Alt / Vogel Molecular Mechanisms of Immunological Self-Recognition

1. Auflage 2014
ISBN: 978-1-4832-1593-8
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 274 Seiten

Molecular Mechanisms of Immunological Self-Recognition covers the understanding of immunological self-recognition. The introductory chapter of the book summarizes the dawn of the insight into immunological tolerance, and provides an overview of research on the underlying mechanisms. The book addresses the developments in the molecular mechanisms of B and T cell tolerance and describes the failure of tolerance in autoimmunity. The text concludes by furnishing orienting perspectives and highlighting new information presented. The novel findings characterized as impressive advances pertain to the areas of B cell development and the generation of molecular diversity; V gene usage, especially from transgenes, in positive and negative thymic selection; the handling of positive and negative signals by T and B cells; anergy in postthymic T cells; the design of peptide-based therapy for autoimmune diseases; and the design of therapy with the aid of monoclonal antibodies. Immunologists will find the text useful.

Autoren/Hrsg.

Alt, Frederick

Vogel, Henry J.

Inhaltsverzeichnis

1;Front Cover;1
2;Molecular Mechanisms of Immunological Self-Recognition;4
3;Copyright Page;5
4;Table of Contents;6
5;Preface;14
6;PART I: INTRODUCTION;16
6.1;Chapter 1. Immunological Tolerance Revisited in the Molecular Era;18
6.1.1;THE DAWN OF IMMUNOLOGIC TOLERANCE;18
6.1.2;ONE CELL-ONE ANTIBODY, AND IMPLICATIONS;20
6.1.3;IN VITRO LYMPHOCYTE CLONING TECHNIQUES VALIDATE REPERTOIRE PURGING AS A TOLERANCE MECHANISM; CLONAL ABORTION VERSUS CLONAL ANERGY;22
6.1.4;CLONAL ABORTION AND CLONAL ANERGY COME OF AGE IN THE MOLECULAR ERA;23
6.1.5;THE GENESIS OF HIGH-AFFINITY ANTIBODIES;25
6.1.6;SOLUBLE ANTIGEN CAN CAUSE ADULT TOLERANCE,
INCLUDING A FAILURE OF APPEARANCE OF
HIGH-AFFINITY B CELLS;26
6.1.7;SUMMARY AND CONCLUSIONS;28
6.1.8;ACKNOWLEDGMENTS;28
6.1.9;REFERENCES;29
7;PART II: B CELL TOLERANCE;32
7.1;Chapter 2. Mechanisms and Meaning of B Lymphocyte Tolerance;34
7.1.1;INTRODUCTION;34
7.1.2;THE DELETION-ANERGY DECISION;34
7.1.3;CONSEQUENCES OF DELETION VERSUS ANERGY;36
7.1.4;REFERENCES;37
7.2;Chapter 3. Tolerant Autoreactive B Lymphocytes in the Follicular Mantle Zone Compartment: Substrates for Receptor Editing and Reform;40
7.2.1;INTRODUCTION;40
7.2.2;LOCALIZATION OF TRANSGENE-EXPRESSING B CELLS WITHIN PERIPHERAL LYMPHOID ORGANS;41
7.2.3;TIMING OF TOLERANCE INDUCTION DURING BONE MARROW B CELL DIFFERENTIATION;44
7.2.4;RECOVERY FROM RECEPTOR MODULATION AND TOLERANCE;46
7.2.5;DOES THE FOLLICULAR MANTLE ZONE SERVE AS A "REFORM SCHOOL" FOR WAYWARD R CELLS?;49
