Material Supplementary 2.DC1http://www.jimmunol.org/content/suppl/2010/01/29/jimmunol.090185

No abstract

Linkages between DA neurodegeneration and microglial neuroinflammatory activities are well-known and demonstrated by large numbers of immune-competent microglia within the substantia nigra of postmortem PD brains (7) appearing as phagocytic cells engulfing damaged DA neurons (7,8). In transgenic mutant ␣-syn mice and in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone (8 -10), similar microglial responses are operative. Importantly, such microglial activation is associated with ␣-syn deposition (11-13) and internalization (14). This occurs throughout disease, suggesting linkages to oxidative damage, ␣-syn nitration and aggregation, and PD-associated neurodegeneration (15, 16) Indeed, microglial activation is strongly associated with neurotoxic responses and collateral neuronal damage (17)(18)(19)(20). Thus, for PD, nitrated-␣-syn (N-␣-syn)-mediated microglial activation and accelerated neuronal death are closely related (21-25).Abundant evidence indicates a significant role for adaptive immunity in neuroregulatory activities (26 -29). Such effects are seen in experimental neurodegenerative models, including PD (29 -31). Principally, these data found that neuronal degeneration or protection is linked to the microglial phenotype and that N-␣-syn-specific effector T cells exacerbate microglial activation and DA neurodegeneration, whereas CD4 ϩ CD25ϩ regulatory T cells (Treg) attenuate those processes; however, how microglia activation is regulated by regulatory and effector T cell subsets is not known. To address this, we used aggregated N-␣-syn as an inducer of microglial activation (23, 24), then studied the microglial immune response as it is affected by activated Treg and CD4 ϩ CD25Ϫ effector T cells (Teff). The observations demonstrate, for the first time, that Treg modulate a broad range of microglial activities, including redox biology, migration, phagocytosis, energy metabolism, and cytokine secretions. Differential outcomes of microglial processes are dependent on the temporal engagement of Treg with N-␣-syn and microglia. The findings provide insights into disease pathobiology and how the adaptive immune system may be harnessed for therapeutic benefit.

Innate and adaptive immunity affect the pathogenesis of Parkinson’s disease (PD). In particular, activation of microglia influences degeneration of dopaminergic neurons during disease. Cell-to-cell interactions and immune regulation critical for neuronal homeostasis are also influenced immune responses. The links between T cell immunity and nigrostriatal degeneration are supported by laboratory, animal model, and human pathologic investigations. Immune associated biomarkers in spinal fluids and brain tissue of patients with idiopathic or familial forms of PD provide means to improve diagnosis and therapeutic monitoring for disease. Relationships between oxidative stress, inflammation, and immune-mediated cell death pathways are examined in this review as they are linked to PD pathogenesis. Harnessing the immune system by drugs or by vaccination remain promising future therapeutic options.

A B S T R A C T Six normal men were fed formula diets containing either highly saturated fat (cocoa butter, iodine value 32) or polyunsaturated fat (corn oil, iodine value 125). The sterol balance technique was used to compare the changes in serum cholesterol concentration with the excretion of fecal steroids. The method used for the analysis of fecal steroids was chemical, with a final identification and quantification by gas-liquid chromatography. It was confirmed that the chemical method for fecal steroid analysis was accurate and reproducible.The three dietary periods were each 3 wk in length. In sequence, cocoa butter (period I), corn oil, and cocoa butter (period III) were fed at 40% of the total calories. All diets were cholesterol free, contained similar amounts of plant sterols, and were identical in other nutrients.Corn oil had a hypocholesterolemic effect. Mean serum cholesterol concentrations were 222 mg/100 ml (cocoa butter, period I), 177 during corn oil, and 225 after the return to cocoa butter. Individual fecal steroids were determined from stools pooled for 7 days. Both neutral steroids and bile acids were altered significantly by dietary polyunsaturated fat. The change in bile acid excretion was considerably greater than the change in neutral steroids. Corn oil caused a greater fecal excretion of both deoxycholic and lithocholic acids. The total mean excretion (milligrams per day) of fecal

Certain proteins are known to play an important part in the proliferation, differentiation and functional activation of haematopoietic progenitor cells in vitro. These proteins include erythropoietin and various colony-stimulating factors (CSFs), one of which is granulocyte-macrophage colony-stimulating factor (GM-CSF). Recently, both murine and human GM-CSF have been purified to homogeneity and complementary DNAs encoding them have been cloned. Although the in vitro activity of recombinant human GM-CSF has been investigated intensively, little is known about the functional activity of this protein in vivo. There is strong evidence that colony-stimulating activities produced by various human and murine tumour tissues and cell lines can stimulate granulopoiesis in mice, as can human urinary extracts. A partially purified preparation of human urinary colony-stimulating factor, however, proved only marginally effective in stimulating granulopoiesis in humans. All these studies suffer from the lack of a homogeneous preparation of colony-stimulating factor. It has recently been shown that recombinant murine multi-CSF or interleukin-3 can stimulate haematopoiesis in mice in vivo. Large-scale production of recombinant human GM-CSF now permits us to examine its effects in vivo using a primate model. We find that the continuous infusion of GM-CSF in healthy monkeys rapidly elicits a dramatic leukocytosis and a substantial reticulocytosis. A similar effect has been observed in one pancytopenic, immunodeficient rhesus macaque. These results suggest that GM-CSF could prove useful in several clinical situations.

Strain relatedness and switching were monitored in Candida albicans strains isolated from different body locations through three episodes of recurrent vulvovaginal candidiasis separated by two treatment-latency periods in a single patient. Strain relatedness was assessed by comparing Southern blot hybridization patterns with the relatively inimobile mid-repeat sequence Ca3. The following conclusions are demonstrated. (i) Three different strains of C. albicans colonized the mouth, the area under the breasts, and the vulvovaginal, anal, and rectal regions, respectively, at the tîme of the first infection. (ii) The same strain of C. albicans was responsible for the three vaginal infections. (iii) Switching of colony phenotype occurred with each new vaginal infection. (iv) Enrichment of drug-resistant switch phenotypes (assessed in vitro) was unlikely the basis for the changes in the switch phenotypes of the strain found in the vulvovaginal, anal, and rectül areas after treatment of the first infection with clotrimazole. (v) The same strain of C. albicans was responsible for the recurrent increases in mouth colonization and was distinct from the recurrent vaginal strain. The results of this case study demonstrate the need for further detailed analyses of full-body mycofloras, strain relatedness, switching repertoires, and changes in drug susceptibility during successive episodes of recurrent vulvovaginal candidiasis.

No abstract