Advances in Immunology, a long established and highly respected publication, 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 1
Contents 6
Contributors 10
Chapter 1: Fate Decisions Regulating Bone Marrow and Peripheral B Lymphocyte Development 12
1. Introduction 13
2. B Lymphocyte Development in the Bone Marrow 14
2.1. Stages of B lymphopoiesis 15
2.2. Specification versus commitment during B lymphopoiesis 17
2.3. Developmental checkpoints during B lymphopoiesis 18
2.4. Selection for functional BCR complexes 21
2.5. The hematopoietic microenvironment 27
2.6. Permissive versus deterministic models of B lymphopoiesis 28
2.7. Maintenance of early B lineage fate 30
2.8. Perturbations affecting primary B lymphopoiesis 30
3. Development of Immature B Cells in the Bone Marrow and Periphery 32
4. BCR-Dependent Signaling and Fate Decisions by Bone Marrow and Peripheral Immature B Lymphocytes 34
4.1. Biochemistry of BCR-induced fate decisions during negative selection 34
4.2. Alternative BCR-induced fate decisions 38
5. BCR Signaling During the Transitional to Mature B-lymphocyte Transition 41
5.1. Igalpha/beta and ITAMs 42
5.2. B-cell linker protein 42
5.3. Bruton's tyrosine kinase 43
5.4. Involvement of other BCR-signaling proteins 43
6. Peripheral B Lymphocyte Survival: Synergy Between BCR and BAFF-R Signaling 44
7. Development of FO and MZ Mature B Lymphocytes 46
8. Concluding Remarks 47
Acknowledgments 47
References 48
Chapter 2: Tolerance and Autoimmunity: Lessons at the Bedside of Primary Immunodeficiencies 62
1. Introduction 63
2. PIDs Systematically Associated with Clinical AI 67
2.1. Immunodysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX) 67
2.2. Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) 73
2.3. Omenn syndrome (OS) 74
2.4. Autoimmune lymphoproliferative syndrome (ALPS) 76
2.5. Complement deficiencies 77
3. PIDs Strongly Associated with Clinical AI 78
3.1. Selective IgA deficiency 78
3.2. Common variable immunodeficiency 79
3.3. Agammaglobulinemia 80
3.4. Hyper-IgM syndrome 80
3.5. Wiskott-Aldrich Syndrome 81
3.6. NF-kappaB essential modulator defects 81
4. PIDs that Are Mildly Associated with Clinical AI 82
5. PIDs that Are Not Associated with AID 83
6. Concluding Remarks 84
Addendum in proof 85
References 85
Chapter 3: B-Cell Self-Tolerance in Humans 94
1. Antibody Diversity 95
2. Antibodies and Self-Tolerance 96
2.1. B-cell development and self-tolerance in the bone marrow 97
2.2. Transitional B cells and peripheral selection of naive cells 100
2.3. Defective early B-cell tolerance checkpoints and autoimmunity 101
2.4. Molecular defects associated with altered self-tolerance in autoimmunity 104
3. Marginal Zone B Cells 105
3.1. Mouse marginal zone B cells 105
3.2. The human MZ and circulating IgM+ CD27+ B cells 105
4. B-Cell Memory 107
4.1. Germinal centers 108
4.2. Activation and selection of autoreactive B cells 109
4.3. Autoreactivity and B-cell memory 110
5. Concluding Remarks 111
References 113
Chapter 4: Manipulation of Regulatory T-Cell Number and Function with CD28-Specific Monoclonal Antibodies 122
1. Aims of this Review 124
2. Positive and Negative Regulation of T-Cell Responses by the CD28/CTLA-4 System 124
3. The Importance of CD28 and CTLA-4 for the Generation and Homeostasis of Treg Cells 126
3.1. "Natural" regulatory cells 126
3.2. IL-2 dependence of Treg cells 127
3.3. Significance of CTLA-4 for Treg function 128
3.4. Role of CD28 in generation and homeostasis of Treg cells 129
3.5. Role of CD28 and IL-2 in antigen-driven expansion and activation of Treg cells 130
4. Manipulating the CD28 Pathway: General Considerations 131
5. Conventional and Superagonistic mAb to the Costimulatory Receptor CD28 132
5.1. Epitope-function relationship 132
5.2. Mode of mAb binding: A clue to superagonism? 133
5.3. Signaling pathways 135
6. In Vitro Expansion of Treg Cells with the Help of CD28-Specific mAb 136
6.1. Costimulation 136
6.2. CD28 superagonists 136
7. In Vivo Effects of Conventional CD28-Specific mAb 137
7.1. General 137
