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Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that specifically catalyzes the conversion of PGH2 to PGE2. We showed that mPGES-1 null mice had a significantly reduced incidence and severity of collagen-induced arthritis compared with wild-type (WT) mice associated with a marked reduction in Abs to type II collagen. In this study, we further elucidated the role of mPGES-1 in the humoral immune response. Basal levels of serum IgM and IgG were significantly reduced in mPGES-1 null mice. Compared with WT mice, mPGES-1 null mice exhibited a significant reduction of hapten-specific serum Abs in response to immunization with the T cell–dependent (TD) Ag DNP-keyhole limpet hemocyanin. Immunization with the T cell–independent type 1 Ag trinitrophenyl-LPS or the T cell–independent type 2 Ag DNP-Ficoll revealed minimal differences between strains. Germinal center formation in the spleen of mPGES-1 null and WT mice were similar after immunization with DNP-keyhole limpet hemocyanin. To determine whether the effect of mPGES-1 and PGE2 was localized to hematopoietic or nonhematopoietic cells, we generated bone marrow chimeras. We demonstrated that mPGES-1 deficiency in nonhematopoietic cells was the critical factor for reduced TD Ab production. We conclude that mPGES-1 and PGE2-dependent phenotypic changes of nonhematopoietic/mesenchymal stromal cells play a key role in TD humoral immune responses in vivo. These findings may have relevance to the pathogenesis of rheumatoid arthritis and other autoimmune inflammatory diseases associated with autoantibody formation.

Activated fibroblasts, also known as myofibroblasts, are mediators of several major human pathologies including proliferative fibrotic disorders, invasive tumor growth, rheumatoid arthritis, and atherosclerosis. We previously identified Niemann-Pick type C2 (NPC2) protein as a negative regulator of fibroblast activation (Csepeggi, C., Jiang, M., Kojima, F., Crofford, L. J., and Frolov, A. (2011) J. Biol. Chem. 286, 2078–2087). Here we report that NPC2-deficiency leads to a dramatic up-regulation of the arachidonic acid (AA) metabolic pathway in human fibroblasts. The major enzymes in this pathway, cPLA2 type IVA, COX-2, and mPGES-1, were dramatically up-regulated at both the transcriptional and translational levels. The specific phenotypic changes resulted in a >10-fold increase in the production and secretion of a key modulator of inflammation and immunity, prostaglandin E2. More importantly, AA metabolome profiling by liquid chromatography/tandem mass-spectrometry revealed the very specific nature of prostaglandin E2 up-regulation as the other analyzed AA metabolites derived from the COX-2, cytochrome P450, 5/15-lipoxygenase, and non-enzymatic oxidative pathways were mostly down-regulated. Blocking activity of cPLA2 efficiently suppressed expression of inflammatory cytokines, IL-1β and IL-6, thereby identifying cPLA2 as an important regulator of the inflammatory program in NPC2-null cells. Altogether, these studies highlight NPC2 as a specific regulator of AA metabolism and inflammation that suggests potential for NPC2 protein or its related signaling in the treatment of inflammatory diseases characterized by the presence of activated fibroblasts. Background: NPC2 is a protein that negatively regulates fibroblast activation. Results: NPC2-null human fibroblasts display induction of cPLA2, COX-2, and mPGES-1 expression that may contribute to the observed robust and selective activation of PGE2 biosynthesis. Conclusion: NPC2 may regulate the activated fibroblast inflammatory program through modulation of a cPLA2-dependent biosynthetic pathway. Significance: NPC2 may represent a novel therapeutic tool for the treatment of inflammatory diseases.

A 69-year-old Caucasian female, with a previous diagnosis of 5q minus myelodysplastic syndrome, presented with conventional renal cell carcinoma (RCC) associated with multiple-epithelioid nonnecrotizing granulomas. Two previous reports of sarcoidosis, primarily involving the lung and skin, have been described in patients with 5q minus myelodysplasia. A cluster of closely linked genes encoding for cytokines such as IL-4, IL-5, and IL-3 are present on chromosome 5q. Hence, in sarcoidosis, cytokine imbalances associated with the deletion of these cytokine genes have been postulated. However, an occurrence of epithelioid granulomas within a carcinoma, in preexisting clonal myelodysplastic syndrome, has not been described. The patient, in the current study, had long standing 5q minus deletion, clinically characterized by refractory anemia associated with hypolobated megakaryocytes. However, the patient's history was negative for sarcoidosis and the extensive nonnecrotizing epithelioid granulomas were confined within RCC. Due to the absence of Th-2 cytokines, such as IL-4 and IL-5, in a subset of 5q minus myelodysplastic syndrome, proinflammatory Th-1 cytokines such as IFN-γand TNF-αmay be exaggerated in an environment conducive to antigen expression. Hence, we propose a greater susceptibility for the development of granulomas, at least in a subset of patients with 5q minus myelodysplasia.

Therapy related acute lymphoblastic leukemia (t-ALL) of B cell origin is rare and constitutes approximately 2% of all ALL. Previously compiled data on the complete cytogenetic analysis of 48 t-B-ALL cases suggested that MLL rearrangement at 11q23 gene locus is the most common abnormality. Philadelphia chromosome (Ph) and a normal karyotype were reported as the second and third most common karyotypes, respectively. We investigated cytogenetic karyotypes of six t-B-ALL cases with a pre-B cell immunophenotype. Ph + t-B-ALL was noted in four of six patients previously treated with radiation and/or chemotherapy. In addition, one case demonstrated MLL rearrangement at 11q23 locus while one case demonstrated normal cytogenetic karyotype. Five of the six t-B-ALL patients had persistent leukemia following initiation of chemotherapy for secondary leukemia with survival ranging from 10 to 21 months. To our knowledge, only fourteen patients with Ph + t-B-ALL have been described in the literature. In the current study, three of four cases with Ph + t-B-ALL were associated with treated breast carcinoma while one patient was treated for Hodgkin lymphoma. All four patients had undergone radiation therapy. The results may indicate a plausible association between Ph+t-B-ALL and prior radiation exposure.

Dear Editor, Epstein Barr virus-positive (EBV +) mucocutaneous ulcer is a recently recognized entity associated with immunosuppression 1,2. We report a case of azathioprine induced EBV + lymphoproliferative disease (LPD) presenting at a site associated with long standing Crohn's associated complex perianal fistulas and recurrent perianal abscess. A 63 year old man was diagnosed with Crohn's disease (CD) approximately 30 years back after he presented with small bowel obstruction and was subsequently managed with ileocolic resection. He was medically treated by long term immunosuppression with azathioprine (150 mg per day) and then he recently underwent seton placement for the management of …

[Figure][1] A 15-year-old boy, who had recently emigrated from Sudan to the United States, presented with persistent high fevers of 2 months’ duration, and a reported diagnosis of malaria with intermittent therapy. On admission, he was pancytopenic and imaging studies showed