Advances in Immunology, a long established and highly respected serial, presents current developments as well as comprehensive reviews in immunology. Articles address the wide range of topics that comprise immunology, including molecular and cellular activation mechanisms, phylogeny and molecular evolution, and clinical modalities. Edited and authored by the foremost scientists in the field, each volume provides up-to-date information and directions for future research.
Cover 2
Copyright Page 4
Contents 6
Contributors 10
Chapter 1: Class Switch Recombination: A Comparison Between Mouse and Human 12
1. Introduction 12
2. Mechanism of CSR 13
2.1. Class Switch Recombination "ABC" 13
2.2. V(D)J Recombination and CSR 14
2.3. CSR and Somatic Hypermutation 14
2.4. Function of AID 15
2.5. dU:dG Mismatches Processing and DNA DSB Resolution in CSR 16
2.6. Regulation of CSR 22
3. Comparison Between Human and Mouse 26
3.1. The Constant Region Gene Locus in Human and Mouse 26
3.2. Switch Regions in Human and Mouse 27
3.3. 3' Enhancers in Human and Mouse 33
3.4. AID in Human and Mouse 36
3.5. Regulation of CSR to IgA in Human and Mouse 37
3.6. Regulation of CSR to IgG Subclasses in Human and Mouse 38
3.7. CD40-CD40L Pathway in Human and Mouse 42
3.8. BAFF-APRIL-TACI Pathway in Human and Mouse 43
3.9. Toll and Toll-Like Receptor in Human and Mouse 44
3.10. DNA Repair Factors and CSR 45
4. Concluding Remarks 53
Notes added in proof 53
Acknowledgments 54
References 54
Chapter 2: Anti-IgE Antibodies for the Treatment of IgE-Mediated Allergic Diseases 74
1. Introduction 75
1.1. The Current Status of the Anti-IgE Development 75
1.2. The Main Chemical Features of the Anti-IgE Therapeutic 76
1.3. IgE-Mediated Allergy Is a Vast Medical Field 77
2. Rationale Leading to the Invention of the Anti-IgE Concept 78
2.1. IgE Isotype-Specific Control and IgE Targeting 78
2.2. The Unique Set of Anti-IgE-Binding Specificities 79
2.3. Structural Basis of the Unique Binding Specificities 80
2.4. Prevailing Concepts at the Time of the Invention 82
3. Anti-IgE Is Approved for Treating Moderate-to-Severe Asthma 84
3.1. "Allergic Asthma" Has Been Adopted as a New Clinical Indication 85
3.2. Clinical Parameters Determined in the Clinical Studies 86
3.3. The Clinical Studies Confirm the Roles of IgE in the Pathogenesis of Asthma 88
3.4. Analyses of Good Responders Among Asthma Patients 89
4. Studies on Other Allergic Diseases 89
4.1. Clinical Applications in Treating Allergic Rhinitis 90
4.2. Anti-IgE Studies on Treating Peanut Sensitivity 91
4.3. Clinical Application in Latex Sensitivity 92
4.4. Allergic Diseases or Conditions for Which Anti-IgE Has Been Tested in Case Studies 92
5. The Potential of Using Anti-IgE to Assist Allergen-Based Immunotherapy 94
5.1. The Combination of Anti-IgE and SIT 95
5.2. Priming Patients with Anti-IgE for Rush Immunotherapy 95
6. Pivotal Roles of IgE and FcepsivRI in Type I Hypersensitivity 96
6.1. Stages Along IgE-Mediated Allergic Pathway 96
6.2. Direct Pharmacological Effects of Anti-IgE 98
7. Neutralization of Free IgE 99
7.1. Total IgE and the Proportion of Allergen-Specific IgE 99
7.2. IgE Concentration versus IgE Occupancy of FcepsivRI 100
8. Downregulation of FcepsivRI 101
8.1. The Dynamical Relationship Between Free IgE and FcepsivRI 101
8.2. Anti-IgE as a Mast "Cell-Stabilizing" Agent 102
8.3. How Low Should FcepsivRI-IgE Fall for a Mast Cell to Become Insensitive? 103
