15 A Toolkit for Health Care Professionals Recurrent Pericarditis Introduction to the Immune System, Inflammation and Mechanisms of Drug Action The immune system plays an important role in defending the body from infectious agents/pathogens, responding to foreign/toxic material and removing abnormal potentially pre-cancerous damaged host cells (cancer surveillance).16 The immune system is divided into two main components: the adaptive immune system and the innate immune system. Each plays a crucial role in defending the body against pathogens. The adaptive immune response involves cells from the immune system recognizing specific antigens, learning to generate specific antibodies to these, or developing specific cell-mediated immunity to pathogens, damaged and infected cells.16 This adaptive process takes time to develop but provides a highly specific targeted response to antigens while minimizing injury to non-target host cells or tissues. It also requires tolerance to develop to healthy host cells and tissues.16 For an antigen the immune system has not encountered before, this process can take at least a week. This is the rationale behind vaccinations, which prime the immune system with the anticipated antigen to accelerate an anamnestic response to the antigen should it be encountered again. If this were the only component of the immune response, potential pathogens would have a significant time advantage over the host, rendering the host undefended and vulnerable to infection. Until adaptive immunity develops, the host relies on the innate immune response.17 The innate immune response refers in part to the system of proteins and phagocytic cells that are designed to recognize (using pattern recognition receptors) highly conserved molecular signatures that are unique to but common among a range of pathogens, toxins or damaged cells.17 This can include, for example, toll-like receptor proteins that recognize pathogen associated molecular patterns, such as bacterial lipopolysaccharide.18 Another group of such proteins that act within the cell to detect pathogens or cell injury are the nucleotide-binding oligomerization domain leucine-rich repeat proteins or NLR — recognizing damage/ danger-associated molecular patterns.19 When activated, one such protein, called pyrincontaining domain-3 (P3), combines with other cell proteins to form an enzyme complex called an (NLR-P3) inflammasome. This contains a cysteine proteinase called caspase-1 (also called interleukin-1 (IL-1) converting enzyme) that is activated by the inflammasome and converts inactive pro-IL-1b to its active form, interleukin-1 beta (IL-1b).19,20 The latter is a key proinflammatory cytokine that orchestrates an ongoing inflammatory response. NLR-P3 is an important inflammasome as it responds to a variety of markers of cell injury or stress, and thereby plays a key role in activating an inflammatory response.20,21 Autoimmune disease results from the inappropriate activation of the adaptive immune system by self- or autoantigens.22 In contrast, the term autoinflammation is used to describe the inappropriate activation and dysregulation of the innate immune response.22 Although acute pericarditis can occur as a complication of a systemic autoimmune disease such as SLE, most cases of idiopathic or presumed viral pericarditis are thought to have a predominantly autoinflammatory basis.23 In reality, most conditions with an immunologic basis do not have a pure autoinflammatory or autoimmune basis, but exist on a continuum with varying contributions of dysregulation of both arms of the immune system, which do not exist in isolation.24 The drugs used to treat pericarditis target different aspects of the inflammatory cascade. Colchicine is thought to inhibit the assembly of the NLR-P3 inflammasome and so indirectly reduce the production of IL-1b.25 One action of IL-1b is to stimulate the production of arachidonic acid by the enzyme lipoxygenase.26 Arachidonic acid in turn is metabolized by the enzyme cyclo oxygenase 2 to produce pro-inflammatory prostaglandins.26 Non-steroidal anti-inflammatory drugs, such as ibuprofen and aspirin, work by inhibiting cyclo-oxygenase. Corticosteroids have more pleiotropic effects, including inhibition of the transcription of pro-inflammatory genes including those for IL-1 precursors.27 Given the key role of interleukin-1b in orchestrating inflammation in acute pericarditis, recent efforts to treat pericarditis have focused on antagonizing the IL-1 receptor (anakinra, a recombinant interleukin-1 receptor antagonist) or by blocking IL-1 itself (rilonocept and goflikicept, IL-1 traps; canakinumab, a monoclonal antibody against IL-1b).23,28
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