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Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.
Autoinflammatory diseases are a separate class from autoimmune diseases; however, both are characterized by an immune system malfunction that may cause similar symptoms, such as rash, swelling or fatigue. However, the main source of the diseases are different. A key difference between the two classes of diseases is that while AIDs trigger a malfunction of the innate immune system, autoimmune diseases trigger a malfunction of the adaptive immune system. [1]
The boundaries between autoinflammation (overactivity of the innate immunity), autoimmunity (overactivity of the adaptive immunity) and immunodeficiency (decreased activity of the innate or adaptive immunity) are often fluid. Clinical phenotypes associated with these processes are driven by the cell type most affected by a particular mutation or signal. Excessive activation of neutrophils, monocytes/macrophages and dendritic cells leads to auto-inflammatory symptoms, while T cell and B cell dysfunction leads to autoimmunity. Failure of innate and/or adaptive immune cells to appropriately activate, recognize, and clear infectious agents causes immunodeficiency and vulnerability to infection. [2]
Most proteins known to be involved in hereditary AIDs are involved in the regulation of interleukin-1 β (IL-1β). Their mutations induce increased and/or prolonged secretion of IL-1β, a pro-inflammatory and pyrogenic cytokine. [4]
Patients with AIDs often suffer from non-infectious fever and systemic and/or disease-specific organ inflammation. The over-secretion of pro-inflammatory cytokines and chemokines leads to organ damage and can be life-threatening. For such patients, excessive IL-1 signaling, constitutive NF-κB activation, and chronic IFN I signaling are specific. Some AIDs seemingly do not have any specific pivotal pro-inflammatory mediators, being caused by the accumulation of metabolites or triggered by intracellular stress or cell death. [2]
Loss of negative regulators results in an inability to attenuate pro-inflammatory cytokine responses, causing autoinflammation.
Among these negative regulators, antagonists of IL-1 receptor (IL-1Ra) or IL-36 receptor (IL-36Ra) can be concluded. Loss-of-function mutations of IL-1Ra can develop fatal systemic inflammatory response syndrome. Another example is the inability of the anti-inflammatory cytokines, such as IL-10, to signal through its receptor. That, again, can lead to systemic inflammation and severe inflammatory bowel disease (IBD). This shows that even single-cytokine dysregulation can cause autoinflammatory diseases. Some mutations can change the ability of cytotoxic cells to induce cell death, failing to terminate macrophage and dendritic cell activation and causing macrophage activation syndrome. [2]
As indicated above, AIDs are caused by abnormal innate immune activation and, in the case of inflammasome disorders, are attributable to activation of an inflammasome complex nucleated by innate immune sensors such as NLRP1 (nucleotide-binding oligomerization domain (NOD)-like receptors), pyrin, or NLRC4 (NOD-like receptors(NLR) Family CARD Domain Containing 4).
Inflammasomes are cytoplasmic protein complexes that can generate active, secreted IL-1β and IL-18 from a cell. The sensors of innate immunity help to activate caspase 1 from pro-caspase 1. When activated, caspase 1 cleaves precursors of the pro-inflammatory cytokines pro-IL-1β and pro-IL-18 to their active forms.
There have been reports of patients with activating mutations in NLRP1, where arginine is affected. There is a de novo heterozygous Pro1214Arg substitution in some cases, while in others there is a homozygous arginine to tryptophan substitution at position 726 (R726W). It has been shown that the mutation position matters. Pro1214Arg is located in the FIIND (from function to find domain) domain, which is important for NLRP1 activation. R726W is located in the linker region between the NOD and LRR (from leucine rich) domains.
All of the patients with such mutations exhibited dyskeratosis, arthritis, recurrent fever episodes, recurrent elevated CRP (from C-reactive protein ) levels, and vitamin A deficiency. [5]
Among the AIDs caused by the NLRP1 mutation are multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). [6]
A hereditary disorder driven by pyrin mutation, called PAAND (Pyrin-associated autoinflammation with neutrophilic dermatosis) [6] , is characterized by neutrophilic dermatosis, recurrent fever, increased acute-phase reactants, arthralgia, or myalgia.
