Regulatory effects of IFN-β on the development of experimental autoimmune uveoretinitis in B10RIII mice

Background

Experimental autoimmune uveoretinitis (EAU) serves as a model for human intraocular inflammation. IFN-β has been used in the treatment of certain autoimmune diseases. Earlier studies showed that it ameliorated EAU; however, the mechanisms involved in this inhibition are still largely unknown.

Methodology/Principal Findings

B10RIII mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) peptide 161–180 in Complete Freund''s adjuvant. Splenocytes from different time points after immunization were used to evaluate the expression of IFN-β. An increased expression of IFN-β was observed during EAU and its highest expression was observed on day 16, 3 days after the peak of intraocular inflammation. Splenocytes and draining lymph node cells from mice immunized with IRBP_161-180 on day 13 and control mice were activated with anti-CD3/anti-CD28 antibodies or IRBP_161-180 to evaluate the production of IFN-γ and IL-17. The results showed that IFN-γ and IL-17 were significantly higher in immunized mice as compared to the control mice when exposed to anti-CD3/anti-CD28 antibodies. However, the production of IFN-γ and IL-17 was detected only in immunized mice, but not in the control mice when stimulated with IRBP_161-180. Multiple subcutaneous injections of IFN-β significantly inhibited EAU activity in association with a down-regulated expression of IFN-γ, IL-17 and an enhanced IL-10 production. In an in vitro system using cells from mice, IFN-β suppressed IFN-γ production by CD4⁺CD62L⁻ T cells, IL-17 production by CD4⁺CD62L^+/- T cells and proliferation of CD4⁺CD62L^+/- T cells. IFN-β inhibited the secretion of IL-6, but promoted the secretion of IL-10 by monocytes. IFN-β-treated monocytes inhibited IL-17 secretion by CD4⁺CD62L^+/- T cells, but did not influence IFN-γ expression and T cell proliferation.

Conclusions/Significance

IFN-β may exert its inhibitory effect on EAU by inhibiting Th1, Th17 cells and modulating relevant cytokines. IFN-β may provide a potential treatment for diseases mediated by Th1 and Th17 cells.     

Does the frequency and avidity spectrum of the neuroantigen-specific T cells in the blood mirror the autoimmune process in the central nervous system of mice undergoing experimental allergic encephalomyelitis?

In humans, studies of autoreactive T cells that mediate multiple sclerosis have been largely confined to testing peripheral blood lymphocytes. Little is known how such measurements reflect the disease-mediating autoreactive T cells in the CNS. This information is also not available for murine experimental allergic encephalomyelitis (EAE); the low number of T cells that can be obtained from the blood or the brain of mice prevented such comparisons. We used single-cell resolution IFN-gamma ELISPOT assays to measure the frequencies and functional avidities of myelin basic protein (MBP:87-99)-specific CD4 cells in SJL mice immunized with this peptide. Functional MBP:87-99-specific IFN-gamma-producing cells were present in the CNS during clinical signs of EAE, but not during phases of recovery. In contrast, MBP:87-99-specific T cells persisted in the blood during all stages of the disease, and were also present in mice that did not develop EAE. Therefore, the increased frequency of MBP:87-99-reactive T cells in the blood reliably reflected the primed state, but not the inflammatory activity of these cells in the brain. The functional avidity of the MBP:87-99-reactive T cells was identical in the brain and blood and did not change over 2 mo as the mice progressed from acute to chronic EAE. Therefore, high-affinity T cells did not become selectively enriched in the target organ, and avidity maturation of the MBP:87-99-specific T cell repertoire did not occur in the observation period. The data may help the interpretation of measurements made with peripheral blood lymphocytes of multiple sclerosis patients.     

