Begell House Inc.
Critical Reviews™ in Immunology
CRI
1040-8401
35
1
2015
The Adhesion- and Degranulation-Promoting Adaptor Protein and Its Role in the Modulation of Experimental Autoimmune Encephalomyelitis
1-14
10.1615/CritRevImmunol.2014012162
Swen
Engelmann
Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany
Mauro
Togni
Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany
Stefanie
Kliche
Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany
Dirk
Reinhold
Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany
Burkhart
Schraven
Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany
Annegret
Reinhold
Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany
EAE
CNS
autoimmunity
adaptor protein
ADAP
Adaptor proteins mediate protein−protein interactions in signal transduction cascades. These signaling molecules are organized in multimolecular complexes that translate information from cell surface receptors into cellular responses. The cytosolic adhesion- and degranulation-promoting adaptor protein (ADAP) is expressed in T cells, natural killer cells, myeloid cells, and platelets. Here we summarize the data about the function of ADAP in these cells with respect to their contribution to the pathogenesis of experimental autoimmune encephalomyelitis. We discuss possible mechanisms of strongly attenuated experimental autoimmune encephalomyelitis in ADAP-deficient mice.
The Ezrin-Radixin-Moesin Family of Proteins in the Regulation of B-Cell Immune Response
15-31
10.1615/CritRevImmunol.2015012327
Debasis
Pore
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
Neetu
Gupta
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
ezrin
radixin
moesin
B cell
membrane dynamics
microclusters
signaling
germinal center
Dynamic reorganization of the cortical cytoskeleton is essential for numerous cellular processes, including B- and T-cell activation and migration. The ezrin-radixin-moesin (ERM) family of proteins plays structural and regulatory roles in the rearrangement of plasma membrane flexibility and protrusions through its members' reversible interaction with cortical actin filaments and the plasma membrane. Recent studies demonstrated that ERM proteins not only are involved in cytoskeletal organization but also offer a platform for the transmission of signals in response to a variety of extracellular stimuli through their ability to cross-link transmembrane receptors with downstream signaling components. In this review, we summarize present knowledge relating to ERMs and recent progress made toward elucidating a novel role for them in the regulation of B-cell function in health and disease.
Orchestration of Invariant Natural Killer T Cell Development by E and Id Proteins
33-48
10.1615/CritRevImmunol.2015012207
Sumedha
Roy
Department of Immunology, Duke University Medical Center, Durham, NC 27710
Yuan
Zhuang
Department of Immunology, Duke University Medical Center, Durham, NC 27710
iNKT
E proteins
Id proteins
development
Natural killer T (NKT) cells are αβ T cells that express a semi-invariant T-cell receptor (TCR) along with natural killer (NK) cell markers and have an innate cell-like ability to produce a myriad of cytokines very quickly upon antigen exposure and subsequent activation. These cells are diverted from conventional single positive (SP) T-cell fate at the double positive (DP) stage, where TCR-mediated recognition of a lipid antigen presented on a CD1d molecule promotes their selection into the NKT lineage. Although many key regulatory molecules have been shown to play important roles in the development of NKT cells, the mechanism of lineage specification and acquisition of effector functions in these cells still remain to be fully addressed. In this review, we specifically discuss the role of a family of class-I helix-loop-helix proteins known as E proteins, and their antagonists Id proteins in NKT celldevelopment. Recent work has shown that these proteins play key roles in invariant NKT (iNKT) development, from the invariant TCR rearrangement to terminal differentiation and maturation. Elucidating these roles provides an opportunity to uncover the transcriptional network that separates NKT cells from concurrently developed conventional αβ T cells.
Interleukin 35−Producing B Cells (i35-Breg): A New Mediator of Regulatory B-Cell Functions in CNS Autoimmune Diseases
49-57
10.1615/CritRevImmunol.2015012558
Charles E.