7.2. Experimental findings 137
8. In Vivo Effects of CD28 Superagonists: Predominance of Treg-Cell Activation 139
8.1. Studies in rats 139
8.2. Studies in mice 140
8.3. A model for preferential expansion of Treg cells in CD28-superagonist-stimulated rodents 140
9. Treatment of Autoimmune and Inflammatory Model Diseases with CD28 Superagonists 143
9.1. Overview 143
9.2. Prevention and treatment of EAE in the LEW rat 145
10. TGN1412„A Superagonistic mAb to Human CD28 146
10.1. Introductory remarks 146
10.2. Development of TGN1412 147
10.3. Biophysical properties of TGN1412 147
10.4. Cytokine release syndrome in humans but not in animal models 148
10.5. Follow-up in vitro studies 150
10.6. Lessons from the TGN1412 trial 151
11. Conclusions 151
Acknowledgments 152
References 152
CH4Chapter 5: Osteoimmunology: A View from the Bone 160
1. Opening Remarks: The Old and the New 161
2. Osteoimmunology: A Developmental Encounter 162
2.1. Bone: Five cell types and two mechanisms of formation 162
2.2. The developmental encounter 162
2.3. Developmental consequences 163
3. The TNF Superfamily: A Developmental Link Between Bone and Immune System 163
3.1. Osteoclasts differentiation 163
3.2. Immune and bone developmental phenotypes in RANK axe mutated mice 164
3.3. TNF-alpha: A nonessential regulator of bone involved in autoimmune-induces bone pathology 165
3.4. RANKL, TNF-alpha: In search for differences 165
4. IFNs: Linking Bone Homeostasis to Immunity and T Cells 166
4.1. Type I IFNs establish an autoinhibitory loop in.osteoclasts 166
4.2. Type II IFN: A potent inhibitor of osteoclastogenesis secreted by T cells 167
5. B Cells and Bone 168
5.1. The hypothesis of myeloid lineage switch 168
5.2. Multiple myeloma: An osteolythic tumor 169
6. A Bone Quality Control of the Immune Response 169
Acknowledgments 171
References 171
Chapter 6: Mast Cell Proteases 178
Abbreviations 180
1. Introduction 180
2. Expression of MC Proteases 182
2.1. Human MC proteases 182
2.2. Murine MC proteases 184
2.3. Rat MC proteases 185
2.4. MC proteases from other species 186
2.5. MC protease expression profiles as MC markers 186
3. Genetic Organization and Regulation of Transcription 187
3.1. The chymase locus 187
3.2. The tryptase locus 190
3.3. The MC-CPA locus 190
3.4. Transcriptional regulation 191
4. Evolution of MC Proteases 193
4.1. MCs in evolution 193
4.2. MC proteases in early evolution 194
4.3. MC chymase in mammalian evolution 194
4.4. MC tryptase in mammalian evolution 195
5. Protein Organization and Processing 195
6. Three-Dimensional Structure 198
6.1. Chymase 198
6.2. Tryptase 200
6.3. MC-CPA 201
7. Cleavage Specificity 201
7.1. Chymase 203
7.2. Tryptase 206
7.3. MC-CPA 206
8. Interaction of MC Proteases with PGs: Implications for Storage, Activity, and Processing 207
8.1. Storage 207
8.2. Effect of PGs on MC protease activity/activation and processing 212
8.3. Structural basis for GAG: MC protease interaction 213
9. Substrates for MC Proteases 214
9.1. Chymase 217
9.2. Tryptase 221
9.3. MC-CPA 224
9.4. Concerted action of the MC proteases 224
10. In Vivo Function 225
10.1. Chymase 225
10.2. Tryptase 233
10.3. MC-CPA 236
11. MC Protease Inhibitors 237
11.1. Synthetic inhibitors 237
11.2. In vivo regulation 238
12. Summary and Future Perspectives 239
Acknowledgments 240
References 240
Index 268
Content of Recent Volumes 280
Color Plate Section 284
Tolerance and Autoimmunity: Lessons at the Bedside of Primary Immunodeficiencies
Magda Carneiro-Sampaio*; Antonio Coutinho‡ * Department of Pediatrics, Children's Hospital, Faculdade de Medicina da Universidade de São Paulo, Brazil
‡ Instituto Gulbenkian de Ciência, Oeiras, Portugal
Abstract
