Li H.,Childrens Hospital |
Li H.,Harvard University |
Pink M.D.,Aurora University |
Murphy J.G.,Aurora University |
And 5 more authors.
Nature Structural and Molecular Biology | Year: 2012
In hippocampal neurons, the scaffold protein AKAP79 recruits the phosphatase calcineurin to L-type Ca 2+ channels and couples Ca 2+ influx to activation of calcineurin and of its substrate, the transcription factor NFAT. Here we show that an IAIIIT anchoring site in human AKAP79 binds the same surface of calcineurin as the PxIxIT recognition peptide of NFAT, albeit more strongly. A modest decrease in calcineurin-AKAP affinity due to an altered anchoring sequence is compatible with NFAT activation, whereas a further decrease impairs activation. Counterintuitively, increasing calcineurin-AKAP affinity increases recruitment of calcineurin to the scaffold but impairs NFAT activation; this is probably due to both slower release of active calcineurin from the scaffold and sequestration of active calcineurin by 'decoy' AKAP sites. We propose that calcineurin-AKAP79 scaffolding promotes NFAT signaling by balancing strong recruitment of calcineurin with its efficient release to communicate with NFAT. © 2012 Nature America, Inc. All rights reserved.
Pastor W.A.,San Diego Institute for Allergy and Immunology |
Pastor W.A.,University of California at Los Angeles |
Aravind L.,U.S. National Institutes of Health |
Rao A.,San Diego Institute for Allergy and Immunology
Nature Reviews Molecular Cell Biology | Year: 2013
In many organisms, the methylation of cytosine in DNA has a key role in silencing 'parasitic' DNA elements, regulating transcription and establishing cellular identity. The recent discovery that ten-eleven translocation (TET) proteins are 5-methylcytosine oxidases has provided several chemically plausible pathways for the reversal of DNA methylation, thus triggering a paradigm shift in our understanding of how changes in DNA methylation are coupled to cell differentiation, embryonic development and cancer. © 2013 Macmillan Publishers Limited. All rights reserved.
Gleissner C.A.,San Diego Institute for Allergy and Immunology |
Gleissner C.A.,University of Heidelberg |
Shaked I.,San Diego Institute for Allergy and Immunology |
Erbel C.,University of Heidelberg |
And 3 more authors.
Circulation Research | Year: 2010
RATIONALE: CXCL4 is a platelet-derived chemokine that promotes macrophage differentiation from monocytes. Deletion of the PF4 gene that encodes CXCL4 reduces atherosclerotic lesions in ApoE-/- mice. OBJECTIVE: We sought to study effects of CXCL4 on macrophage differentiation with possible relevance for atherogenesis. METHODS AND RESULTS: Flow cytometry for expression of surface markers in macrophage colony-stimulating factor (M-CSF)-and CXCL4-induced macrophages demonstrated virtually complete absence of the hemoglobin scavenger receptor CD163 in CXCL4-induced macrophages. mRNA for CD163 was downregulated as early as 2 hours after CXCL4. CD163 protein reached a minimum after 3 days, which was not reversed by treatment of cells with M-CSF. The CXCL4 effect was entirely neutralized by heparin, which bound CXCL4 and prevented CXCL4 surface binding to monocytes. Pretreatment of cells with chlorate, which inhibits glycosaminoglycan synthesis, strongly inhibited CXCL4-dependent downregulation of CD163. Similar to recombinant CXCL4, releasate from human platelets also reduced CD163 expression. CXCL4-differentiated macrophages were unable to upregulate the atheroprotective enzyme heme oxygenase-1 at the RNA and protein level in response to hemoglobin-haptoglobin complexes. Immunofluorescence of human atherosclerotic plaques demonstrated presence of both CD68+CD163+ and CD68 +CD163- macrophages. PF4 and CD163 gene expression within human atherosclerotic lesions were inversely correlated, supporting the in vivo relevance of CXCL4-induced downregulation of CD163. CONCLUSIONS: CXCL4 may promote atherogenesis by suppressing CD163 in macrophages, which are then unable to upregulate the atheroprotective enzyme heme oxygenase-1 in response to hemoglobin.
