Summary In systemic lupus erythematosus (SLE) self-reactive antibodies can target the kidney (lupus nephritis) leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE, causes their homing to lymph nodes, promoting TH2 cell differentiation, and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in Lyn−/− mice. SLE patients also have elevated serum IgE, self-reactive IgE's, and activated basophils that express CD62L and the MHC Class II molecule, HLA-DR; parameters that were found to be associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of SLE patients. Thus, in Lyn−/− mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in SLE patients, the presence of IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.

Although adoptive transfer of regulatory T cells (Foxp3 ؉ Tregs) has proven to be efficacious in the prevention and treatment of autoimmune diseases and graftversus-host disease in rodents, a major obstacle for the use of Treg immunotherapy in humans is the difficulty of obtaining a highly purified preparation after ex vivo expansion. We have identi- IntroductionRegulatory T cells (CD4 ϩ FOXP3 ϩ , Tregs) are central to the maintenance of self-tolerance and the control of immune homeostasis. 1 A diminished frequency or dysfunction of Tregs has been reported in many human diseases, including systemic lupus erythematosus (SLE), 2 type 1 diabetes, 3 multiple sclerosis, 4 aplastic anemia, 5 idiopathic thrombocytopenic purpura, 6 graft-versushost disease (GVHD) 7 and transplant rejection. 8 A detailed cellular and molecular understanding of the mechanisms of action of Tregs should provide a strong foundation for pharmacologic and therapeutic manipulation of their functions. Although numerous mechanisms have been proposed to explain the suppressive function of Tregs, none appears to be unifying, and the development of immunomodulating pharmacotherapies has been limited. 9 In mouse models, adoptive immunotherapy with Tregs has been shown to be effective in the prevention of experimental autoimmune encephalomyelitis, 10 type 1 diabetes, 11 SLE, 12 autoimmune gastritis, 13 inflammatory bowel disease, 14 aplastic anemia, 15 graft rejection, 16 and GVHD. 17 It is likely that CD4 ϩ FOXP3 ϩ Tregs represent a mixture of thymic-derived and FOXP3 ϩ Tregs that are generated at peripheral sites. 18 Human Tregs can be expanded ex vivo, 19,20 and their use for the cell-based tolerogenic therapy of autoimmune diseases, graft rejection, or GVHD has been advocated. 21,22 The major obstacle for the use of human Tregs in cell-based therapy is the difficulty of obtaining a highly pure population after ex vivo expansion. A CD4 ϩ FOXP3 ϩ population of greater than 90% purity can be isolated by fluorescence-activated cell sorting (FACS) of the top 2% to 4% of CD4 ϩ T cells with high CD25 expression (CD25 hi ) from peripheral blood, but frequently the percentage of FOXP3 ϩ T cells decreases to 75% after 1 week and to 50% after 2 weeks of expansion by stimulation with anti-CD3/CD28 and IL-2. 23 A more complex problem is the validity of FOXP3 as a bona fide marker of human Tregs. We have recently shown that expression of FOXP3 can be induced by T-cell receptor (TCR) stimulation of human CD4 ϩ CD25 Ϫ FOXP3 Ϫ T cells in the presence of TGF␤, but the induced cells lack all the functional properties of Tregs. 24 Because TGF␤ is present in the serum used for cultures, a similar induction of FOXP3 expression in contaminating FOXP3 Ϫ T cells may occur during expansion cultures of partially purified Tregs. Although the expanded population might appear to be highly enriched in FOXP3 ϩ cells, many of these cells may be induced FOXP3 ϩ cells that lack Treg functions.We have identified 3 unique cell-surface markers, latencyassociated peptide (LAP) and IL-...

There is a well described temporal relation between hormonal secretion and sleep phase, with hormones of the hypothalamic-pituitary-adrenal (HPA) axis possibly playing a role in determining entry into and duration of different sleep stages. In this study sleep features were studied in primary Addison's patients with undetectable levels of cortisol treated in a double blind, randomized, cross-over fashion with either hydrocortisone or placebo supplementation. We found that REM latency was significantly decreased in Addison's patients when receiving hydrocortisone at bedtime, whereas REM sleep time was increased. There was a trend toward an increase in the percentage of time in REM sleep and the number of REM sleep episodes. Waking time after sleep onset was increased, whereas no differences were observed between the two conditions when total sleep time or specific non-REM sleep parameters were evaluated. Our results suggest that in Addison's patients, cortisol plays a positive, permissive role in REM sleep regulation and may help to consolidate sleep. These effects may be mediated either directly by the central effects of glucocorticoids and/or indirectly through CRH and/or ACTH.