9. Potential Beneficial Effects of IgE:Anti-IgE Immune Complexes 104
9.1. How Soon Can Clinical Improvement Be Observed? 104
9.2. The Rapidly Accumulated Immune Complexes May Serve as Antigen Trappers 106
10. Can Anti-IgE Modulate IgE-Committed B Lymphoblasts and Memory B Cell? 107
11. Other Immunoregulatory Effects of Anti-IgE 109
11.1. Anti-IgE Should Neutralize the Cytokinergic Properties of IgE 109
11.2. The Overall Attenuation of Immune Reactivity 110
11.3. Local Environment in Disease-Affected Tissues is of Utmost Interest 110
12. Can Anti-IgE Attain a Long-Term Remission State? 111
13. Are There Adverse Effects Associated with Anti-IgE Therapy? 112
13.1. Is Immune Defense Function Compromised? 112
13.2. Observed Adverse Reactions 114
14. Other Approaches for Targeting IgE or IgE-Expressing B Cells 114
14.1. Approaches for Attenuating IgE-Mediated Allergic Pathway 114
14.2. An Approach to Target a Unique Epitope on mIgE 115
15. Concluding Remarks 117
Acknowledgments 118
References 118
Chapter 3: Immune Semaphorins: Increasing Members and Their Diverse Roles 132
1. Introduction 132
2. Sema4D 133
2.1. Sema4D-CD72 Interactions in B Cell Signaling 134
2.2. Sema4D-CD72 Interactions in Maintaining B Cell Homeostasis 135
2.3. Sema4D in T Cell-Mediated Immunity 137
3. Sema4A 138
3.1. Distinct Roles of DC-Derived and T Cell-Derived Sema4A in Immune Responses 138
3.2. Receptors for Sema4A in the Immune System 141
4. Sema6D and Its Receptor Plexin-A1 141
4.1. Sema6D–Plexin-A1 Interactions in Cardiac Development 142
4.2. Sema6D-Plexin-A1 Interactions in DC Function 142
4.3. Sema6D–Plexin-A1 Interactions in Osteoclastogenesis 143
4.4. Plexin-A1 Forms a Receptor Complex with TREM-2 and DAP12 in DCs and Osteoclasts 143
5. Sema7A 146
5.1. Sema7A as a Monocyte Stimulator 146
5.2. Sema7A as a Negative Regulator for T Cells 147
6. Other Semaphorins 148
6.1. Viral Semaphorins 148
6.2. Class III Semaphorins 148
7. Summary and Perspectives 149
Acknowledgments 150
References 150
Chapter 4: Tec Kinases in T Cell and Mast Cell Signaling 156
1. Introduction 156
1.1. Overview of Tec Kinases 156
1.2. Regulation of Tec Kinase Expression Levels 157
2. Subcellular Localization of Tec Kinases 158
2.1. Regulation of Membrane Recruitment 158
2.2. Nuclear Localization and Functions of Tec Kinases 161
3. Tec Kinases in Signaling Pathways 162
3.1. Antigen Receptor Signaling Pathways 162
3.2. Interactions with Negative Regulators of Signaling 165
3.3. Interactions with the Cytoskeletal Components 167
3.5. Associations with Additional Signaling Proteins 168
4. Regulation of Tec Kinase Activation 171
4.1. Regulation by Tyrosine Phosphorylation 171
4.2. Inter- and Intramolecular Domain Interactions 172
5. Distinct Versus Redundant Functions of Tec Kinases 174
5.1. Tec Kinases in T Cell Development 174
5.2. Tec Kinases in Other Cell Types 175
5.3. Redundancy Among Tec Kinase Family Members 175
6. Tec Kinases in Mast Cell Signaling 177
6.1. Overview of Mast Cells 177
6.2. FcepsilonR1 Signaling 178
6.3. Btk in Mast Cell Function and Signaling 180
6.4. Possible Role of Ikt in Mast Cells 181
6.5. Potential Positive Roles of Multiple Tec Kinases in Mast Cells 181
6.6. Potential Negative Roles for Tec Kinases in Mast Cell Signaling 182
7. Conclusions 183
Acknowledgments 183
References 183
Chapter 5: Integrin Regulation of Lymphocyte Trafficking: Lessons from Structural and Signaling Studies 196
1. Introduction 196
2. Leukocyte Integrins 197
3. Affinity and Valency Regulation 200
