-1. Pro-caspase-1 is activated via the formation of the inflammasome, which then cleaves pro-IL-1β and pro-IL-18 to their active forms. (Broderick, 2019; Mariathasan and Monack, 2007)Diseases with NLRP3 inflammasome gain-of-function mutation are collectively known as cryopyrin-associated periodic syndrome (CAPS), as NLRP3 was initially named cryopyrin. Patients of CAPS shared symptoms of recurrent fever, joint pain and swelling. 

Next is the pyrin inflammasome, which has a similar structure to the NLRP3 inflammasome. It is widely known for mutation of pyrin gene on chromosome 16, MEFV, (Kelley et al., 2019) which causes Familial Mediterranean fever. Pyrin-associated autoinflammation with neutrophilic dermatosis(PAAND)e is also another mutation which increases pyrin inflammasome activation and IL-1β secretion. Patients with PAAND experiences different symptoms such as lymphadenopathy and joint pain.(Kelley et al., 2019) However, the release of activated cytokines through caspase-1 reaction is not the only way the pyrin inflammasome causes local damage. The interaction between pyrin and ASC suggests another regulation between leukocyte apoptosis and NF-κB activation.(Broderick, 2019) Pyrin inflammasome is regulated by phosphorylation and constitutive inhibition; however, it is not clearly understood how these signals inhibit or activate phosphatase. Furthermore, mouse models of autoinflammatory disease suggest that the pyrin inflammasome might have a role in inflammasome sensor of actin dynamics, which later increases the IL-18 secretion. 

Beyond the inflammasome, cytokines play a major role in cell signalling and inflammation. Cytokines can be separated to 2 categories: pro-inflammatory cytokines such as IL-1β and IL-18, and anti-inflammatory cytokines such as IL-4 and IL-10. (Zhang and An, 2007) TGF-β can be both pro-inflammatory and anti-inflammatory cytokine depending on the circumstances. The cytokine of interest is IL-1β, whose activation is the downstream effect of inflammasomes assembly. Alongside IL-1β, IL-1α has a controversial role in autoinflammation. (Rösen-Wolff and Rubartelli, 2019) Specifically, it has been observed that IL-1α secretion is increased in CAPS diseases, although the release is not inflammasome-dependent. (Carta et al., 2015) In recurrent macrophage activation syndrome, IL-18 is observed to be secreted at high levels and injection of IL-18 binding protein has been able to produce protective effect to patient’s health. (Rösen-Wolff and Rubartelli, 2019) 

It is undeniable that autoinflammation can lead to drastic consequences to patients. At present, genetic testing helps to identify mutations in a patient in the diagnosis process. Nevertheless, as different patients manifest different symptoms, the diagnosis process has been difficult for both the clinicians and the patients. Patients with autoinflammatory diseases faces huge challenge in leading their life as they experience pain, swelling and periodic fever. Currently, colchicine is widely used to treat FMF, and IL-1 targeted therapy such as Anakinra is used to inhibit downstream effect of caspase-1 in other overactivated inflammasomes. (Hoffman, 2009) However, these drugs may interfere with the inflammatory response when the patient is exposed to bacterial or viral infections. Regular monitoring is required to maintain or improve the quality of life. Therefore, more research and studies are anticipated to help in understanding autoinflammatory disease, to ease the symptoms or develop treatments. 


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