Egwuagu
Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland 20892
Cheng-Rong
Yu
Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland 20892
interleukin 35
interleukin 10
regulatory B cell or Breg
interleukin 35-producing Breg or i35-Breg
autoimmunity
experimental autoimmune uveitis
Neuroinflammation contributes to neuronal deficits in neurodegenerative CNS (central nervous system) autoimmune diseases, such as multiple sclerosis and uveitis. The major goal of most treatment modalities for CNS autoimmune diseases is to limit inflammatory responses in the CNS; immune-suppressive drugs are the therapy of choice. However, lifelong immunosuppression increases the occurrence of infections, nephrotoxicity, malignancies, cataractogenesis, and glaucoma, which can greatly impair quality of life for the patient. Biologics that target pathogenic T cells is an alternative approach that is gaining wide acceptance as indicated by the popularity of a variety of Food and Drug Administration (FDA)-approved anti-inflammatory compounds and humanized antibodies such as Zenapax, Etanercept, Remicade, anti-ICAM, rapamycin, or tacrolimus. B cells are also potential therapeutic targets because they provide costimulatory signals that activate pathogenic T cells and secrete cytokines that promote autoimmune pathology. B cells also produce autoreactive antibodies implicated in several organ-specific and systemic autoimmune diseases including lupus erythematosus, Graves' disease, and Hashimoto's thyroiditis. On the other hand, recent studies have led to the discovery of several regulatory B-cell (Breg) populations that suppress immune responses and autoimmune diseases. In this review, we present a brief overview of Breg phenotypes and in particular, the newly discovered IL35-producing regulatory B cell (i35-Breg). We discuss the critical roles played by i35-Bregs in regulating autoimmune diseases and the potential use of adoptive Breg therapy in CNS autoimmune diseases.
CD28-CD80/86 and CD40-CD40L Interactions Promote Thymic Tolerance by Regulating Medullary Epithelial Cell and Thymocyte Development
59-76
10.1615/CritRevImmunol.2015012501
Joy A.
Williams
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
Xuguang
Tai
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
Richard J.
Hodes
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
FoxP3
T regulatory
mTEC
negative selection
thymus and costimulation
Development and central tolerance of T lymphocytes in the thymus requires both TCR signals and collaboration with signals generated through costimulatory molecule interactions. In this review, we discuss the importance of CD28-CD80/86 and CD40-CD40L costimulatory interactions in promoting normal thymic development. This discussion includes roles in the generation of a normal thymic medulla, in the development of specific T-cells subsets, including iNKT and T regulatory cells, and in the generation of a tolerant mature T-cell repertoire. We discuss recent contributions to the understanding of CD28-CD80/86 and CD40-CD40L costimulatory interactions in thymic development, and we highlight the ways in which the many important roles mediated by these interactions collaborate to promote normal thymic development.
Lipocalin-2 in the Inflammatory Activation of Brain Astrocytes
77-84
10.1615/CritRevImmunol.2015012127
Shinrye
Lee
Korea Brain Research Institute (KBRI), Daegu, Republic of Korea
Mithilesh Kumar
Jha
Department of Pharmacology, Brain Science & Engineering Institute, Department of Biomedical Science, BK21 PLUS KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea
Kyoungho
Suk
Department of Pharmacology, Brain Science & Engineering Institute, Department of Biomedical Science, BK21 PLUS KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea
lipocalin-2
astrocytes
neuroinflammation
central nervous system
chemokine
polarization
Lipocalin-2 (LCN2), a secretory protein, regulates diverse cellular processes such as cell death/survival, cell migration/invasion, cell differentiation, iron delivery, inflammation, insulin resistance, and tissue regeneration. Recently, we reported that LCN2 is secreted by brain astrocytes under inflammatory conditions and that it promotes apoptosis, morphological changes, and migration in astrocytes both in vitro and in vivo. Activated astrocytes release LCN2 not only to induce the morphological transformation associated with reactive astrocytosis, but also to promote their own death. Under inflammatory conditions, activated astrocytes also show functional dichotomy similar to the M1/M2 phenotypes of microglia and macrophages. LCN2 is thought to be a chemokine inducer and an autocrine promoter of the classical proinflammatory activation of astrocytes. This article summarizes the current knowledge regarding the role of astrocyte-derived LCN2 as a proinflammatory mediator in the central nervous system and discusses LCN2's role in neuroinflammatory disorders.