27 research outputs found
Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity
Objectives. B cells drive the production of autoreactive antibodysecreting cells, ASCs, in autoimmune diseases such as Systemic Lupus Erythematosus, SLE, and Sjogren, s syndrome, causing long-, term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI-, could deplete ASCs in autoimmune conditions in vivo and in vitro. Methods. Use of a BMI-, inhibitor in both mouse and human autoimmune settings was investigated. Lyn, mice, a model of SLE, were treated with the BMI-, small molecule inhibitor PTC-, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast-based assay was established, and the impact of PTC-, on ASCs derived from Sjogren, s syndrome, patients was evaluated. Results. BMI-, inhibition significantly decreased splenic and bone marrow ASCs in Lyn, mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG, immune complexes and anti-DNA IgG. PTC-, was also efficacious in reducing ex vivo plasma cell survival from both Sjogren, s syndrome, patients and age-matched healthy donors. Conclusion. These data provide evidence that inhibiting BMI-, can deplete ASC in a variety of contexts and thus BMI-, is a viable therapeutic target for antibody-mediated autoimmune diseases.Jack Polmear, Lauren Hailes, Moshe Olshansky, Maureen Rischmueller, Elan L'Estrange-Stranieri, Anne L Fletcher, Margaret L Hibbs, Vanessa L Bryant, Kim L Good-Jacobso
RG flows from Spin(7), CY 4-fold and HK manifolds to AdS, Penrose limits and pp waves
We obtain explicit realizations of holographic renormalization group (RG)
flows from M-theory, from E^{2,1} \times Spin(7) at UV to AdS_4 \times
\tilde{S^7} (squashed S^7) at IR, from E^{2,1} \times CY4 at UV to AdS_4 \times
Q^{1,1,1} at IR, and from E^{2,1} \times HK (hyperKahler) at UV to AdS_4 \times
N^{0,1,0} at IR. The dual type IIA string theory configurations correspond to
D2-D6 brane systems where D6 branes wrap supersymmetric four-cycles. We also
study the Penrose limits and obtain the pp-wave backgrounds for the above
configurations. Besides, we study some examples of non-supersymmetric and
supersymmetric flows in five-dimensional gauge theories.Comment: 42 pages, 6 eps figures, typos and misprints correcte
Multiband tight-binding theory of disordered ABC semiconductor quantum dots: Application to the optical properties of alloyed CdZnSe nanocrystals
Zero-dimensional nanocrystals, as obtained by chemical synthesis, offer a
broad range of applications, as their spectrum and thus their excitation gap
can be tailored by variation of their size. Additionally, nanocrystals of the
type ABC can be realized by alloying of two pure compound semiconductor
materials AC and BC, which allows for a continuous tuning of their absorption
and emission spectrum with the concentration x. We use the single-particle
energies and wave functions calculated from a multiband sp^3 empirical
tight-binding model in combination with the configuration interaction scheme to
calculate the optical properties of CdZnSe nanocrystals with a spherical shape.
In contrast to common mean-field approaches like the virtual crystal
approximation (VCA), we treat the disorder on a microscopic level by taking
into account a finite number of realizations for each size and concentration.
We then compare the results for the optical properties with recent experimental
data and calculate the optical bowing coefficient for further sizes
Responses of Rumen Microflora to High-Concentrate Low-Roughage Diets Containing Whey Products
The relationship between pollen and extant vegetation across an arid urban ecosystem and surrounding desert in Southwest USA
Haploinsufficiency of the NF-kappaB1 Subunit p50 in Common Variable Immunodeficiency
Item does not contain fulltextCommon variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In approximately 90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-kappaB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105DeltaEx8) is degraded, but is not processed to p50DeltaEx8. Altered NF-kappaB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50-translated from the non-mutated alleles-were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-kappaB1 p50 haploinsufficiency
Partial IFN-?R2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation
PubMed ID: 23963039We report a molecular study of the two known patients with autosomal recessive, partial interferon-? receptor (IFN-?R)2 deficiency (homozygous for mutations R114C and G227R), and three novel, unrelated children, homozygous for S124F (P1) and G141R (P2 and P3). IFN-?R2 levels on the surface of the three latter patients' cells are slightly lower than those on control cells. The patients' cells also display impaired, but not abolished, response to IFN-?. Moreover, the R114C, S124F, G141R and G227R IFNGR2 hypomorphic alleles all encode misfolded proteins with abnormal N-glycosylation. The mutants are largely retained in the endoplasmic reticulum, although a small proportion reach and function at the cell surface. Strikingly, the IFN-? response of the patients' cells is enhanced by chemical modifiers of N-glycosylation, as previously shown for patients with gain-of-glysosylation T168N and misfolding 382-387dup null mutations. All four in-frame IFNGR2 hypomorphic mutant alleles encoding surface-expressed receptors are thus deleterious by a mechanism involving abnormal N-glycosylation and misfolding of the IFN-?R2 protein. The diagnosis of partial IFN-?R2 deficiency is clinically useful, as affected patients should be treated with IFN-, unlike patients with complete IFN-?R2 deficiency. Moreover, inhibitors of glycosylation might be beneficial in patients with complete or partial IFN-?R2 deficiency due to misfolding or gain-of-glycosylation receptors. © 2013 by The American Society of Hematology.Rockefeller Foundation Institut National de la Santé et de la Recherche Médicale, Inserm Agence Nationale de la Recherche, ANR: HEALTH-F3-2008-200732 National Center for Advancing Translational Sciences, NCATS Institut National de la Santé et de la Recherche Médicale, Inserm Rockefeller University Shanghai Educational Development Foundation Center for Clinical and Translational Science, Ohio State University, CCTS, OSU: 8UL1TR000043 St. Giles Foundation Université Paris Descartes National Center for Advancing Translational Sciences, NCATS National Center for Research Resources, NCRR AXA Research Fund, AXA Bill and Melinda Gates Foundation, BMGF National Council for Eurasian and East European Research, NCEEER: ERC-2010-AdG-268777 National Institute of Allergy and Infectious Diseases, NIAID: 1R01AI089970 Jeffrey Modell Foundation, JMF Stony Wold-Herbert FundThis study was conducted in accordance with the Helsinki Declaration, with written informed consent obtained from the patient family. Approval for this study was obtained from the Comité de Protection des Personnes and Institut National de la Santéet de la Recherche Médicale in France and the Rockefeller Institutional Review Board (New York, NY). -- This work was supported by grants from the European Research Council (ERC-2010-AdG-268777), Institut National de la Santé et de la Recherche Médicale, University Paris Descartes, French National Agency for Research (ANR), the EU-grant HOMITB (grant HEALTH-F3-2008-200732), the Bill and Melinda Gates Foundation, the St. Giles Foundation, the Jeffrey Modell Foundation,and Talecris Biotherapeutics, Rockefeller University Center for Clinical and Translational Science grant 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), the Rockefeller University, and the National Institute of Allergy and Infectious Diseases (grant 1R01AI089970). R.M.-B. is supported by the EMBO Long Term Fellowship program. X.-F.K. is supported by the Stony Wold-Herbert Fund, Choh-Hao Li Memorial Fund Scholar award, and the Shanghai Educational Development Foundation, Y.I. was supported by the AXA Research Fund. V.L.B. was supported by the Stony Wold-Herbert Fund, and A.Y.K. was supported by the Fondation Médicale Medische Stichting Mathilde E. Horlait-Dapsens. -