Autoinflammatory diseases
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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 in the two classes of diseases is that while AIDs triggers 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]
Classification
Clinical classification
- Episodic and multisystem AIDs (PFAPA (Periodic fever syndrome, aphthous stomatitis, pharyngitis, and cervical adenitis) or TRAPS(tumor necrosis factor (TNF) receptor–associated periodic fever syndrome))
- Episodic, affecting the joints (Gout)
- Episodic, affecting bone (Chronic recurrent multifocal osteomyelitis (CRMO))
- Persistent and multisystemic (Schnitzler syndrome, Crohn's disease, or DIRA)
- Persistent, affecting the skin (Sweet syndrome or Neutrophilic panniculitis) [3]
Molecular mechanism of the origin
- Inflammasome activation (Mevalonate kinase deficiency or Muckle–Wells syndrome)
- NFκB activation (NLRP12-associated disease, Crohn's disease or Blau syndrome)
- IL‑1β pathway dysregulation (PFAPA, Schnitzler syndrome, DIRA or DITRA)
- Impaired efficacy of cytotoxic T lymphocytes with compensatory macrophage activation (Familial hemophagocytic lymphohistiocytosis (HLH))
- Inactivation of IL‑10 signaling (Early-onset enterocolitis)
- Multiple (TRAPS) and Uncharacterized (CRMO or Behçet disease)[3]
Simplified classification by the predominant cytokine or pathway
Mechanisms of the origin
Most proteins known to be involved in hereditary AIDs are involved in the regulation of
Patients with AIDs often suffer from noninfectious 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
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 (
Inflammasome mediated autoinflammatory disorders
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.
NLRP1
There have been reports of patients with
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]
Pyrin
A hereditary disorder driven by pyrin mutation, called PAAND (Pyrin-associated autoinflammation with neutrophilic dermatosis), 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
Relopathies (NFkBopathies)
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
Interferonpathies
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]
Dysregulation of proteasomes
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]
Persistent macrophage activation
Systemic activation of