Michels A.W.,University of Colorado at Denver |
Von Herrath M.,San Diego Institute for Allergy and Immunology
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2011
Purpose of Review: To update on the clinical trials using antigen-specific therapies in autoimmune diabetes. Recent Findings: Type 1 diabetes is now a predictable disease with the measurement of islet autoantibodies, and the incidence is increasing dramatically. Well tolerated and effective interventions are needed to stop the underlying autoimmune destruction of insulin-producing beta cells. Beta-cell antigens, insulin and glutamic acid decarboxylase, are being used to preserve endogenous insulin production in individuals with new-onset diabetes and to prevent diabetes. The results of antigen-specific immune intervention trials are reviewed and consideration is given to future directions for inducing tolerance in type 1 diabetes. Summary: Antigen-specific immune therapies act by enhancing regulatory T cell function, in animal models often locally and selectively in islets or pancreatic lymph nodes while inhibiting effector T cells. This therapeutic pathway provides a safe treatment to preserve beta cell function in new-onset diabetic individuals with the GAD-Alum vaccine being the most extensively studied therapy. Insulin is being used in many forms to prevent diabetes and stop the underlying autoimmune process. For the future, combination immune therapies targeting different pathways in the immune system will be needed to effectively induce sustained tolerance in type 1 diabetes. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Coppieters K.T.,Novo Nordisk AS |
Von Herrath M.,Novo Nordisk AS |
Von Herrath M.,San Diego Institute for Allergy and Immunology
Journal of Pathology | Year: 2013
Type 1 diabetes (T1D) is caused by the destruction of insulin-producing pancreatic β cells by the patient's immune system. While the underlying genetics and immunopathology are fairly well characterized, the environmental trigger remains unidentified. Numerous studies have centred on the role of enteroviruses as aetiological factors that could initiate or accelerate T1D development. The most convincing evidence to date consists of an array of reports documenting the presence of enteroviral nucleic acids in peripheral blood at diagnosis. A prominent hypothesis is that enteroviruses may infect the pancreatic islets and thus be responsible for the islet-specific up-regulation of MHC class I that is commonly observed, possibly enabling T cell recognition and cytotoxicity. Past immunohistochemical studies have indeed shown that antibodies binding the enteroviral capsid protein VP1 preferentially stain the pancreatic β cells from diabetic individuals. New data now indicate that the VP1 antibody used in these studies cross-reacts with mitochondrial proteins. Copyright © 2013 Pathological Society of Great Britain and Ireland.
Crotty S.,San Diego Institute for Allergy and Immunology
Annual Review of Immunology | Year: 2011
T cell help to B cells is a fundamental aspect of adaptive immunity and the generation of immunological memory. Follicular helper CD4 T (TFH) cells are the specialized providers of B cell help. TFH cells depend on expression of the master regulator transcription factor Bcl6. Distinguishing features of TFH cells are the expression of CXCR5, PD-1, SAP (SH2D1A), IL-21, and ICOS, among other molecules, and the absence of Blimp-1 (prdm1). TFH cells are important for the formation of germinal centers. Once germinal centers are formed, TFH cells are needed to maintain them and to regulate germinal center B cell differentiation into plasma cells and memory B cells. This review covers TFH differentiation, TFH functions, and human TFH cells, discussing recent progress and areas of uncertainty or disagreement in the literature, and it debates the developmental relationship between TFH cells and other CD4 T cell subsets (Th1, Th2, Th17, iTreg). © 2011 by Annual Reviews. All rights reserved.
Chang X.,San Diego Institute for Allergy and Immunology |
Li B.,San Diego Institute for Allergy and Immunology |
Rao A.,San Diego Institute for Allergy and Immunology |
Rao A.,University of California at San Diego
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015
Posttranscriptional regulation is a major mechanism to rewire transcriptomes during differentiation. Heterogeneous nuclear RNA-binding protein LL (hnRNPLL) is specifically induced in terminally differentiated lymphocytes, including effector T cells and plasma cells. To study the molecular functions of hnRNPLL at a genomewide level, we identified hnRNPLL RNA targets and binding sites in plasma cells through integrated Photoactivatable-Ribonucleoside-Enhanced Cross-Linking and Immunoprecipitation (PAR-CLIP) and RNA sequencing. hnRNPLL preferentially recognizes CA dinucleotide-containing sequences in introns and 3′ untranslated regions (UTRs), promotes exon inclusion or exclusion in a context-dependent manner, and stabilizes mRNA when associated with 3′ UTRs. During differentiation of primary B cells to plasma cells, hnRNPLL mediates a genome-wide switch of RNA processing, resulting in loss of B-cell lymphoma 6 (Bcl6) expression and increased Ig production - both hallmarks of plasma-cell maturation. Our data identify previously unknown functions of hnRNPLL in B-cell to plasma-cell differentiation and demonstrate that the RNA-binding protein hnRNPLL has a critical role in tuning transcriptomes of terminally differentiating B lymphocytes. © 2015, National Academy of Sciences. All rights reserved.
