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Li H.,Immune Disease Institute and Program in Cellular and Molecular Medicine | 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.

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.

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.

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.

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.

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