The recent progress in the genetic characterization of many primary immunodeficiencies (PIDs) allows for a better understanding of immune molecular and cellular mechanisms. The present chapter discusses associations between PIDs and autoimmune diseases (AIDs) in this new light. PIDs are classified according to the frequency of association with AIDs, defining four groups of conditions: systematic (more than 80% of all patients), strong (10–80%), mild (less than 10%), and absent (no available descriptions). Several general conclusions could be drawn: (1) pathological autoimmune (AI) manifestations are very frequently associated with PIDs, indicating that, contrary to conventional notions, antimicrobial protection and natural tolerance to body tissues share many basic mechanisms; (2) in some gene defects, association is so strong that one could speak of “monogenic” AIDs; (3) basic types of PIDs are selectively associated with AID of a particular set of target tissues; (4) while for some gene defects, current theory satisfactorily explains pathogenesis of the corresponding AID, other situations suggest extensive gaps in the present understanding of natural tolerance; and (5) not exceptionally, observations on the AI phenotype for the same gene defect in mouse and man are not concordant, perhaps owing to the limited genetic diversity of mouse models, often limited to a single mouse strain. Overall, clinical observations on PID support the new paradigm of “dominant” tolerance to self-components, in which AID owes to deficits in immune responses (i.e., in regulatory mechanisms), rather than from excessive reactivity.
1 Introduction
Acquisition of natural tolerance remains the central question of immunology. Over the last few years, however, a marked progress in the understanding of the mechanisms regulating autoimmunity (AI) has been achieved. Thus, beyond the purging of autoreactive repertoires ensured by negative selection that had been demonstrated in the 80's (von Boehmer et al., 1989), much evidence has been accumulated for the critical role of regulatory T cells (Tregs) in the control of pathogenic reactivities (Coutinho et al., 2005). In other words, current understanding has moved from a predominant notion of natural tolerance based on “recessive” mechanisms to that of a “dominant” process owing to the activity of a special class of autoreactive cells. Some go as far as speaking of a paradigmatic shift, for the new perspective turns problems and solutions around. Thus, while AI disease (AID) was previously viewed as an excess of autoreactivity and was treated by immunosuppression, it may now be expected to represent one of the manifestations of immunodeficiency, the therapeutics of which await novel drugs to selectively stimulate regulatory mechanisms.
The “experiments of nature” that are afforded by genetic diseases have always provided useful insights into physiology. While targeted gene inactivation in mice has provided a powerful means in such analysis, the forward genetics of human diseases offers a broader view and a wider range of phenomenology, notably by including allelic series and partial defects in gene function, all in richly heterogeneous “genetic backgrounds.” The recent and extraordinary progress in the genetic characterization of primary immunodeficiency diseases (PIDs) provides for novel possibilities of analysis (Cunningham-Rundles and Ponda, 2005; Notarangelo et al., 2006). We felt it timely, therefore, to revisit gene defects leading to PID, in the light of their associations with AIDs. This seemed all the more appropriate as the study of “regulatory” mechanisms ensuring natural tolerance revealed a series of evolutionary “solutions” that are based on novel and quite unexpected genetic, molecular, and cellular mechanisms. Other than unraveling putative mechanisms of tolerance, the analysis of AI manifestations in PIDs offers another advantage. All major AIDs that have been studied to date are of multifactorial origin, with complex genetics involving a number of susceptibility loci (Concannon et al., 2005; Krishnan et al., 2006; Morahan and Morel, 2002; Nath et al., 2004; Tsao, 2004; Wandstrat and Wakeland, 2001; Wicker et al., 2005). In contrast, PIDs are simple monogenic disorders, such that their specific association with AI illustrates the importance of a given gene (molecular or cellular mechanism) in tolerance.