7.2.6;REFERENCES;50
8;PART III: LYMPHOCYTE SIGNALING;52
8.1;Chapter 4. T Cell Anergy;54
8.1.1;INTRODUCTION;54
8.1.2;CELLULAR CHARACTERISTICS;54
8.1.3;BIOCHEMICAL EVENTS RESULTING FROM TCR OCCUPANCY;59
8.1.4;REVERSAL OF ANERGY;64
8.1.5;CONCLUSION;67
8.1.6;REFERENCES;67
8.2;Chapter 5. THE T CELL ANTIGEN RECEPTOR: BIOCHEMICAL ASPECTS OF SIGNAL TRANSDUCTION;70
8.2.1;INTRODUCTION;70
8.2.2;SUBSTRATE ANALYSIS IN MURINE AND HUMAN T CELLS;
POSSIBLE TYROSINE KINASE REGULATION OF
PHOSPHOLIPASE C;73
8.2.3;ANALYSIS OF TYROSINE PHOSPHATASES;76
8.2.4;THE SERINE KINASE PATHWAY;78
8.2.5;FYN IS A T CELL RECEPTOR-ASSOCIATED TYROSINE KINASE;79
8.2.6;REFERENCES;82
8.3;Chapter 6. Structure and Signaling Function of B Cell Antigen Receptors of Different Classes;84
8.3.1;INTRODUCTION;84
8.3.2;RESULTS;85
8.3.3;REFERENCES;89
9;PART IV: T CELL TOLERANCE;92
9.1;Chapter 7. Self-Nonself Discrimination by T Lymphocytes;94
9.1.1;INTRODUCTION;94
9.1.2;NEGATIVE AND POSITIVE SELECTION OF A TRANSGENIC RECEPTOR SPECIFIC FOR THE MALE-SPECIFIC PEPTIDE PRESENTED BY CLASS I H-2Db MHC MOLECULES;96
9.1.3;LACK OF ALLELIC EXCLUSION OF THE a TCR CHAIN IN aß TCR TRANSGENIC MICE;98
9.1.4;MUTATIONS IN THE PEPTIDE-BINDING GROOVE OF MHC
MOLECULES AFFECT ANTIGENICITY AND NEGATIVE AS
WELL AS POSITIVE SELECTION;99
9.1.5;POSITIVE SELECTION: EXPANSION OF
MATURE THYMOCYTES OR MATURATION OF
IMMATURE THYMOCYTES?;101
9.1.6;POSTTHYMIC EXPANSION OF MATURE T CELLS;106
9.1.7;POSTTHYMIC TOLERANCE;106
9.1.8;DISCUSSION;109
9.1.9;REFERENCES;111
9.2;Chapter 8. Transgenic Mouse Model of Lymphocyte Development;114
9.2.1;INTRODUCTION;114
9.2.2;T CELL RECEPTOR TRANSGENIC MOUSE AS A MODEL SYSTEM TO STUDY T LYMPHOCYTE DEVELOPMENT;115
9.2.3;CLONAL DELETION OF SELF-REACTIVE T CELLS;116
9.2.4;POSITIVE SELECTION MODEL OF THE ORIGIN OF MHC-RESTRICTED T CELLS;116
9.2.5;MOLECULAR REQUIREMENTS FOR POSITIVE SELECTION;117
9.2.6;FUTURE ISSUES IN T CELL DEVELOPMENT USING TCR TRANSGENIC MICE;118
9.2.7;REFERENCES;118
9.3;Chapter 9. Recognition Requirements for the Positive Selection of the T Cell Repertoire: A Role of Self-Peptides and Major Histocompatibility Complex Pockets;120
9.3.1;INTRODUCTION;120
9.3.2;RESULTS AND DISCUSSION;122
9.3.3;SUMMARY;128
9.3.4;REFERENCES;129
9.4;Chapter 10. Mechanisms of Peripheral Tolerance;130
9.4.1;INTRODUCTION;130
9.4.2;RESULTS;131
9.4.3;DISTINCT MECHANISMS OF PERIPHERAL TOLERANCE;133
9.4.4;CONCLUSIONS;135
9.4.5;ACKNOWLEDGMENTS;136
9.4.6;REFERENCES;136
9.5;Chapter 11. An Analysis of T Cell Receptor-Iigand Interaction Using a Transgenic Antigen Model for T Cell Tolerance and T Cell Receptor Mutagenesis;138
9.5.1;INTRODUCTION;138
9.5.2;T CELL RECEPTOR MUTAGENESIS;139
9.5.3;A PAIRED ANTIGEN/TCR TRANSGENIC SYSTEM;140
9.5.4;ACKNOWLEDGMENTS;141
9.5.5;REFERENCES;142
9.6;Chapter 12. T Cell Repertoire and Tolerance;144
9.6.1;INTRODUCTION;144
9.6.2;SUPERANTIGENS;145
9.6.3;TOLERANCE TO SELF-SUPERANTIGENS SHAPES THE T CELL REPERTOIRE;146
9.6.4;Vß INTERACTION WITH THE SELF-SUPERANTIGEN, Mls-1a;147
9.6.5;Vß INTERACTION WITH THE FOREIGN SUPERANTIGENS;148
9.6.6;REFERENCES;150
9.7;Chapter 13. Sequential Occurrence of Positive and Negative Selection during T Lymphocyte Maturation;152
9.7.1;INTRODUCTION;152
9.7.2;RESULTS AND DISCUSSION;153
9.7.3;REFERENCES;161
9.8;Chapter 14. Tolerance Induction in the Peripheral Immune System;164
9.8.1;INTRODUCTION;164
9.8.2;MATERIALS AND METHODS;165
9.8.3;RESULTS;165
9.8.4;DISCUSSION;168
9.8.5;ACKNOWLEDGMENTS;170
9.8.6;REFERENCES;170
10;PART V: AUTOIMMUNITY;172
10.1;Chapter 15. Activation-Induced Cell Death of Effector T Cells: A Third Mechanism of Immune Tolerance;174
10.1.1;INTRODUCTION;174
10.1.2;EXPERIMENTAL RESULTS;175
10.1.3;INTERPRETATIONS;176
10.1.4;ACKNOWLEDGMENTS;179
10.1.5;REFERENCES;179
10.2;Chapter 16. T Cells Involved in Inductive Events in the Pathogenesis of Autoimmune Diabetes Mellitus;180
10.2.1;ACKNOWLEDGMENTS;186
10.2.2;REFERENCES;186
10.3;Chapter 17. Genetic Control of Diabetes and Insulitis in the Nonobese Diabetic Mouse: Analysis of the B10.H-2b and BI0.H2nod Strains;188
10.3.1;INTRODUCTION;188
10.3.2;MATERIALS AND METHODS;190
10.3.3;RESULTS AND DISCUSSION;191
10.3.4;CONCLUDING REMARKS;195
10.3.5;ACKNOWLEDGMENT;195
10.3.6;REFERENCES;196
10.4;Chapter 18. Islet Tolerance in Humans and Transgenic Mice;198
10.4.1;REFERENCES;201
10.5;Chapter 19. Fluorescence-Activated Cell Sorter Analysis of Peptide–Major Histocompatibility Complex;202
10.5.1;INTRODUCTION;202
10.5.2;FACS BINDING ASSAY;203
10.5.3;RESULTS;204
10.5.4;DISCUSSION;206
10.5.5;ACKNOWLEDGMENTS;207
10.5.6;REFERENCES;207
10.6;Chapter 20. Tolerance to Self: A Delicate Balance;208
10.6.1;INTRODUCTION;208
10.6.2;MONOIDIOTYPY;209
10.6.3;TCR-SPECIFIC ANTIBODY MODULATION OF DISEASE;209
10.6.4;TCR PEPTIDE MODULATION;210
10.6.5;DISCUSSION;211
10.6.6;REFERENCES;211
10.7;Chapter 21. Prevention, Suppression, and Treatment of Experimental Autoimmune Encephalomyelitis with a Synthetic T Cell Receptor V Region Peptide;214
10.7.1;INTRODUCTION;215
10.7.2;ANIMAL STUDIES;216
10.7.3;HUMAN STUDIES;235
10.7.4;SUMMARY;242
10.7.5;ACKNOWLEDGMENTS;243
10.7.6;REFERENCES;243
11;PART VI: PERSPECTIVES;246
11.1;Chapter 22. Tolerance of Self: Present and Future;248
11.1.1;THE 1975 BASELINE;248
11.1.2;F LIVER ANTIGEN;250
11.1.3;NEGATIVE SIGNALING;251
11.1.4;ANERGY, AND THE NEED FOR A DEFINED ANERGIC PHENOTYPE;252
11.1.5;THYMUS LOBE CULTURES;252
11.1.6;AUTOIMMUNITY AND EPITOPE LINKAGE;253
11.1.7;TOWARD GENE THERAPY IN AUTOIMMUNITY;254
11.1.8;REFERENCES;256
12;Index;258

Leseproben

2

Mechanisms and Meaning of B Lymphocyte Tolerance

DAVID NEMAZEE,     Division of Basic Sciences, Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206

Publisher Summary

This chapter discusses the mechanism involved in B-cell lymphocyte tolerance. B lymphocytes have two antigen-specific functions in the immune response: (1) antibody formation and (2) receptor-mediated antigen uptake for presentation to major histocompatibility complex (MHC) class II-restricted T lymphocytes. The outcome of B lymphocyte tolerance leads to two discernible phenotypes: (1) deletion and (2) anergy. The distinction between these two mechanisms of B-cell tolerance is demonstrated either in immunoglobulin transgenic mouse models, in which a large clone of B cells of predefined specificity can be followed in the presence and absence of antigen, or in certain examples of anti-immunoglobulin M (IgM)-mediated immunosuppression. Two concepts are important in discussing the consequences of B-cell tolerance: (1) B-cell life span and (2) the reversibility of tolerance. Deleted B cells have a very short half-life, and the deletion process is irreversible. It is less clear whether anergic B cells have a much longer half-life than deleted B cells and whether the anergy is reversible. Most B cells have a lifespan of 1–2 days, but a small subpopulation is admitted to the long-lived, recirculating B lymphocyte pool, which can have a half-life of many weeks.

INTRODUCTION

B lymphocytes have two antigen-specific functions in the immune response: antibody formation and receptor-mediated antigen uptake for presentation to major histocompatibility complex (MHC) class II-restricted T lymphocytes. The outcome of B lymphocyte tolerance leads to two discernible phenotypes, deletion and anergy. What determines these alternative fates and what are the consequences for the immune system?

THE DELETION-ANERGY DECISION

The distinction between these two mechanisms of B cell tolerance is demonstrated either in immunoglobulin transgenic mouse models, in which a large clone of B cells of predefined specificity can be followed in the presence and absence of antigen (1–4), or in certain examples of anti-immunoglobulin M (IgM)-mediated immunosuppression (5–7). In the hen egg lysozyme : anti-hen egg lysozyme (HEL) system, tolerance to the soluble, transgene-encoded, lysozyme leads to functional inactivation, without deletion, of a high-affinity antilysozyme B cell clone, whose IgR are similarly encoded by transgenes (1,2). By contrast, in mice transgenic for immunoglobulin genes encoding an allele-specific anti-MHC class I antibody, autoreactive B cells are eliminated soon after they emerge in the bone marrow, where they first make contact with self-antigen (3,4). Chronic or anti-IgM treatment from early time points in B cell development can lead to profound B cell deletion (5,6) or anergy (7).

To explain the differences in the fates of the autoreactive clones in the various experimental systems, a number of models could be proposed:

1 The extent of Ig receptor occupancy determines the fate of the B cell

The extent of B cell surface immunoglobulin receptor occupancy by antigen has been suggested to be an important parameter in B cell tolerance in anti-HEL/HEL double transgenic mice (1) because HEL concentrations leading to 5% receptor occupancy failed to induce B cell tolerance, whereas HEL concentrations resulting in 45% receptor occupancy anergized (2). To explain the deletion with membrane Kk based on a receptor occupancy model one would need to assert that occupancy of even greater than 45% of receptors must be achieved with this membrane antigen to achieve deletion. However, because monovalent ligand is probably unable to transmit signals via immunoglobulin receptor (8), it is likely that the form of HEL that tolerizes in this double transgenic system is aggregated in some way. In addition, for B cell as few as 10–20 surface Ig molecules need be engaged, provided these are appropriately cross-linked together (9,10). Thus the correlation between the extent of receptor occupancy and tolerance may be misleading, because only a small fraction of the measured antigen may be in a tolerogenic form. Furthermore, Gause showed that B cell anergy could be induced in mice with a monoclonal anti-µ antibody under conditions where virtually 100% receptor occupancy was achieved (7). On the other hand, Pike, Boyd, and Nossal showed in experiments that high concentrations of a monoclonal anti-µ could lead to a B cell deletion–like phenomenon, whereas lower doses of the same antibody generated anergic cells (11). This last is consistent with both receptor occupancy and cross-linking models (see item 4 below) because it is possible that the quality of receptor cross-linking is profoundly affected by the antibody/antigen ratio.

