Molecules, Cells, and Parasites in Immunology contains the proceedings of a symposium on immunology held in Mexico City in the fall of 1979 under the auspices of the National University of Mexico (UNAM). This volume brings together prominent foreign scientists and Mexican investigators to discuss the areas of immunology that being developed at UNAM. Either in the form of reviews or of original presentations, the various authors proffer observations and ideas that generally relate to the regulation of the immune response at the molecular and cellular levels. The topic of Molecules encompasses the effect of molecular aggregation upon the triggering of physiological events, cooperative binding, and the expression of immunoglobulins during the lymphocyte differentiation process. Under the heading of Cells, there are contributions dealing with the physiological and pathological roles of interiorized antibodies; the mechanisms of antigen recognition by T cells; and the synthesis of membrane proteins by myeloma cells which somehow protect them from killer T cells. The section on Parasites includes some unique contributions on the immunology of human and animal cysticercosis and amebiasis, complemented by a general discussion of host-parasite relationships.
Front Cover 1
Molecules, Cells, and Parasites in Immunology 4
Copyright Page 5
Table of Contents 6
CONTRIBUTORS 8
PREFACE 12
ACKNOWLEDGMENTS 14
CHAPTER 1. MOLECULAR MECHANISMS OF ANTIBODY ACTION: USE OF CROSS-LINKING REAGENTS 16
I. INTRODUCTION 16
II. NEW STUDIES 17
III. CONCLUDING STATEMENT 24
REFERENCES 25
CHAPTER 2.
28
I. THE CONCEPT OF A RECEPTOR 28
II. EXCITABLE TISSUE ANAPHYLAXIS 30
III. CONNECTIVE TISSUE INVOLVEMENT 36
IV. TWO DISTINCT RECEPTOR COMPONENTS 40
ACKNOWLEDGMENTS 41
REFERENCES 42
CHAPTER 3.
44
I. INTRODUCTION 44
II. EXPERIMENTAL RESULTS 45
III. COOPERATIVITY OR ARTIFACT? 47
IV. ESTIMATION OF THE PARAMETERS OF COOPERATIVITY 52
V. PREVIOUS OBSERVATIONS 55
VI. DISCUSSION 55
VII. CONCLUDING REMARKS 56
ACKNOWLEDGMENTS 56
REFERENCES 56
CHAPTER 4.
58
I. INTRODUCTION 58
II. GENERATION OF B-LYMPHOCYTES 59
III. THE PRE-B CELL 59
IV. THE IMMATURE B-CELL 60
V. DEVELOPMENT OF HEAVY CHAIN CLASS (ISOTYPE) HETEROGENEITY 62
VI. THE PROBLEM OF MULTIPLE CLASS REPRESENTATION 63
VII. THE ROLE OF IgD 64
VIII. MODE OF MEMBRANE INSERTION OF SURFACE IMMUNOGLOBULIN 64
ACKNOWLEDGMENT 65
REFERENCES 65
CHAPTER 5. ANTIBODY PENETRATION INTO LIVING CELLS:
68
I. INTRODUCTION 68
II. ANTIBODY PENETRATION AND THE Fc RECEPTOR 69
III. EVIDENCE OF ANTIBODY PENETRATION IN VIVO 71
IV. CONSEQUENCES OF ANTIBODY PENETRATION 73
V. ROLE OF ANTIBODY PENETRATION IN IMMUNOBIOLOGY 76
ACKNOWLEDGMENT 77
REFERENCES 77
CHAPTER 6. LAMBDA LIGHT CHAINS
80
I. INTRODUCTION 80
II. . LIGHT CHAINS 82
III. Id+ ANTI-NP T CELLS 84
IV. DEPENDENCE OF THE SPECIFICITY OF ANTI-Id ANTIBODIES ON VL DOMAINS OF THE Id-BEARING MOLECULE 86
V. LOGISTICS 87
REFERENCES 88
CHAPTER 7. CELLULAR RECOGNITION IN TUMOR IMMUNOLOGY: TUMOR RESISTANCE TO IMMUNE DESTRUCTION
90
I. INTRODUCTION 90
II. MATERIALS AND METHODS 91
III. RESULTS 93
IV. DISCUSSION 101
REFERENCES 103
CHAPTER 8.