Depressive effect of LHRH on the numbers of “synaptic” ribbons and spherules in the pineal gland of diestrous rats

Summary Previous studies have shown that LHRH or LHRH-like substances are present in the pineal gland. In order to investigate whether exogenous LHRH may affect the pineal gland, in the present study the effects of a single dose of LHRH (1 g, i.p.) on pineal synaptic ribbons and spherules as well as serum melatonin levels were examined in diestrous Wistar rats. One hour after the injection both ribbons and spherules exhibited a statistically significant decrease in number. Serum melatonin levels were not affected. It is concluded that humoral feedback mechanisms may exist between the hypothalamus and the pineal gland.Supported by grant Vo 135/7 within the Schwerpunktprogramm Neuroendokrinolgoie of the Deutsche Forschungsgemeinschaft     

The effect of motion sickness on the sleep–wake cycle in rats exposed to prenatal hypoxia

This study is a follow-up to our previous research of the phenomenology and mechanisms of motion sickness (MS) and its relationship with changes in the sleep–wake cycle (SWC). We report data on the effect of MS on the SWC in 30-day-old intact rats and those exposed to prenatal hypoxia on days 13 and 19 of gestation. In all animal groups, MS was shown to decrease significantly the waking time and increase that of paradoxical sleep (PS). A link between hypothalamic MS and SWC regulatory mechanisms was revealed, and the role of this teamwork in the development of the sopite syndrome, which may be a sole manifestation of MS in some animals and man, was suggested. It was established that hypoxic exposure on day 19 of gestation had a greater damaging effect on the thalamocortical sleep-regulating structures than that on day 13, when it is only the hypothalamic-hippocampal slow-sleep regulatory systems that were found to be affected. Against this background, MS appreciably suppresses the brain excitatory systems that maintain wakefulness (supposed to be the ascending reticular activating system) and enhances those activating systems that regulate PS. It is exactly prenatal hypoxic exposure of rats on day 19 of gestation that enabled demonstrating the role of the evolutionarily young thalamocortical system in PS control.     

Erratum to: An in silico biomechanical analysis of the stent–esophagus interaction

Biomechanics and Modeling in Mechanobiology - In the original publication of the article, Tables 2 and 3 were published with error. The correct tables are provided below (Tables 2, 3). The...     

Metallic gold beads in hyaluronic acid: a novel form of gold-based immunosuppression? Investigations of the immunosuppressive effects of metallic gold on cultured J774 macrophages and on neuronal gene expression in experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a neurodegenerative disease caused by recurring attacks of neuroinflammation leading to neuronal death. Immune-suppressing gold salts are used for treating connective tissue diseases; however, side effects occur from systemic spread of gold ions. This is limited by exploiting macrophage-induced liberation of gold ions (dissolucytosis) from gold surfaces. Injecting gold beads in hyaluronic acid (HA) as a vehicle into the cavities of the brain can delay clinical signs of disease progression in the MS model, experimental autoimmune encephalitis (EAE). This study investigates the anti-inflammatory properties of metallic gold/HA on the gene expression of tumor necrosis factor (Tnf-α), Interleukin (Il)-1β, Il-6, Il-10, Colony-stimulating factor (Csf)-v2, Metallothionein (Mt)-1/2, Bcl-2 associated X protein (Bax) and B cell lymphoma (Bcl)-2 in cultured J774 macrophages and in rodents with early stages of EAE. Cells grew for 5 days on gold/HA or HA, then receiving 1,000 ng/mL lipopolysaccharide (LPS) as inflammatory challenge. In the EAE experiment, 12 Lewis rats received gold injections and control groups included 11 untreated and 12 HA-treated EAE rats and five healthy animals. The experiment terminated day 9 when the first ten animals showed signs of EAE, only one of which were gold-treated (1p = 0.0367). Gene expression in the macrophages showed a statistically significant decrease in Il-6, Il-1β and Il-10-response to LPS; interestingly HA induced a statistically significant increase of Il-10. In the EAE model gene expression of inflammatory cytokines increased markedly. Compared to EAE controls levels of Tnf-α, Il-1β, Il-10, Il-6, IL-2, Ifn-γ, Il-17, transforming growth factor (Tgf)-β, superoxide dismutase (Sod)-2, Mt-2 and fibroblast growth factor (Fgf)-2 were lower in the gold-treated group. HA-treated animals expressed similar or intermediate levels. Omnibus testing for reduced inflammatory response following gold-treatment was not significant, but tendencies towards a decrease in the Sod-2, Fgf-2, Il-1β response and a higher Bdnf and IL-23 gene expression were seen. In conclusion, our findings support that bio-liberation of gold from metallic gold surfaces have anti-inflammatory properties similar to classic gold compounds, warranting further studies into the pharmacological potential of this novel gold-treatment and the possible synergistic effects of hyaluronic acid.     