Patients with PAAND have a serine-to-arginine substitution at position 242 in pyrin. This loss of serine at position 242 causes the inability of 14-3-3 to bind to this region and to inhibit pyrin, resulting in spontaneous inflammasome formation by pyrin, increased recruitment of pro-caspase-1 via ASC (from adaptor molecule apoptosis-associated speck-like protein containing a CARD ), increased IL-1β secretion, and pyroptosis.
The 14-3-3 molecule can bind and inhibit pyrin inflammasome activity due to RhoA activity. RhoA regulates pyrin through the activation of serine-threonine kinases, which phosphorylate the serine of pyrin at S208 and S242 and allow the signaling molecule 14-3-3 to bind pyrin. Already mentioned serine-to-arginine substitution at position 242 in pyrin causes the loss of RhoA activity and thus activation of the pyrin inflammasome.
One of the best-known pyrin AIDs is Mevalonate kinase deficiency, which is an enzyme in the cholesterol biosynthesis pathway. This loss/lack of enzyme results in mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS). [5]
It has been proven that NF-κB (nuclear factor κB) is overactivated in cells of the gut mucosa of patients with inflammatory bowel diseases, including Crohn's disease (CD), which is a well known AID. [7] The constitutive activation of NF-κB, not only in CD, is in particular caused by alanine (A20) deficiency. [8]
NFκB pathway is tightly regulated through multiple posttranslational mechanisms including ubiquitination. Mutations in these regulatory pathways often cause diseases connected with malfunctions of NF-κB. The loss-of-function mutations in HOIL-1L and HOIP, which are subunits of the linear ubiquitin chain assembly complex (LUBAC), result in phenotypes, characterized by immunodeficiency, multi-organ autoinflammation, and elevated NF-κB signaling. Also the hypomorphic mutations in deubiquitinase enzyme OTULIN (from OTU deubiquitinase with linear linkage specificity), results in elevated NF-κB signaling causing an autoinflammatory syndrome. Similarly, patients with high-penetrance heterozygous mutations in the gene encoding A20 display excessive ubiquitination and increased activity of NFκB. Such patients present with Behçet-like characteristics or an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. [9]
In addition to antivirus and antitumor effects, interferons (IFNs) also have broad immune-modulating functions, including enhancing the antigen-presentation function of dendritic cells, promoting T lymphocyte response and B lymphocyte antibody production, and restraining proinflammatory cytokine production. The production and signaling of IFNs are tightly regulated and dysregulation has been linked to inflammatory diseases, such as systemic lupus erythematosus and a growing number of conditions that clinically present as autoinflammatory diseases. It is very often a mutation that somehow influences the expression/function of IFNs. In the case of Aicardi-Goutieres syndrome 7 (AGS7), the gain-of-function mutation in a sensor molecule in the RNA-sensing pathway leads to both spontaneous and enhanced ligand-induced IFN-β transcription. [2]
Some AIDs, such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), appear to be associated with dysfunction of the proteasome. This syndrome is caused by a mutation in the gene that encodes subunit β type-8 of the proteasome ( PSMB8 gene). Due to this mutation, there is a problem with the proteolysis of proteins and their presentation to the cells of innate immunity. This results in the accumulation of intermediates in the cell and accumulation of the proteins in the tissues. This leads to elevated cell stress, activation of Janus kinase, and production of IFNs. [10]
Systemic activation of macrophages is characterized by the accumulation of activated macrophages, which secrete a large number of inflammatory mediators, such as cytokines, chemokines, DAMPs, etc. They can become hemophagocytes. Once considered the diagnostic hallmarks of macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH), they can be abundant in organs of the reticuloendothelial system during systemic inflammation. These inflammatory cytokines cannot be cleared and inflammatory mediators cause fever, cytopenias, coagulopathy, and central nervous system inflammation, which can progress to sepsis-like pathophysiology, shock, and death. The progression of macrophage activation in the context of rheumatic diseases is historically called MAS, and in the context of the familial monogenic defects resulting in impaired NK (natural killer cells) or CD8+ T cell cytotoxicity, it is called HLH. Systemic macrophage activation is also associated with chronic overproduction of IL-18, which may also impair cytotoxicity. Chronic IL-18 exposure may cause impairments in cytotoxicity or NK cell death, thus promoting macrophage activation by priming lymphocyte inflammatory response or disabling/depleting NK cells. IL-18-induced NK cell dysfunction resulting is a defect shared between MAS and cytotoxicity-related HLH. This macrophage activation can be caused by increased activity of intracellular sensor NLRC4 and subsequent constitutive NLRC4 inflammasome activation. The macrophage activation can be due to the loss of the negative regulatory effect of cytotoxicity. [2]
Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are susceptible to FMF, it usually occurs in people of Mediterranean origin—including Sephardic Jews, Mizrahi Jews, Ashkenazi Jews, Assyrians, Armenians, Azerbaijanis, Druze, Levantines, Kurds, Greeks, Turks and Italians.
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed mainly by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.
Caspase recruitment domains, or caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARDs are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.
Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.
Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3). ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B). The second chain of αMβ2 is the common integrin β2 subunit known as CD18, and integrin αMβ2 thus belongs to the β2 subfamily integrins.
Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of the adaptive immune system, people with autoinflammatory diseases do not produce autoantibodies or antigen-specific T or B cells. Instead, the autoinflammatory diseases are characterized by errors in the innate immune system.
NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.
Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.
NLRP1 encodes NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1 in humans. NLRP1 was the first protein shown to form an inflammasome. NLRP1 is expressed by a variety of cell types, which are predominantly epithelial or hematopoietic. The expression is also seen within glandular epithelial structures including the lining of the small intestine, stomach, airway epithelia and in hairless or glabrous skin. NLRP1 polymorphisms are associated with skin extra-intestinal manifestations in CD. Its highest expression was detected in human skin, in psoriasis and in vitiligo. Polymorphisms of NLRP1 were found in lupus erythematosus and diabetes type 1. Variants of mouse NLRP1 were found to be activated upon N-terminal cleavage by the protease in anthrax lethal factor.
Nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain (PYD)-containing protein 12 is a protein that in humans is encoded by the NLRP12 gene.
The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the cell via phagocytosis or pores, and damage-associated molecular patterns (DAMPs) that are associated with cell stress. They are types of pattern recognition receptors (PRRs), and play key roles in the regulation of innate immune response. NLRs can cooperate with toll-like receptors (TLRs) and regulate inflammatory and apoptotic response.
Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.
Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome, the Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway, and keratoendotheliitis fugax hereditaria in which the autoinflammatory symptoms affect only the anterior segment of the eye.
A pyrin domain is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the pyrin protein, or marenostrin, encoded by MEFV. The mutation of the MEFV gene is the cause of the disease known as Familial Mediterranean Fever. The domain is encoded in 23 human proteins and at least 31 mouse genes.
NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6
The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. NOD-like receptors are a type of pattern recognition receptor that are found in the cytosol of the cell, recognizing signals of antigens in the cell. NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or pathogen-associated molecular patterns, such as such as peptidoglycan, which is found on some bacterial cells. It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the inflammasome, including K+ efflux and caspase 1 activation. NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. As of now, there are at least 14 different known NLRP genes in humans, which are named NLRP1 through NLRP14. The genes translate into proteins with differing lengths of leucine-rich repeat domains.
The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.
Thirumala-Devi Kanneganti is an immunologist and is the Rose Marie Thomas Endowed Chair, Vice Chair of the Department of Immunology, and Member at St. Jude Children's Research Hospital. She is also Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude Children's Research Hospital. Her research interests include investigating fundamental mechanisms of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer.