ebook ebooks e-book e-books downloaden bei MyEbooks.ch downloaden

BLyS Ligands and Receptors

:	M. P. Cancro
:	Michael P. Cancro
:	BLyS Ligands and Receptors
:	Humana Press
:	9781603270137
:	1
:	CHF 189.90
:

:	Nichtklinische Fächer
:	English

:	284
:	Wasserzeichen
:	PC/MAC/eReader/Tablet
:	PDF

Discovery of the BLyS (also known as BAFF) family of ligands and receptors has yielded a paradigm shift in our view of B-lymphocyte selection, survival, activation, and homeostasis. Previously, the B-cell antigen receptor (BCR) was viewed as the sole mediator of these parameters, in which BCR signals were not only dominant but were also linearly related to consequent outcomes. However, appreciating that BLyS signaling is an equal partner in establishing and maintaining B-cell pools in- cated that additional regulatory complexity - apparently based on population density and homeostatic demands - had to be included in models of B-cell behavior. This mounting interest was ampli?ed by evidence of a clear relationship to autoim- nity. The resulting ?urry of research activity has yielded a wealth of information and insights, impacting basic concepts in B-cell tolerance and activation as well as revealing novel translational strategies for autoimmunity, neoplasia, and transplant tolerance. This book includes 12 chapters that together yield an overview of these advances and ideas. The initial excitement generated by associations with humoral autoimmunity, coupled with profound B lineage phenotypes in knockout mouse models, prompted immediate questions: What do these receptors and cytokines look like, how do they interact, what cells express them, and how does this inform our understating of their biology? Indeed, probing the structural features of BLyS family ligands and rec- tors has afforded substantial insight, as have studies directed toward understanding the basic biological actions of these molecules.

	Preface	4
	Acknowledgements	6
	Contributors	9
	Contents	7
	1 The Beautiful Structures of BAFF, APRIL, and Their Receptors	12
	1.1 Introduction	13
	1.2 Multiple Forms of BAFF and APRIL	14
	1.3 Structure of BAFF and APRIL	14
	1.3.1 Structural Comparison to Other TNF Family Members	14
	1.3.2 BAFF Forms Virus-Like Particles	15
	1.3.3 APRIL Binds to Proteoglycans	17
	1.4 Receptor Binding	18
	1.4.1 Structure of BCMA, TACI, and BAFF-R	18
	1.4.2 Comparison of Ligand--Receptor Binding in the TNF Family	19
	1.4.3 Structural Determinants of Binding Specificity	21
	1.5 Receptor Signaling	22
	1.5.1 Signaling Overview	22
	1.5.2 TRAF Binding	23
	1.6 Oligomerization-Dependent Signaling	24
	1.7 Conclusions and Open Questions	25
	References	26
	2 BAFF Receptor Regulation of Peripheral B-Lymphocyte Survival and Development	30
	2.1 Introduction	30
	2.2 Peripheral B-Cell Development	31
	2.3 BAFF/BR3 in B-Cell Survival and Development	36
	2.4 Mechanisms of BR3-Mediated B-Cell Survival	37
	2.5 Mechanisms of BAFF-Mediated Activation of Classical and Alternative NF-B Pathways	39
	2.6 A Unified View of How BCR and BR3 Regulate B-Cell Development and Activation: BCR-Positive Regulation of BR3-Induced NF-B Activation	42
	References	45
	3 Regulation of B-Cell Self-Tolerance By BAFF and the Molecular Basis of Its Action	53
	3.1 Regulation of Self-Reactive B Cells by BAFF	54
	3.1.1 The Requirement for B-Cell Self-Tolerance	54
	3.1.2 Self-Tolerance Checkpoints During B-Cell Development	54
	3.1.2.1 Immature Bone Marrow B Cells	54
	3.1.2.2 Immature to Mature B-Cell Transition in the Periphery	55
	3.1.2.3 Marginal Zone B-Cell Development	56
	3.1.3 Points of Action of BAFF and BAFF-R During B-Cell Development	57
	3.1.4 BAFF and the Regulation of B-Cell Self-Tolerance Checkpoints	58
	3.1.4.1 Immature Bone Marrow B Cells	58
	3.1.4.2 Immature to Mature B-Cell Transition in the Periphery	59
	3.1.5 Marginal Zone B-Cell Development	60
	3.2 Signalling BAFF-Dependent B-Cell Survival	61
	3.2.1 The NF- B Signalling Pathways	61
	3.2.1.1 The Canonical NF-B Pathway	62
	3.2.1.2 The Alternative NF-B Pathway	63
	3.2.2 The Contribution of the Canonical NF- B Pathway to B-Cell Survival	63
	3.2.3 The Alternative NF- B Pathway Is the Major Contributor to B-Cell Survival Downstream of BAFF-R	64
	3.2.3.1 TRAF Proteins Are Fundamental Regulators of NF-B2 Signalling	64
	3.2.3.2 Unravelling the Proximal Signalling Events That Allow TRAFs to Suppress NF-B2 Signalling	65
	3.2.3.3 BAFF Is an Obligate Survival Factor for B Cells Because It Reverses the Suppression of NF-B2	67
	3.2.4 Other Intracellular Mediators of B-Cell Survival Initiated by BAFF	67
	3.2.4.1 Increasing Glycolysis	68
	3.2.4.2 Modulation of Pro- and Anti-apoptotic Proteins	68
	3.3 Conclusions	68
	References	69
	4 Role of BAFF and APRIL in Antibody Production and Diversification	74
	4.1 Introduction	74
	4.2 Role of BAFF and APRIL in B-Cell Survival and Activation	75
	4.2.1 Structure of BAFF and APRIL	75
	4.2.2 Expression of BAFF and APRIL	75
	4.2.3 BAFF and APRIL Receptors	76
	4.2.4 BAFF and APRIL Signaling	76
	4.2.5 Role of BAFF and APRIL in B-Cell Survival	77
	4.2.6 Role of BAFF and APRIL in B-Cell Activation and Differentiation	78
	4.3 Role of BAFF and APRIL in Antibody Production	79
	4.3.1 Regulation of Adaptive Immune Responses by DCs	79
	4.3.2 Role of Specific DC Subsets	80
	4.3.3 DC Regulation of TD Antibody Responses	81
	4.3.4 Function of BAFF and APRIL in TD Antibody Responses	82
	4.3.5 Role of TI Antibody Responses in Protective Immunity	83
	4.3.6 Dendritic Cell Regulation of TI Antibody Responses	84
	4.3.7 Function of BAFF and APRIL in TI Antibody Responses	85
	4.4 Role of BAFF and APRIL in Antibody Diversification	87
	4.4.1 Processes Mediating Antibody Diversification	87
	4.4.2 Mechanism and Requirements of Class Switching	88
	4.4.3 CD40L Signaling in TD Class Switching	90
	4.4.4 BAFF and APRIL Signaling in TI Class Switching	91
	4.5 Role of BAFF and APRIL in Antibody Disorders	92
	4.5.1 Autoimmune Disorders	92
	4.5.2 Immunodeficiencies	93
	4.6 Conclusions	94
	References	94
	5 Signal Transduction by Receptors for BAFF and APRIL	102
	5.1 Proximal Signaling