Abstract
PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, and Acne) is an autosomal dominant, hereditary auto-inflammatory disease arising from mutations in the PSTPIP1/CD2BP1 gene on chromosome 15q. These mutations produce a hyper-phosphorylated PSTPIP1 protein and alter its participation in activation of the “inflammasome” involved in interleukin-1 (IL-1β) production. Overproduction of IL-1β is a clear molecular feature of PAPA syndrome. Ongoing research is implicating other biochemical pathways that may be relevant to the distinct pyogenic inflammation of the skin and joints characteristic of this disease. This review summarizes the recent and rapidly accumulating knowledge on these molecular aspects of PAPA syndrome and related disorders.
Highlights
The auto-inflammatory disorders bear resemblance to classic autoimmune diseases such as systemic lupus in that they present with seemingly unprovoked inflammation but, unlike most autoimmune diseases, high-titer auto-antibodies or antigenic-specific T lymphocytes are not found [1,2,3]
Familial Mediterranean Fever (FMF), a recessive disorder caused by mutations in the gene encoding the pyrin protein, is the founding member of this disease class [3] that is marked by episodic inflammation of serosal or synovial tissue, fever, and occasional lesions of the skin
More recent studies have suggested an alternative mechanism in which the balance of interaction between PSTPIP1, pyrin and a caspase recruitment domain (ASC) is altered by PSTPIP1 variants E250Q and A230T in monocytes, leading to activation of the so-called “pyroptosome” that leads to cell death and release of cytokines such as IL-1 [49, 55]
Summary
The auto-inflammatory disorders bear resemblance to classic autoimmune diseases such as systemic lupus in that they present with seemingly unprovoked inflammation but, unlike most autoimmune diseases, high-titer auto-antibodies or antigenic-specific T lymphocytes are not found [1,2,3]. Other PAPA syndrome patients with either of these PSTPIP1 mutations have been reported more recently [25, 26]. CD2BP1 (PSTPIP1) and CARD15 mutations are not associated with pyoderma gangrenosum in patients with inflammatory bowel disease (Table 1) [29].
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