Primary bilateral adrenal diffuse large B-cell lymphoma demonstrating adrenal failure.

Primary adrenal lymphoma (PAL) is extremely rare although involvement of malignant lymphoma into adrenals is common. We report a case of a 58-year-old man with bilateral PAL who demonstrated adrenal insufficiency. Primary large B-cell lymphoma was proven by a computed tomography-guided needle biopsy of the adrenal tumor. Although a complete remission was once achieved by combination chemotherapy plus rituximab, a recurrence occurred with brain metastasis leading to his death. We concluded that PAL should be considered as a possible cause of bilateral adrenal incidentalomas with progressive adrenal insufficiency.

Resistance to collagen-induced arthritis in SHPS-1 mutant mice.

SHPS-1 is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on dendritic cells and macrophages. Here we show that mice expressing a mutant form of SHPS-1 fail to develop type-II collagen (CII)-induced arthritis (CIA), a model for rheumatoid arthritis in humans. Histological examinations of the arthritic paws from immunized wild-type mice revealed that cartilage was destroyed in association with marked mononuclear cell infiltration, while only mild cell infiltration was observed in immunized SHPS-1 mutant mice. Consistently, the serum levels of both IgG and IgG2a specific to CII and of IL-1beta in immunized SHPS-1 mutant mice were markedly reduced compared with those apparent for wild-type mice. The CII-induced proliferation of, and production of cytokines by, T cells from immunized SHPS-1 mutant mice were reduced compared to wild-type cells. These results suggest that SHPS-1 is essential for development of CIA.

[Efficacy of steroid pulse therapy in patients with IgA nephropathy and impaired renal function].

OBJECTIVE: In the current study, we evaluated the efficacy of methylprednisolone (MP) pulse therapy in IgA nephropathy (IgAN) patients with established renal function impairment. PATIENTS AND METHODS: We retrospectively analyzed the effect of MP pulse therapy in patients with histologically active IgAN (8 males, 12 females) whose estimated glomerular filtration rate was less than 60 mL/min/1.73 m2 (33.4 +/- 13.1, mean +/- SD). The efficacy of the MP pulse therapy was analyzed by calculating the regression coefficients (dL/mg/month) from the slopes of the 1/serum creatinine (Cr), urine protein/creatinine ratio (g/g x Cr), and the estimated interval from the pulse therapy to dialysis (that is, for Cr to reach 8 mg/dL, as calculated from the slope of 1/Cr) or the actual interval. RESULTS: All patients showed improved regression coefficients (-0.0214 +/- 0.00166 vs. 0.00236 +/- 0.00895, 1 year before vs. after treatment, p < 0.01). The severity of proteinuria decreased significantly from a mean urine protein/creatinine ratio of 2.9 +/- 1.7 before therapy to 1.1 +/- 0.8 (p < 0.01) at 6 months and 0.8 +/- 0.7(p < 0.01) at 12 months after therapy. Although 7 patients underwent dialysis, the average interval from pulse therapy to dialysis was prolonged from an estimated interval of 1.1 +/- 0.9 years to an actual interval of 4.1 +/- 3.5 years. Six patients showed positive regression coefficients at the last observation (4.1 +/- 3.0 years after therapy). The remaining 7 patients who had not undergone dialysis also showed prolongation of the estimated interval from pulse therapy to dialysis of 5.9 +/- 5.1 years before pulse therapy to 25.7 +/- 20.6 years at the final observation (4.9 +/- 3.5 years after therapy). No serious side effects were observed in any of the patients. CONCLUSION: MP pulse therapy can slow the progression of renal deterioration in patients with active IgAN, even in those patients in whom renal function impairment has set in.

Resistance to experimental autoimmune encephalomyelitis and impaired T cell priming by dendritic cells in Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 mutant mice.