Effect of BRAND’s Essence of Chicken on the resetting process of circadian clocks in rats subjected to experimental jet lag

BRAND’s Essence of Chicken (BEC) has been widely used as a traditional remedy by people in Southeast Asia, which is proved to have an effect on the central nervous system (CNS) and autonomic nervous system (ANS). However, whether and how BEC consumption may affect mammalian circadian system is still largely unknown. In the present study, we investigated the effect of BEC feeding on the adaptation of circadian clocks to the experimental jet lag in rats. After the 12-h experimental jet lag through extending the light period, BEC feeding markedly facilitated the re-entrainment of all examined clock genes (Bmal1, Cry1, Per1, and Per2) in the pineal gland. The resetting time course of pineal clock genes was reduced from 7 days to only 3–5 days by BEC feeding, which was almost equal to the effect of melatonin feeding. In the liver clock, the facilitating effect of BEC feeding was mainly displayed in the re-entrainment of Bmal1 and Per2 by shortening their resetting processes for nearly 2 days. However, the resetting rate of locomotor activity rhythm was not affected by BEC feeding, suggesting that BEC might be unable to affect the behavioral rhythm.     

Persistence of abnormal melanocytes in immunosuppressed chickens of the autoimmune “DAM” line

Summary The delayed amelanotic (DAM) line of chickens (Gallus gallus) is characterized by the postnatal elimination of melanocytes from regenerating feathers and from the choroid. The process of elimination is accompanied by a massive infiltration of mononuclear leukocytes (MNL) into the supporting connective tissues. When surgically bursectomized at day of hatching, chickens from this lineage develop significantly less amelanosis of the feathers. We report here a histological analysis of regenerating feathers and choroids from bursectomized birds that maintained their plumage pigmentation. In the feathers we observed the presence of morphologically abnormal melanocytes in the absence of MNL infiltration. Choroids also contained abnormal melanocytes without MNL infiltration; however, we observed a few cases of amelanotic choroids with a few MNL. These findings indicate that melanocytes of pigmented birds are morphologically abnormal even in the absence of a bursa and in the absence of leukocytic infiltrates into regenerating feathers and possibly into the choroids. We conclude from these findings that the amelanosis in unbursectomized DAM birds is due to the response of the immune system to an abnormality in the melanocytes which, by itself, does not lead to depigmentation.     

Studies of the MHC-linked “CT” alloantigenic systems in rats

Cytotoxic T lymphocyte (CTL) populations from Lewis rats were generated by combined immunization in vivo and restimulation in vitro with lymphoid cells from Fischer 344 donors. This strain combination is phenotypically identical at the MHC (Ag-B) by serologic, MLC, and GVH criteria, and thus, it is to be expected that CTL raised in this combination would show MHC restricted cytolysis against the existing minor alloantigenic differences. Previous studies demonstrated instead that CTL are effective against target cells from a variety of strains, regardless ofMHC haplotype, and that these cytotoxic T cell defined target antigens (CT antigens) are controlled by genes which map with the MHC. The present studies show that the CT antigens defined by LF CTL are unlike gene products expected for eitherSD-like orLD-like region genes, and it is therefore concluded that they mark a novel subregion of the rat MHC or are specified by a locus (loci) linked to, but outside MHC.Supported by U.S.P.H. Grants CA-15822, CA-09140, and AI-10961     

Erratum to: “Effects of Different Conservation Methods on the Genetic Stability of Potato Germplasm”

Russian Journal of Plant Physiology -     

Functional diversity of bioactive peptides in the nervous system itself: “How the brain may understand”

The interactions involving cells of the nervous system are a complex form of intercellular communication. Biosynthesis of peptide hormones or active neuropeptides is generally through a precursor which provides increased product choices as a function of the processing pathway. Proteolytic processing as well as other molecular modification lead to a wide range of mature products which may vary in different tissues even though they are derived from the same precursor. Also the same neuropeptide may exhibit different bioactivities for different target cells. Finally, by means of collective packaging in secretory organelles, a cell may be able by synergism to further broaden its biologic effects. In these ways, what is seen as added complication in the CNS, may be from the point of view of the cell, a successful attempt to increase its survival ability to adapt and influence its bioenvironment.