A molecular dissection of lymphocyte unresponsiveness induced by sustained calcium signalling.

In lymphocytes, integration of Ca2+ and other signalling pathways results in productive activation, while unopposed Ca2+ signalling leads to decreased responsiveness to subsequent stimulation (anergy). The Ca(2+)-regulated transcription factor NFAT has an integral role in both aspects of lymphocyte function. NFAT cooperates with the transcription factor AP-1 (Fos/Jun) to up-regulate genes involved in productive activation of lymphocytes.

Regulation of dendritic cell subsets by NKT cells.

NKT cells expressing both invariant TCRs and NK cell receptors are an important regulatory cell subset active during initiation of innate immune responses. They are involved in a wide variety of immune responses, but the molecular details of their regulatory action are unknown. Transcriptional profiling has been used for analysis of NKT cell activation profiles, revealing that NKT cells differ from conventional T cells and would be expected to regulate immune responses by controlling dendritic cell activation.

Rac2, a hematopoiesis-specific Rho GTPase, specifically regulates mast cell protease gene expression in bone marrow-derived mast cells.

Rho family GTPases activate intracellular kinase cascades to modulate transcription of multiple genes. Previous studies have examined the roles of the ubiquitously expressed Rho GTPase, Rac1, in regulation of gene expression in cell lines and implicated NF-kappaB, serum response factor, and kinase signaling pathways in this regulation. To understand the role of the closely related but hematopoiesis-specific Rho GTPase, Rac2, in regulation of gene transcription, we compared the gene expression profiles between wild-type and Rac2(-/-) bone marrow-derived mast cells.

Gene array profiling and immunomodulation studies define a cell-mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans.

Alopecia areata is a suspected autoimmune hair loss disease. In a rodent model, alopecia areata can be induced in normal haired C3H/HeJ mice by transfer of skin grafts from mice with spontaneous alopecia areata. At weeks 2, 4, 6, and 10 after surgery, grafted mice were euthanized, skin collected and processed for histology, and RNA extracted.

Transcriptional mechanisms underlying lymphocyte tolerance.

In lymphocytes, integration of Ca2+ and other signaling pathways results in productive activation, while unopposed Ca2+ signaling leads to tolerance or anergy. We show that the Ca2+-regulated transcription factor NFAT has an integral role in both aspects of lymphocyte function. Ca2+/calcineurin signaling induces a limited set of anergy-associated genes, distinct from genes induced in the productive immune response; these genes are upregulated in vivo in tolerant T cells and are largely NFAT dependent.

Knockout of pentraxin 3, a downstream target of growth differentiation factor-9, causes female subfertility.

The ovulatory process is tightly regulated by endocrine as well as paracrine factors. In the periovulatory period, extensive remodeling of the follicle wall occurs to allow the extrusion of the oocyte and accompanying cumulus granulosa cells. Growth differentiation factor-9 (GDF-9) and bone morphogenetic protein-15 (BMP-15) are secreted members of the TGFbeta superfamily that are expressed beginning in the oocyte of small primary follicles and through ovulation.

Renal transplant in patients with Alport's syndrome.

We evaluated 52 renal grafts transplanted into 41 patients with a pretransplantation diagnosis of Alport's syndrome. Overall 1-, 5-, and 10-year patient and graft survival rates were 95.1%, 90.

CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor.

CD4(+)CD25(+) immunoregulatory T cells represent a unique lineage of thymic-derived cells that potently suppress both in vitro and in vivo effector T cell function. We analyzed CD4(+)CD25(+) and CD4(+)CD25(-) T cells by DNA microarray, identifying 29 genes differentially expressed in the resting subpopulations, and 77 that were differentially expressed following activation. Most of these genes were elevated in the CD4(+)CD25(+) population, suggesting a previously activated phenotype.