Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system.
Failure of innate and/or adaptive immune cells to appropriately activate, recognize, and clear infectious agents causes immunodeficiency and vulnerability to infection.
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.
[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).
[6] Among the AIDs caused by the NLRP1 mutation are multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC).
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.
One of the best-known pyrin AIDs is Mevalonate kinase deficiency, which is an enzyme in the cholesterol biosynthesis pathway.
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.
Similarly, patients with high-penetrance heterozygous mutations in the gene encoding A20 display excessive ubiquitination and increased activity of NFκB.
[10] 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.
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.