Kashiwakura J.-I.,San Diego Institute for Allergy and Immunology |
Otani I.M.,San Diego Institute for Allergy and Immunology |
Kawakami T.,San Diego Institute for Allergy and Immunology
Advances in Experimental Medicine and Biology | Year: 2011
Mast cells play a major role in allergy and anaphylaxis, as well as a protective role in immunity against bacteria and venoms (innate immunity) and T-cell activation (acquired immunity).1,2 It was long thought that two steps are essential to mast cell activation. The first step (sensitization) occurs when antigen-specific IgE binds to its high-affinity IgE receptor (FcεRI) expressed on the surface of mast cells. The second step occurs when antigen (Ag) or anti-IgE binds antigen-specific IgE antibodies bound to FcεRI present on the mast cell surface (this mode of stimulation hereafter referred to as IgE+Ag or IgE+anti-IgE stimulation, respectively). Conventional wisdom has been that monomeric IgE plays only an initial, passive role in mast cell activation. However, recent findings have shown that IgE binding to its receptor FcεRI can mediate mast cell activation events even in the absence of antigen (this mode of stimulation hereafter referred to as IgE(-Ag) stimulation). Different subtypes of monomeric IgEs act via IgE(-Ag) stimulation to elicit varied effects on mast cells function, survival and differentiation. This chapter will describe the role of monomeric IgE molecules in allergic reaction, the various effects and mechanisms of action of IgE(-Ag) stimulation on mast cells and what possible developments may arise from this knowledge in the future. Since mast cells are involved in a variety of pathologic and protective responses, understanding the role that monomeric IgE plays in mast cell function, survival and differentiation will hopefully lead to better understanding and treatment of asthma and other allergic diseases, as well as improved understanding of host response to infections. © 2011 Landes Bioscience and Springer Science+Business Media.
Pipkin M.E.,San Diego Institute for Allergy and Immunology
EMBO Reports | Year: 2011
Under the cover of snow in February 2011, immunologists convened in Banff, Alberta, Canada, for the Keystone symposium Immunologic Memory, Persisting Microbes and Chronic Diseaseg. These are wide-ranging topics that are typically addressed in separate experimental settings. However, a theme that emerged was the way in which these subjects are inextricably linked, and the importance of addressing them together and deciphering their molecular determinants. © 2011 European molecular biology organization.
Ponomarenko J.,University of California at San Diego |
Papangelopoulos N.,University of California at San Diego |
Zajonc D.M.,San Diego Institute for Allergy and Immunology |
Peters B.,San Diego Institute for Allergy and Immunology |
And 2 more authors.
Nucleic Acids Research | Year: 2011
IEDB-3D is the 3D structural component of the Immune Epitope Database (IEDB) available via the 'Browse by 3D Structure' page at http://www.iedb .org. IEDB-3D catalogs B- and T-cell epitopes and Major Histocompatibility Complex (MHC) ligands for which 3D structures of complexes with antibodies, T-cell receptors or MHC molecules are available in the Protein Data Bank (PDB). Journal articles that are primary citations of PDB structures and that define immune epitopes are curated within IEDB as any other reference along with accompanying functional assays and immunologically relevant information. For each curated structure, IEDB-3D provides calculated data on intermolecular contacts and interface areas and includes an application, EpitopeViewer, to visualize the structures. IEDB-3D is fully embedded within IEDB, thus allowing structural data, both curated and calculated, and all accompanying information to be queried using multiple search interfaces. These include queries for epitopes recognized in different pathogens, eliciting different functional immune responses, and recognized by different components of the immune system. The query results can be downloaded in Microsoft Excel format, or the entire database, together with structural data both curated and calculated, can be downloaded in either XML or MySQL formats. © The Author(s) 2010.