4. Integrin Conformational Changes 200
4.1. Global Changes of Extracellular Domains in Integrins That Lack the alphal Domains 200
4.2. Extensions of Extracellular Domains of beta2 Integrins 201
4.3. Multiple Affinity States of the alphal Domain 203
4.4. Regulation of the alphaI Domain Conformations by the betaI Domain 203
4.5. Regulation of the betaI Domain by Extensions and Divalent Metals 203
4.6. Cytoplasmic Domain 204
5. Integrin-Mediated Adhesion Steps in Lymphocyte Trafficking 206
5.1. Conversion of Rolling to Firm Adhesion by Chemokines 206
5.2. Transmigration 210
5.3. Interstitial Migration in Lymphoid Tissues 210
5.4. Interactions with APC 211
6. Talin as Intracellular Regulator for Lymphocyte Adhesion and Migration 212
7. Intracellular Signals in Chemokine-Induced Adhesion and Migration 214
7.1. PI3K Pathways 214
7.2. Rho Pathways 215
7.3. Rap1 Pathways 216
7.4. Rac Pathways 219
7.5. RhoH 221
8. Inside-Out Signaling Events in TCR-Stimulated Lymphocytes 222
8.1. Tec Family Kinases 223
8.2. Rac Signaling Pathways 223
8.3. Rap1 Signaling Pathways 224
8.4. PKD 1 225
8.5. Adhesion and Degranulation Adaptor Protein 225
9. Concluding Remarks 226
Acknowledgments 226
References 227
Chapter 6: Regulation of Immune Responses and Hematopoiesis by the Rap1 Signal 240
1. Introduction 240
2. General Biology of the Rap1 Signal 241
2.1. Regulation of Rap1 Activation 241
2.2. Biological Function of Rap1 244
3. Rap1 Signal in Lymphocyte Development and Immune Responses 248
3.1. Thymic T Cell Development: Distinct Roles of Rap1 and Ras 248
3.2. Immunological Synapse and T Cell Activation 251
3.3. T Cell Nonresponsiveness and Anergy 252
3.4. B Cell Development and Self-Tolerance 255
3.5. Lymphocyte Migration and Homing 258
4. Rap1 Signal in Hematopoiesis and Leukemia 259
4.1. Hematopoietic Stem Cells and the Niche 259
4.2. Dysregulated Rap1 Signal and Myeloproliferative Disorders 260
4.3. Role of Rap1 in Generation and Function of Platelets 264
5. Rap1 Signal in Malignancy: New Aspects in Cancer 264
6. Conclusions and Perspectives 266
Acknowledgments 266
References 267
Chapter 7: Lung Dendritic Cell Migration 276
1. Introduction 276
2. Airway DC Subsets: Localization and Phenotype 277
3. Recruitment of DCs to the Lung 278
4. Migration of Airway DCs to the LNs 280
4.1. Migration of DCs Under Steady-State Conditions 280
4.2. Migration of DCs Under Inflammatory Conditions 281
5. Recruitment of pDCs to the Sites of Inflammation 283
6. Conclusions 283
References 284
Index 290
Contents of Recent Volumes 302
Class Switch Recombination: A Comparison Between Mouse and Human
Qiang Pan-Hammarström; Yaofeng Zhao; Lennart Hammarström Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden
Abstract
Humans and mice separated more than 60 million years ago. Since then, evolution has led to a multitude of changes in their genomic sequences. The divergence of genes has resulted in differences both in the innate and adaptive immune systems. In this chapter, we focus on species difference with regard to immunoglobulin class switch recombination (CSR). We have compared the immunoglobulin constant region gene loci from human and mouse, with an emphasis on the switch regions, germ line transcription promoters, and 3′ enhancers. We have also compared pathways/factors that are involved in CSR. Although there are remarkable similarities in the cellular machinery involved in CSR, there are also a number of unique features in each species.