2 The stage of B cell development at which autoantigen is encountered is critical; antigens that are seen in the post–bone marrow stage of B cell development anergize, whereas antigens seen in the bone marrow delete

This possibility is appealing because of the apparent analogy with T cells: autoreactive T cells encountering class I or class II in the thymus are deleted, whereas those encountering the same antigens in the periphery are anergized. In addition, in a number of systems immature (neonatal spleen or adult bone marrow) B cells require much less antigen for tolerance than more mature, adult splenic B cells (12). However, there is evidence against this simple model for B cells. Bone marrow B cells react with HEL, yet are not deleted (1), but anti–MHC class I B cells that encounter Kk or Kb either in the bone marrow or exclusively in the periphery are deleted (3,4, and our unpublished results).

3 IgD expression on B cells determines the tolerance phenotype: B cells lacking IgD are deleted, whereas IgD-bearing cells are anergized

Elements of this idea, albeit in a somewhat different form, have been popular since the discovery that IgD is expressed on most mature B cells but is not expressed on newly generated B cells (13). The available evidence argues against this possibility also: anti-HEL transgenic mice made using IgM + IgD, IgM-only, and IgD-only heavy chain constructs all demonstrated anergy in the presence of lysozyme (14). IgM-only anti-Kk mice delete autoreactive B cells, and IgM + IgD anti-Kk mice have only recently been generated (D. N. Buerki and K. Buerki, unpublished results). It will be of interest if these mice demonstrate anergy rather than deletion.

4 The extent of surface Ig cross-linking determines B cell fate: strongly cross-linking antigens, like MHC class I, delete, whereas weakly cross-linking antigens, like lysozyme, anergize

This model has not been adequately tested but, almost by default, appears to best explain the current data. The difficulty here is in defining “strong” and “weak” cross-linking and in explaining in biochemical terms how a quantitative difference in this parameter can determine the qualitative difference in cellular function. Certainly for B cell activation the extent of sIg cross-linking can have profound and striking effects (9).

CONSEQUENCES OF DELETION VERSUS ANERGY

Two concepts are important in discussing the consequences of B cell tolerance: B cell life span and the reversibility of tolerance. It is obvious that deleted B cells have a very short half-life and that the deletion process is, by definition, irreversible. It is less clear whether anergic B cells have a much longer half-life than deleted B cells and whether the anergy is reversible. Most B cells have a lifespan of 1–2 days, but a small subpopulation is admitted to the long-lived, recirculating B lymphocyte pool, which can have a half-life of many weeks (15). Admittance of a B cell to this long-lived pool probably is determined by both its specificity and the extent of competition with other B cells (16). Anergic B cells generated in the HEL : anti-HEL transgenic model appear to have a reasonably long half-life of at least several days in adoptive recipients. It will be of great importance to determine the half-life of these cells in the presence of an excess of competing clones. It is possible that the half-life of the anergic cells under these conditions is rather short, thus minimizing the significance of the functional distinction between the two mechanisms of anergy and deletion, except perhaps in cases of leukopenia. It is of interest in this regard that adults of certain autoimmune-prone mouse strains have profound defects in B cell generation (17,18).

If it proves that anergic B cells indeed have a significant life span, it will be of importance to determine the logic of the immune system in maintaining them. One possibility is that they serve as a pool of B...