Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder that primarily affects bone but is often accompanied by inflammation of the skin and/or gastrointestinal tract. The etiology is unknown but evidence suggests a genetic component to disease susceptibility. Although most cases of CRMO are sporadic, there is an autosomal recessive syndromic form of the disease, called Majeed syndrome, which is due to homozygous mutations in LPIN2. In addition, there is a phenotypically similar mouse, called cmo (chronic multifocal osteomyelitis) in which the disease is inherited as an autosomal recessive disorder. The cmo locus has been mapped to murine chromosome 18. In this report, we describe phenotypic abnormalities in the cmo mouse that include bone, cartilage and skin inflammation. Utilizing a backcross breeding strategy, we refined the cmo locus to a 1.3 Mb region on murine chromosome 18. Within the refined region was the gene pstpip2, which shares significant sequence homology to the PSTPIP1. Mutations in PSTPIP1 have been shown to cause the autoinflammatory disorder PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne). Mutation analysis, utilizing direct sequencing, revealed a single base pair change c.293T → C in the pstpip2 gene resulting in a highly conserved leucine at amino acid 98 being replaced by a proline (L98P). No other mutations were found in the coding sequence of the remaining genes in the refined interval, although a 50 kb gap remains unexplored. These data suggest that mutations in pstpip2 may be the genetic explanation for the autoinflammatory phenotype seen in the cmo mouse.

The mouse Lupo (I282N) mutation in proline-serine-threonine phosphataseinteracting protein 2 (PSTPIP2) leads to reduced expression of PSTPIP2 that is associated with a macrophage-mediated autoinflammatory disease. Another mutation in PSTPIP2, L98P, termed chronic multifocal osteomyelits (cmo), leads to a disease in mice that resembles chronic recurrent multifocal osteomyelits in humans. The cellular basis of cmo disease was investigated. cmo disease develops independently of lymphocytes and is cured by bone marrow transplantation. Macrophages, mast cells, and osteoclasts from cmo mice fail to express detectable PSTPIP2 protein. Asymptomatic Pstpip2 cmo/cmo mice have increased circulating levels of macrophage inflammatory protein 1-␣ and interleukin-6, and their macrophages exhibit increased production of these inflammatory mediators, which is normalized by retroviral expression of wild-type PSTPIP2. Spleens of asymptomatic cmo mice contain increased numbers of macrophage precursors, and cmo mice mobilize more macrophage precursors in response to a sterile inflammatory stimulus. Signal transducer and activator of transcription 1 is elevated in cmo splenic macrophages, which also exhibit increased colonystimulating factor-1-stimulated proliferation and increased extracellular signalregulated kinase 1/2 phosphorylation. PSTPIP2 overexpression in macrophages leads to the opposite phenotype. Thus, PSTPIP2 deficiency causes both an expansion of macrophage progenitors and increased responsiveness of mature macrophages to activating stimuli, which together prime the organism for exaggerated and sustained responses leading to autoinflammatory disease. IntroductionProline-serine-threonine phosphatase-interacting protein 2 (PST-PIP2), 1 also known as macrophage actin-associated and tyrosine phosphorylated protein (ie, MAYP), 2 belongs to the Pombe Cdc15 homology (PCH) family of proteins that has recently been shown to coordinate membrane and cytoskeletal dynamics. 3,4 Several PCH proteins play important roles in immunity by regulating neutrophil migration, 5 T-cell activation, 6-8 cell-surface expression of Fas ligand, 9,10 and cytokine production. 11,12 Mutations in PSTPIP1, the PCH family member most similar to PSTPIP2, lead to pyogenic arthritis, pyoderma gangrenosum, and acne (ie, PAPA) syndrome in humans by promoting interleukin-1␤ (IL-1␤) processing. 11,13 PSTPIP2 is selectively expressed in macrophages and macrophage precursors 2,12 and is an actin-bundling protein that regulates filopodia formation and macrophage motililty. 14 We have previously described the Lupo Pstpip2 mutation in mice. This I282N missense mutation leads to a macrophage-mediated autoinflammatory disease characterized by skin necrosis, inflammation of paws and ears, and inflammatory bone resorption. 12 PSTPIP2 expression in Pstpip2 Lupo/Lupo bone marrow-derived macrophages (BMMs) was reduced 3-fold resulting from the instability of the mutant protein. In addition, Lupo macrophages exhibited increased constitutive production of markers of macroph...

This model of ethanol administration is convenient, sustainable for up to 1 year, demonstrably feasible in several mouse strains, permits good weight gains in most strains, and results in significant changes in a number of organs. The administration method also will permit modeling of long-term steady abuse punctuated by major binges, and is suitable for supplementation studies using water soluble additives. Overall, the method is useful for a wide range of studies requiring a chronic low-stress method of ethanol administration.

Background: Chronic alcoholics experience increased incidence and severity of infections, the mechanism of which is incompletely understood. Dendritic cells (DC) migrate from peripheral locations to lymph nodes (LN) to initiate adaptive immunity against infection. Little is known about how chronic alcohol exposure affects skin DC numbers or migration.