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. 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.
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
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. Among the AIDs caused by the NLRP1 mutation are multiple self-healing
palmoplantar carcinoma (MSPC) and
familial keratosis lichenoides chronica (FKLC).
Pyrin A hereditary disorder driven by
pyrin mutation, called PAAND (Pyrin-associated autoinflammation with neutrophilic dermatosis), The constitutive activation of NF-κB, not only in CD, is in particular caused by
alanine (A20) deficiency. 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.
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.
Persistent macrophage activation 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. ==See also==