Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

AbstractMultiple sclerosis (MS) is an immune-mediated disease of the central nervous system leading to demyelination and axonal/neuronal loss. Cumulating evidence points to a key role for CD8 T cells in this disabling disease. Oligoclonal CD8 T cells reside in demyelinating plaques where they are likely to contribute to tissue destruction. Histopathological analyses and compelling observations from animal models indicate that cytotoxic CD8 T cells target neural cell populations with the potential of causing lesions reminiscent of MS. However, CD8 T cell differentiation results in several subsets of effector CD8 T cells that could be differentially implicated in the mechanisms contributing to tissue damage. Moreover CD8 regulatory T cells arise as important populations involved in restoring immune homoeostasis and in maintaining immune privileged sites. Here we examine the current literature pertaining to the role of CD8 effector and regulatory T cell subsets in the pathogenesis of MS

Cosmic Flows on 100 Mpc/h Scales: Standardized Minimum Variance Bulk Flow, Shear and Octupole Moments

The low order moments, such as the bulk flow and shear, of the large scale peculiar velocity field are sensitive probes of the matter density fluctuations on very large scales. In practice, however, peculiar velocity surveys are usually sparse and noisy, which can lead to the aliasing of small scale power into what is meant to be a probe of the largest scales. Previously, we developed an optimal ``minimum variance'' (MV) weighting scheme, designed to overcome this problem by minimizing the difference between the measured bulk flow (BF) and that which would be measured by an ideal survey. Here we extend this MV analysis to include the shear and octupole moments, which are designed to have almost no correlations between them so that they are virtually orthogonal. We apply this MV analysis to a compilation of all major peculiar velocity surveys, consisting of 4536 measurements. Our estimate of the BF on scales of ~ 100 Mpc/h has a magnitude of |v|= 416 +/- 78 km/s towards Galactic l = 282 degree +/- 11 degree and b = 6 degree +/- 6 degree. This result is in disagreement with LCDM with WMAP5 cosmological parameters at a high confidence level, but is in good agreement with our previous MV result without an orthogonality constraint, showing that the shear and octupole moments did not contaminate the previous BF measurement. The shear and octupole moments are consistent with WMAP5 power spectrum, although the measurement noise is larger for these moments than for the BF. The relatively low shear moments suggest that the sources responsible for the BF are at large distances.Comment: 13 Pages, 7 figures, 4 tables. Some changes to reflect the published versio

SUSY Higgs at the LHC: Effects of light charginos and neutralinos

In view of the latest LEP data we consider the effects of charginos and neutralinos on the two-photon and bbbar signatures of the Higgs at the LHC. Assuming the usual GUT inspired relation between M_1 and M_2 we show that there are only small regions with moderate tanbeta and large stop mixings that may be dangerous. Pathological models not excluded by LEP which have degeneracy between the sneutrino and the chargino are however a real danger because of large branching fraction of the Higgs into invisibles. We have also studied models where the gaugino masses are not unified at the GUT scale. We take M_1=M_2/10 as an example where large reductions in the signal at the LHC can occur. However we argue that such models with a very light neutralino LSP may give a too large relic density unless the sleptons are light. We then combine this cosmological constraint with neutralino production with light sfermions to further reduce the parameter space that precludes observability of the Higgs at the LHC. We still find regions of parameter space where the drops in the usual Higgs signals at the LHC can be drastic. Nonetheless, in such scenarios where Higgs may escape detection we show that one should be able to produce all charginos and neutralinos. Although the heavier of these could cascade into the Higgs, the rates are not too high and the Higgs may not always be recovered this way.Comment: 37 pages, 17 figures, Latex file, Paper with high resolution figures can be found at http://wwwlapp.in2p3.fr/web/lapp/preplapp/psth/LAPTH774.ps.g

Precision Physics at LEP

1 - Introduction 2 - Small-Angle Bhabha Scattering and the Luminosity Measurement 3 - Z^0 Physics 4 - Fits to Precision Data 5 - Physics at LEP2 6 - ConclusionsComment: Review paper to appear in the RIVISTA DEL NUOVO CIMENTO; 160 pages, LateX, 70 eps figures include

Graft-versus-host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF–licensed myeloid cells

Allogeneic hematopoietic cell transplantation (allo-HCT) not only is an effective treatment for several hematologic malignancies but can also result in potentially life-threatening graft-versus-host disease (GvHD). GvHD is caused by T cells within the allograft attacking nonmalignant host tissues; however, these same T cells mediate the therapeutic graft-versus-leukemia (GvL) response. Thus, there is an urgent need to understand how to mechanistically uncouple GvL from GvHD. Using preclinical models of full and partial MHC-mismatched HCT, we here show that the granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by allogeneic T cells distinguishes between the two processes. GM-CSF drives GvHD pathology by licensing donor-derived phagocytes to produce inflammatory mediators such as interleukin-1β and reactive oxygen species. In contrast, GM-CSF did not affect allogeneic T cells or their capacity to eliminate leukemic cells, retaining undiminished GvL responses. Last, tissue biopsies and peripheral blood mononuclear cells from patients with grade IV GvHD showed an elevation of GM-CSF–producing T cells, suggesting that GM-CSF neutralization has translational potential in allo-HCT

