Advances in Immunology (eBook)

Front Cover 1
Advances in Immunology 4
Copyright Page 5
Contents 6
Contributors 8
Chapter 1: The Physiological Role of Lysyl tRNA Synthetase in the Immune System 10
1. Gene Sharing and Noncanonical Protein Roles 11
2. Aminoacyl-tRNA Synthetases (AaRSs) and the Multisynthetas Complex 12
2.1. General description 12
2.2. The multisynthetase complex as a protein ``depot´´ 15
3. LysRS 17
3.1. Structural and molecular characteristics 17
3.2. Interacting proteins 18
3.2.1. PDZ domain interactions 19
3.2.2. Elongation factor 1A (EF-1A) and LysRS 20
3.2.3. Mutated superoxide dismutase 21
3.3. LysRS and the autoimmune response 22
3.4. Functional roles 22
3.4.1. Lysine residue adenylation 23
3.4.2. Synthesis of dinucleotides 23
3.4.3. LysRS as a cytokine-like molecule 24
3.4.4. Physiological roles of LysRS 25
3.4.4.1. LysRS and transcription factors 25
3.4.4.2. LysRS and HIV 28
4. Concluding Remarks 30
References 30
Chapter 2: Kill the Bacteriahellipand Also Their Messengers? 38
1. Lipopolysaccharide (LPS) Sensing by MD-2-TLR4 39
2. Acyloxyacyl Hydrolase 40
2.1. Structure, biosynthesis 41
2.2. Enzymatic activity 45
3. LPS Deacylation In Vivo 45
4. Inactivating LPS In Vivo 47
4.1. AOAH-dependent phenotypes 48
4.1.1. Prolonged elevations in polyclonal plasma IgM and IgG3 antibodies 48
4.1.2. Persistent hepatomegaly 49
4.1.3. Prolonged tolerance and immunosuppression 50
4.1.4. Do AOAH-dependent phenotypes require exposure to LPS? 50
4.2. AOAH-dependent immunomodulation: Only in vivo? 51
4.3. Providing AOAH prevents prolonged responses to LPS in vivo 51
5. Potential Clinical Connections 52
5.1. AOAH deficiency 52
5.2. Host inactivation of microbial agonists other than LPS 52
6. Conclusion 53
Acknowledments 53
References 53
Chapter 3: Role of SOCS in Allergic and Innate Immune Responses 58
1. Atopic Immune Responses 60
2. SOCS Family 62
3. SOCS Genes 67
3.1. Evolution 67
3.2. SOCS1 67
3.2.1. Roles of SOCS1 domains 68
3.2.2. Knockout mouse studies 68
3.2.3. SOCS1 in innate immunity 70
3.2.4. SOCS1 in adaptive immune responses 72
3.3. CIS 72
3.4. SOCS2 73
3.5. SOCS3 73
3.5.1. SOCS3 in dendritic cells 74
3.5.2. SOCS3 in adaptive immunity 75
3.5.3. SOCS3 in cancer 75
3.6. SOCS4 76
3.7. SOCS5 76
3.8. SOCS6 77
3.9. SOCS7 77
4. Conclusion 78
References 79
Chapter 4: Multitasking by Exploitation of Intracellular Transport Functions: The Many Faces of FcRn 86
1. Introduction 88
2. FcRn: A Historical Perspective 88
3. FcRn is a Multitasking Receptor 89
3.1. A role for FcRn in regulating IgG levels 89
3.2. FcRn-mediated transport of IgG across cellular barriers: Opportunities for drug delivery 91
3.3. FcRn can deliver antigen for presentation 92
3.4. Possible functions of FcRn in specialized cell types 92
4. The Molecular Nature of FcRn-IgG Interactions 93
4.1. The interaction site for FcRn on IgG 93
4.2. The interaction site for IgG on FcRn 94
4.3. The stoichiometry of the FcRn-IgG interaction 96
5. The Intracellular Trafficking of FcRn 96
5.1. A model for FcRn trafficking 96
5.2. Endosomal sorting of IgGs within endothelial cells 98
5.3. Exocytic processes that result in IgG release from endothelial cells 99
5.4. Imaging FcRn trafficking in three dimensions using multifocal plane microscopy 100
5.5. FcRn trafficking in polarized epithelial cells 101
5.6. Molecular determinants and effectors of FcRn trafficking 102
5.7. Effects of ligand valency on intracellular trafficking 104
6. Regulation of FcRn Expression 105
7. The Complexity of Engineering FcRn-IgG Interactions 106
7.1. Antibody engineering: From variable to constant regions 106
7.2. Modulating the pharmacokinetic properties of IgG: The importance of pH dependence 107
7.3. Generation of inhibitors of FcRn function to lower endogenous IgG levels 108
8. Cross-Species Differences in FcRn-Binding Specificity and Implications for Preclinical Models 111
9. Concluding Remarks 113
Acknowledments 113
References 113
Subject Index 126
Contents of Recent Volumes 132