Arthritis was one of the clinical manifestations in Bruton's first description of a PID (Bruton, 1952; Stiehm and Johnstone, 2005). Reports of AI phenomena in PIDs have become frequent, as improved medical management of PID patients greatly prolongs their survival and allows time for the clinical expression of AI phenomena (Arkwright et al., 2002; Etzioni, 2003; O'Shea et al., 2003; Rioux and Abbas, 2005; Ulmanen et al., 2005; Wulfraat et al., 2005). In some PIDs, such as immunodysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX syndrome); AI polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED); Omenn syndrome, AI lymphoproliferative syndrome (ALPS); and C1q deficiency, AI is the central disease component and is present in nearly all cases. In many other PIDs, AI manifestations occur also frequently [e.g., Wiskott–Aldrich syndrome (WAS), other deficiencies of early components of the classical complement pathway, IgA deficiency, common variable immunodeficiency (CVID), X-linked Hyper-IgM syndrome], and very few actually exist where no AI has been described (Table 1). This contrasts with ∼5% prevalence of AID in the general population (Davidson and Diamond, 2001), knowing that AIDs typically appear in young adults while most PID patients are detected in early childhood. Yet, the current understanding of PID does not systematically include AID as a major characteristic of such conditions. In light of the present chapter, however, AID and PID seem to be manifestations of the same basic processes, such that they could be aggregated within a single nosologic category. This conclusion gives credit to the new paradigm on “dominant tolerance,” and provides a better understanding of genotype–phenotype relationships, disease mechanisms, and respective clinical syndromes.
Table 1
Association between primary immunodeficiencies and autoimmunity
Systematically associated (>80%)
IPEX (100%)
APECED (almost 100%)
Omenn syndrome (100%)
ALPS (more than 80%)
C1q deficiency (93%)
Strongly associated (<80%>10%) C4 (75%) C1r/C1s (65%) and C2 (10–25%) deficiencies
Selective IgA deficiency (7–38%)
CVID (26%)
XL-Agammaglobulinemia (11–15%)
Hyper-IgM type 2 (AID deficiency) (21–25%)
XL-Hyper-IgM (CD40L def.) −20%
Wiskott-Aldrich syndrome (40–72%)
NEMO deficiencies (XL-EDA-ID) (23%)
Mildly associated (<10%)
C3 and C5–9 deficiencies
DiGeorge syndrome (5–10%)
Chronic granulomatous disease
Neutropenias
Hyper-IgE syndrome
MHC class I deficiency
MHC class II deficiency
FcγRIIIb deficiency
No descriptions found
Asplenia
Factor D deficiency
IL-12/IL-23–IFN-γ axis deficiencies
Ataxia telangiectasia syndrome
IRAK-4 deficiencya
WHIM syndromeb
b Gulino, 2003; Gulino et al., 2004; Diaz, 2005. The references for the other diseases are in the text and/or in Tables 2, 3, and 4.
Our review of clinical observations of AI manifestations in PID patients is summarized in Tables 2–4, relating each AID to the PIDs in which it has been described. In Table 1, however, this presentation is reversed, classifying all PIDs, according to the frequency of clinical descriptions of any AI manifestations. We define association of PID with AI disorders as “systematic,” when AI manifestations are described in most cases (>80%), and as “strong,” when 10–80% of the cases present AI phenomena. Table 1 also lists PIDs in which a few cases of AI manifestations were already described (mildly associated) in spite of their recent identification, as well as PIDs where we could not find association with AID.
