Syndrome of Pyogenic Arthritis Pyoderma Gangrenosum and Acne

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As noted above, the B-box and coiled-coil motifs of pyrin are also protein interaction domains, mediating binding to proline-serine-threonine phos-phatase interacting protein 1 (PSTPIP1) (Shoham et al. 2003), also known as CD2-binding protein 1 (CD2BP1) (Li et al. 1998). PSTPIP1 is a 416-amino acid protein encoded on chromosome 15q24 (Wise et al. 2002). PSTPIP1

consists of an N-terminal Fer-CIP4 domain (Aspenstrom 1997), followed by a coiled-coil region, and finally an SH3 domain at the C-terminus (Fig. 2). Both the coiled-coil and the SH3 motif are necessary for interaction with pyrin (Shoham et al. 2003).

Patients with certain mutations in the coiled-coil domain of PSTPIP1 have a condition called the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), an autosomal dominant disease associated with deforming, sterile arthropathy, severe cutaneous ulcers with pathergic reactions at sites of minor trauma (pyoderma gangrenosum), and cystic acne (Wise et al. 2002). PAPA mutations in PSTPIP1 attenuate its association with protein tyrosine phosphatase with a PEST (proline, glutamate, serine, threonine) domain (PTP-PEST) (Spencer et al. 1997; Wise et al. 2002; Badour et al. 2004), resulting in hyperphosphorylation of PSTPIP1 (Cote et al. 2002). Hyperphos-phorylation in turn increases the strength of the interaction between pyrin and PSTPIP1 (Shoham et al. 2003), perhaps preventing pyrin from exerting negative regulatory effects on the innate immune response.

Consistent with a major role for the pyrin-PSTPIPl interaction in the pathogenesis of PAPA syndrome, both proteins are expressed at high levels in neutrophils (Shoham et al. 2003), and neutrophils are the major effector cell in this disorder (Lindor et al. 1997), as is the case for FMF. Moreover, cell lines co-transfected with pyrin and PAPA-associated PSTPIP1 mutants secreted significantly more IL-1ß than cells co-transfected with pyrin and wild-type PSTPIP1 (Shoham et al. 2003), and peripheral blood leukocytes from a patient with clinically active PAPA syndrome were found to secrete high levels of IL-1ß when cultured in vitro. These results are consistent with

Papa Syndrome

Fig. 2 Protein schematic of PSTPIP1, showing the domains and binding partners. PSTPIP1 interacts with a variety of proteins involved in immune regulation, including PTP-PEST, pyrin, CD2, and WASp. Also shown are the main kinases responsible for phosphorylation events (Fyn, cAbl), as well as proteins involved in actin polymerization (cdc42, Arp2/3)

Fig. 2 Protein schematic of PSTPIP1, showing the domains and binding partners. PSTPIP1 interacts with a variety of proteins involved in immune regulation, including PTP-PEST, pyrin, CD2, and WASp. Also shown are the main kinases responsible for phosphorylation events (Fyn, cAbl), as well as proteins involved in actin polymerization (cdc42, Arp2/3)

the hypothesis that PAPA-associated PSTPIP1 mutants exert their effects in neutrophils by inducing the sequestration of pyrin, with consequent excessive IL-1ß production.

PSTPIP1 may also play a role in the regulation of the adaptive immune response. In T lymphocytes, PSTPIP1 interacts with several key molecules implicated in the formation of the "immunologic synapse" in antigen recognition (Badour et al. 2003a, b, 2004). Recent studies have clearly demonstrated a necessary role for PSTPIP1 in coupling the CD2 T cell membrane receptor with the Wiskott-Aldrich syndrome protein (WASp), thereby linking CD2 engagement with WASp-induced actin polymerization and synapse formation. This process is, in part, regulated by the phosphorylation status of both CD2 (Li et al. 1998) and WASp (Cote et al. 2002), with PTP-PEST playing a negative regulatory role (Badour et al. 2004). Although PAPA-associated mutations in PSTPIP1 do not affect its interaction with either CD2 or WASp (Wise et al. 2002), they may nevertheless accentuate immunologic synapse formation in T cells by limiting the participation of PTP-PEST in the macromolecular complex. The ramifications of these potential perturbations in the adaptive immune response for the granulocyte-mediated pathology of PAPA syndrome remain to be determined. The predicted lesion in dephosphorylation of the CD2-PSTPIP1-WASp complex might also lead to as yet undocumented increased resistance to viral or intracellular bacterial pathogens in PAPA patients, or to increased susceptibility to contact-inducted delayed-type hypersensitivity reactions.

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