1 Introduction
Owing to development of the gene “knockout” technology, Mus musculus has emerged as a leading mammalian system for biomedical research over the past decades. Mouse models have served as surrogates for exploring human physiology and pathology, leading to major discoveries in many areas of biomedical research, including immunology. The availability of the human, mouse, and rat genome sequences (Gibbs et al., 2004; Lander et al., 2001; Venter et al., 2001; Waterston et al., 2002) has provided possibilities for cataloging the murine orthologs of human genes and allowed a way to identify and to perform functional studies on human disease associated genes.
One concern, however, is if mouse models faithfully represent human disease processes or not. Humans and mice separated more than 60 million years ago (Madsen et al., 2001; Murphy et al., 2001). Since then, evolution has led to a multitude of changes in their genomic sequences, including mutations, insertions, deletions, and duplications. The average divergence rate is about one substitution for every two nucleotides (Waterston et al., 2002) and genes encoding various classes of proteins have evolved with different paces. One notable set of proteins that seem to be under positive or purifying selection, and thus evolves rapidly, are those implicated in host defense (Waterston et al., 2002).
The divergence of genes in the mouse and human genomes has resulted in differences both in the innate and in the adaptive immune systems, leading to development of different pathways, involving a variety of chemical messengers. In this chapter, we will highlight some of these differences and address species differences related to immunoglobulin (Ig) class switch recombination (CSR).
2 Mechanism of CSR
2.1 Class Switch Recombination “ABC”
The first antibodies produced in a humoral immune response are of the IgM class. Activated B cells subsequently undergo isotype switching to secrete antibodies of different isotypes: IgG, IgA, and IgE. Isotype switching does not affect the antibody specificity, but alters the effector functions of the antibody. The change in antibody class is effectuated by a deletional recombination event called class switch recombination (CSR), where the constant region gene of the μ heavy chain (Cμ) is replaced by a downstream CH gene (Cγ, Cα, or Cε) and intervening sequences are excised as circular DNA (Iwasato et al., 1990; Matsuoka et al., 1990; von Schwedler et al., 1990).
CSR involves DNA regions, called “switch (S) regions,” that are located in the intron upstream of each C region gene. S regions are composed of tandemly repeated sequences that contain common pentamer sequences (GAGCT and GGGGT), but differ in length and degree of sequence similarity with Sμ.
CSR is a unique form of recombination. It is referred to as a “region-specific” rather than “site-specific” process, as no consensus sequence has been identified at the junctions of recombined S regions. It is also distinct from homologous recombination (HR), as it does not depend on a long stretch of homology between the sequences involved.
CSR is influenced in both a positive and a negative manner by a number of cytokines and B cell activators. The mechanism involved is partly mediated through the ability of cytokines and activators to regulate transcription of unrearranged CH genes prior to CSR, yielding what are referred to as germ line (GL) transcripts (Stavnezer-Nordgren and Sirlin, 1986; Yancopoulos et al., 1986). GL transcripts all have a similar structure, resulting from the initiation of transcription from an I (intervening) exon upstream of the S region and are spliced to the first exon of the corresponding CH gene. GL transcripts are required for CSR, and targeting of CSR to a given C region gene is considered to be tightly correlated with transcription from the corresponding upstream GL promoter (Chaudhuri et al., 2004; Stavnezer, 1996).