Table 2
Connective tissue disorders in PIDs
| SLE | C1q deficiency (93%a) (Manderson et al., 2004; Pickering et al., 2001; Sullivan, 2004) | C1q |
| C4 deficiency (75%) (Manderson et al., 2004; Pickering et al., 2001;... |
| Erscheint lt. Verlag | 1.10.2007 |
|---|---|
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber |
| Medizin / Pharmazie ► Allgemeines / Lexika | |
| Medizin / Pharmazie ► Medizinische Fachgebiete | |
| Studium ► Querschnittsbereiche ► Infektiologie / Immunologie | |
| Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie | |
| Naturwissenschaften ► Biologie ► Zellbiologie | |
| ISBN-10 | 0-08-055370-2 / 0080553702 |
| ISBN-13 | 978-0-08-055370-2 / 9780080553702 |
| Haben Sie eine Frage zum Produkt? |
PDF (Adobe DRM)Größe: 6,7 MB
Kopierschutz: Adobe-DRM
Adobe-DRM ist ein Kopierschutz, der das eBook vor Mißbrauch schützen soll. Dabei wird das eBook bereits beim Download auf Ihre persönliche Adobe-ID autorisiert. Lesen können Sie das eBook dann nur auf den Geräten, welche ebenfalls auf Ihre Adobe-ID registriert sind.
Details zum Adobe-DRM
Dateiformat: PDF (Portable Document Format)
Mit einem festen Seitenlayout eignet sich die PDF besonders für Fachbücher mit Spalten, Tabellen und Abbildungen. Eine PDF kann auf fast allen Geräten angezeigt werden, ist aber für kleine Displays (Smartphone, eReader) nur eingeschränkt geeignet.
Systemvoraussetzungen:
PC/Mac: Mit einem PC oder Mac können Sie dieses eBook lesen. Sie benötigen eine
eReader: Dieses eBook kann mit (fast) allen eBook-Readern gelesen werden. Mit dem amazon-Kindle ist es aber nicht kompatibel.
Smartphone/Tablet: Egal ob Apple oder Android, dieses eBook können Sie lesen. Sie benötigen eine
Geräteliste und zusätzliche Hinweise
Zusätzliches Feature: Online Lesen
Dieses eBook können Sie zusätzlich zum Download auch online im Webbrowser lesen.
Buying eBooks from abroad
For tax law reasons we can sell eBooks just within Germany and Switzerland. Regrettably we cannot fulfill eBook-orders from other countries.
EPUB (Adobe DRM)Größe: 6,1 MB
Kopierschutz: Adobe-DRM
Adobe-DRM ist ein Kopierschutz, der das eBook vor Mißbrauch schützen soll. Dabei wird das eBook bereits beim Download auf Ihre persönliche Adobe-ID autorisiert. Lesen können Sie das eBook dann nur auf den Geräten, welche ebenfalls auf Ihre Adobe-ID registriert sind.
Details zum Adobe-DRM
Dateiformat: EPUB (Electronic Publication)
EPUB ist ein offener Standard für eBooks und eignet sich besonders zur Darstellung von Belletristik und Sachbüchern. Der Fließtext wird dynamisch an die Display- und Schriftgröße angepasst. Auch für mobile Lesegeräte ist EPUB daher gut geeignet.
Systemvoraussetzungen:
PC/Mac: Mit einem PC oder Mac können Sie dieses eBook lesen. Sie benötigen eine
eReader: Dieses eBook kann mit (fast) allen eBook-Readern gelesen werden. Mit dem amazon-Kindle ist es aber nicht kompatibel.
Smartphone/Tablet: Egal ob Apple oder Android, dieses eBook können Sie lesen. Sie benötigen eine
Geräteliste und zusätzliche Hinweise
Zusätzliches Feature: Online Lesen
Dieses eBook können Sie zusätzlich zum Download auch online im Webbrowser lesen.
Buying eBooks from abroad
For tax law reasons we can sell eBooks just within Germany and Switzerland. Regrettably we cannot fulfill eBook-orders from other countries.
aus dem Bereich