Toxoplasmosis-associated IRIS involving the CNS: a case report with longitudinal analysis of T cell subsets

Background: HIV-infected patients may present an unforeseen clinical worsening after initiating antiretroviral therapy known as immune reconstitution inflammatory syndrome (IRIS). This syndrome is characterized by a heightened inflammatory response toward infectious or non-infectious triggers, and it may affect different organs. Diagnosis of IRIS involving the central nervous system (CNS-IRIS) is challenging due to heterogeneous manifestations, absence of biomarkers to identify this condition, risk of long-term sequelae and high mortality. Hence, a deeper knowledge of CNS-IRIS pathogenesis is needed. Case presentation: A 37-year-old man was diagnosed with AIDS and cerebral toxoplasmosis. Anti-toxoplasma treatment was initiated immediately, followed by active antiretroviral therapy (HAART) 1 month later. At 2 months of HAART, he presented with progressive hyposensitivity of the right lower limb associated with brain and dorsal spinal cord lesions, compatible with paradoxical toxoplasmosis-associated CNS-IRIS, a condition with very few reported cases. A stereotactic biopsy was planned but was postponed based on its inherent risks. Patient showed clinical improvement with no requirement of corticosteroid therapy. Routine laboratorial analysis was complemented with longitudinal evaluation of blood T cell subsets at 0, 1, 2, 3 and 6 months upon HAART initiation. A control group composed by 9 HIV-infected patients from the same hospital but with no IRIS was analysed for comparison. The CNS-IRIS patient showed lower percentage of memory CD4(+) T cells and higher percentage of activated CD4(+) T cells at HAART initiation. The percentage of memory CD4(+) T cells drastically increased at 1 month after HAART initiation and became higher in comparison to the control group until clinical recovery onset; the percentage of memory CD8(+) T cells was consistently lower throughout follow-up. Interestingly, the percentage of regulatory T cells (Treg) on the CNS-IRIS patient reached a minimum around 1 month before symptoms onset. Conclusion: Although both stereotactic biopsies and steroid therapy might be of use in CNS-IRIS cases and should be considered for these patients, they might be unnecessary to achieve clinical improvement as shown in this case. Immunological characterization of more CNS-IRIS cases is essential to shed some light on the pathogenesis of this condition.Portuguese Foundation for Science and Technology (FCT; PIC/IC/83313/2007) and co-financed by the Portuguese North Regional Operational Program (ON.2 - O Novo Norte) under the National Strategic Reference Framework (QREN) through the European Regional Development Fund (FEDER). A FCT fellowship was attributed to RRS (PD/BD/106047/2015; Inter-University Doctoral Program in Ageing and Chronic Disease) and to CN [SFRH/BPD/65380/2009; Programa Operacional Potencial Humano (POPH) through the Fundo Social Europeu (FSE)]info:eu-repo/semantics/publishedVersio

Tests of CPT Invariance at Neutrino Factories

We investigate possible tests of CPT invariance on the level of event rates at neutrino factories. We do not assume any specific model but phenomenological differences in the neutrino-antineutrino masses and mixing angles in a Lorentz invariance preserving context, such as it could be induced by physics beyond the Standard Model. We especially focus on the muon neutrino and antineutrino disappearance channels in order to obtain constraints on the neutrino-antineutrino mass and mixing angle differences; we found, for example, that the sensitivity $|m_3 - \bar{m}_3| \lesssim 1.9 \cdot 10^{-4} \mathrm{eV}$ could be achieved.Comment: 6 pages, 1 figure, RevTeX4. Final version to be published in Phys. Rev.

Associated Charm Production in Neutrino-Nucleus Interactions

In this paper a search for associated charm production both in neutral and charged current $\nu$-nucleus interactions is presented. The improvement of automatic scanning systems in the {CHORUS} experiment allows an efficient search to be performed in emulsion for short-lived particles. Hence a search for rare processes, like the associated charm production, becomes possible through the observation of the double charm-decay topology with a very low background. About 130,000 $\nu$ interactions located in the emulsion target have been analysed. Three events with two charm decays have been observed in the neutral-current sample with an estimated background of 0.18$\pm$0.05. The relative rate of the associated charm cross-section in deep inelastic $\nu$ interactions, $\sigma(c\bar{c}\nu)/\sigma_\mathrm{NC}^\mathrm{DIS}= (3.62^{+2.95}_{-2.42}({stat})\pm 0.54({syst}))\times 10^{-3}$ has been measured. One event with two charm decays has been observed in charged-current $\nu_\mu$ interactions with an estimated background of 0.18$\pm$0.06 and the upper limit on associated charm production in charged-current interactions at 90% C.L. has been found to be $\sigma (c\bar{c} \mu^-)/\sigma_\mathrm{CC} < 9.69 \times 10^{-4}$.Comment: 10 pages, 4 figure