At the DNA level, CSR is initiated by activation-induced deaminase (AID; Muramatsu et al., 2000; Revy et al., 2000), probably by deamination of dC residues within the S regions. The initial lesions are subsequently processed and DNA double strand breaks (DSBs) are introduced that may lead to recombination of the two S regions involved. These processes require activation of a number of DNA damage response/repair pathways, including ataxia-telangiectasia mutated (ATM)/ataxia-telangiectasia and Rad3-related (ATR)-dependent signaling, base excision repair (BER), mismatch repair (MMR), and nonhomologous end joining (NHEJ; Chaudhuri and Alt, 2004).
2.2 V(D)J Recombination and CSR
Mammalian organisms require an additional form of DNA recombination, V(D)J recombination, in order to produce functional antibody encoding genes. V(D)J recombination mediates assembly of the gene segments that encode the Ig heavy- and light-chain variable domains. It is distinct from CSR in several regards: it occurs early in B cell development in the bone marrow; it is initiated by the lymphocyte-specific proteins RAG1 and RAG2 instead of AID; it proceeds through precise DNA cleavage at conserved signal sequences and is therefore a “site-specific” rather than a “region-specific” recombination process (Dudley et al., 2005; Jung and Alt, 2004; Schatz, 2004). There are, however, also similarities between the two types of recombination. Both V(D)J recombination and CSR involve DNA deletion by a mechanism whereby intervening sequences are excised as circular DNA. Moreover, CSR resembles V(D)J recombination in that DSBs are generated during the switch reaction (Catalan et al., 2003; Schrader et al., 2005; Wuerffel et al., 1997). Furthermore, components of the NHEJ machinery are implicated in resolution of the DSBs in both recombination processes (Chaudhuri and Alt, 2004; Lieber et al., 2004), whereas other DNA repair pathways/factors appear to be more “CSR specific” or “V(D)J specific” (see discussion in Section 2.5.3).
2.3 CSR and Somatic Hypermutation
Somatic hypermutation (SHM), a process where point mutations are introduced at a high rate into the Ig variable (V) genes, helps shape the Ig repertoire and, similar to CSR, occurs in the germinal center. Both SHM and CSR require transcription through the targeted regions and are initiated by the B cell-specific factor AID (Muramatsu et al., 2000; Revy et al., 2000). Resolution of the initial lesions in the V and S region genes is, however, somewhat different (see discussion in Section 2.5.3), and DSBs seem not to be prominent intermediates. Instead, single-strand breaks (SSBs) or single-strand nicks appear to be essential in SHM (Faili et al., 2002b; Li et al., 2004b; Neuberger et al., 2005).
2.4 Function of AID
AID was discovered by Honjo and coworkers and shown to be a B cell factor that is essential for both SHM and CSR (Muramatsu et al., 1999, 2000). AID-deficient mice are devoid of both SHM and CSR (Muramatsu et al., 2000), as are patients with an autosomal recessive form of the hyper-IgM syndrome (HIGM2), caused by mutations in the human AID-encoding gene (Revy et al., 2000). Ectopic expression of AID in nonlymphoid cells is sufficient to induce both SHM and CSR, suggesting that it is the only B cell-specific factor needed for these processes (Martin et al., 2002; Okazaki et al., 2002; Yoshikawa et al., 2002). AID is also essential for gene conversion (Arakawa et al., 2002; Harris et al., 2002), which is the dominant mechanism for V region diversification in selected animal species, including chickens and possibly sheep.
AID was initially thought to edit mRNA, as it shares a high degree of sequence homology with the RNA-editing enzyme APOBEC-1 (apolipoprotein B mRNA editing catalytic polypeptide...
| Erscheint lt. Verlag | 21.3.2007 |
|---|---|
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber |
| Medizin / Pharmazie ► Allgemeines / Lexika | |
| Medizinische Fachgebiete ► Innere Medizin ► Hämatologie | |
| Studium ► Querschnittsbereiche ► Infektiologie / Immunologie | |
| Naturwissenschaften ► Biologie | |
| ISBN-10 | 0-08-047507-8 / 0080475078 |
| ISBN-13 | 978-0-08-047507-3 / 9780080475073 |
| Haben Sie eine Frage zum Produkt? |
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