Src homology 2 domain-containing protein tyrosine phosphatase (SHP) substrate-1 (SHPS-1) is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is expressed on the surface of CD11c(+) dendritic cells (DCs) and macrophages. In this study, we show that mice that express a mutant form of SHPS-1 lacking most of the cytoplasmic region are resistant to experimental autoimmune encephalomyelitis (EAE) in response to immunization with a peptide derived from myelin oligodendrocyte glycoprotein (MOG (35-55)). The MOG (35-55)-induced proliferation of, and production of IFN-gamma, IL-2, and IL-17, by T cells from immunized SHPS-1 mutant mice were reduced compared with those apparent for wild-type cells. The abilities of splenic DCs from mutant mice to stimulate an allogenic MLR and to prime Ag-specific T cells were reduced. Both IL-12-stimulated and TLR-dependent cytokine production by DCs of mutant mice were also impaired. Finally, SHPS-1 mutant mice were resistant to induction of EAE by adoptive transfer of MOG (35-55)-specific T cells. These results show that SHPS-1 on DCs is essential for priming of naive T cells and the development of EAE. SHPS-1 is thus a potential therapeutic target in inflammatory disorders of the CNS and other autoimmune diseases.

Regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of alpha-galactosylceramide-induced antimetastatic activity and Th1 and Th2 responses of NKT cells.

Interaction of alpha-galactosylceramide (alpha-GalCer) presented by CD1d on dendritic cells (DCs) with the invariant TCR of NKT cells activates NKT cells. We have now investigated the role of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), a transmembrane protein abundantly expressed on DCs, in regulation of NKT cells with the use of mice that express a mutant form of SHPS-1. The suppression by alpha-GalCer of experimental lung metastasis was markedly attenuated in SHPS-1 mutant mice compared with that apparent in wild-type (WT) mice. The antimetastatic effect induced by adoptive transfer of alpha-GalCer-pulsed DCs from SHPS-1 mutant mice was also reduced compared with that apparent with WT DCs. Both the production of IFN-gamma and IL-4 as well as cell proliferation in response to alpha-GalCer in vitro were greatly attenuated in splenocytes or hepatic mononuclear cells from SHPS-1 mutant mice compared with the responses of WT cells. Moreover, CD4+ mononuclear cells incubated with alpha-GalCer and CD11c+ DCs from SHPS-1 mutant mice produced markedly smaller amounts of IFN-gamma and IL-4 than did those incubated with alpha-GalCer and CD11c+ DCs from WT mice. SHPS-1 on DCs thus appears to be essential for alpha-GalCer-induced antimetastatic activity and Th1 and Th2 responses of NKT cells. Moreover, our recent findings suggest that SHPS-1 on DCs is also essential for the priming of CD4+ T cells by DCs.

SHPS-1 promotes the survival of circulating erythrocytes through inhibition of phagocytosis by splenic macrophages.

The lifespan of circulating red blood cells (RBCs) produced in bone marrow is determined by their elimination through phagocytosis by splenic macrophages. The mechanism by which RBC elimination is regulated has remained unclear, however. The surface glycoprotein SHPS-1, a member of the immunoglobulin superfamily, is abundant in macrophages. We have now examined the regulation of RBC turnover with the use of mice that express a mutant form of SHPS-1 lacking most of its cytoplasmic region. The mutant mice manifested mild anemia as well as splenomegaly characterized by expansion of the red pulp. The numbers of erythroid precursor cells in the spleen and of circulating reticulocytes were also increased in the mutant mice. In contrast, the half-life of circulating RBCs was reduced in these animals, and the rate of clearance of injected opsonized RBCs from the peripheral circulation was increased in association with their incorporation into splenic macrophages. Phagocytosis of opsonized RBCs by splenic macrophages from mutant mice in vitro was also increased compared with that observed with wild-type macrophages. These results suggest that SHPS-1 negatively regulates the phagocytosis of RBCs by splenic macrophages, thereby determining both the lifespan of individual RBCs and the number of circulating erythrocytes.