106
I. INTRODUCTION 106
II. CHEMOTAXIS: GENERAL AND TECHNICAL CONSIDERATIONS 107
III. CHEMOTAXIS IN HUMAN NEWBORNS AND AMEBIASIS 111
REFERENCES 115
CHAPTER 9. BIOCHEMICAL CHARACTERIZATION OF LYMPHOCYTE MEDIATOR-MACROPHAGE INTERACTIONS 118
I. INTRODUCTION 118
II. RESULTS AND DISCUSSION 120
REFERENCES 126
CHAPTER 10. B LYMPHOCYTE STIMULATION BY PARASITIC ORGANISMS 128
I. INTRODUCTION 128
II. METHODS 129
III. RESULTS 129
IV. DISCUSSION 134
ACKNOWLEDGMENT 137
REFERENCES 137
CHAPTER 11. THE IMMUNOLOGY OF HUMAN CYSTICERCOSIS 140
I. INTRODUCTION 140
II. IMMUNODIAGNOSIS OF BRAIN CYSTICERCOSIS 141
III. SEROEPIDEMIOLOGY 144
IV. HUMORAL IMMUNE RESPONSE 148
V. IMMUNITY TO CYSTICERCOSIS 152
VI. CELLULAR IMMUNE RESPONSE 154
VII. HOST-PARASITE INTERFACE 154
VIII. CONCLUSIONS 154
REFERENCES 156
CHAPTER 12.
160
I. HOST-PARASITE SPECIFICITY 160
II. ULTRASTRUCTURE OF THE PARASITE SURFACE 162
IIII. SYNTHESIS OF PARASITE PROTEINS 166
IV. HOST RESPONSE 168
ACKNOWLEDGMENTS 176
REFERENCES 176
CHAPTER 13.
178
I. INTRODUCTION 178
II. HUMORAL IMMUNE REACTIONS 178
III. CELLULAR IMMUNE REACTIONS 181
IV. IMMUNITY AND ANTIAMEBIC IMMUNIZATION 184
REFERENCES 190
CHAPTER 14.
194
I. INTRODUCTION 194
II. SUSCEPTIBILITY TO INFECTION 194
III. IMMUNOSUPPRESSION AND IMMUNOPOTENTIATION 197
IV. ANTIGENS 199
V. CONCLUSIONS 201
REFERENCES 202
CHAPTER 15.
206
I. INTRODUCTION 206
II. CIRCUMSTANCE AND IMMUNITY AT THE LEVEL OF A COMMUNITY 207
III. CIRCUMSTANCE AND IMMUNITY AT THE LEVEL OF AN ORGANISM 213
IV. CIRCUMSTANCE AT THE CELLULAR LEVEL 218
V. CIRCUMSTANCE AT THE MOLECULAR LEVEL 220
VI. DISCUSSION 225
REFERENCES 228
CHAPTREC 16. HEMICAL SYNTHESIS FOR THE UNDERSTANDING OF IMMUNE RESPONSE PHENOMENA AND FOR THEIR MEDICAL APPLICATION 230
I. INTRODUCTION 230
II. SYNTHETIC ANTIGENS WITH PEPTIDE DETERMINANTS OF DEFINED SEQUENCE 231
III. SYNTHETIC PEPTIDE OF CARCINOEMBRYONIC ANTIGEN OF THE COLON 236
IV. SUPPRESSION OF EAE AND POSSIBLY OF MULTIPLE SCLEROSIS WITH A BASIC SYNTHETIC COPOLYMER 238
V. ANTIVIRAL EFFECT ON MS-2 COLIPHAGE OBTAINED WITH A SYNTHETIC ANTIGEN 239
VI. CHALLENGE OF THE COMBINED USE OF SYNTHETIC ANTIGENS AND SYNTHETIC ADJUVANTS 241
VII. CONCLUDING REMARKS 241
REFERENCES 242
INDEX 244
MOLECULAR MECHANISMS OF ANTIBODY ACTION: USE OF CROSS-LINKING REAGENTS*
HENRY METZGER, HELEN HARTMANN, DAVID HOLOWKA and CLARE FEWTRELL, Section on Chemical Immunology, Arthritis and Rheumatism Branch, National Institute of Arthritis Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Maryland, U.S.A.
Publisher Summary
This chapter discusses the molecular mechanisms of antibody action and describes the use of cross-linking reagents. Antibodies have no ability to alter the antigen with which they combine directly; they change the ultimate fate of the antigen only by interacting with effector system. When the high molecular weight product of cross-linking with the cleavable reagent is rerun under conditions where the crosslinks are broken, a new component is observed that has a molecular weight of about 30,000. The cross-linked product can be observed after reacting either intact cells or cells solubilized with nonionic detergents. Some of the serotonin that can be released by the higher oligomers is completely resistant to release by dimers. Dimers by themselves are adequate to stimulate secretion of at least a portion of the releasable serotonin. Trimers are more active than dimers, while the higher oligomers are even more effective.
I INTRODUCTION
Immunologists have traditionally delighted in clumping things together. This is reflected in the by-now classical methods of precipitin analysis and agglutination as well as in the new clumping methods which are constantly being developed. Lately, ‘rosette’ formation has become a popular technique among immunologists, and most recently, the use of ‘patching’ and ‘capping’ and of cell fusion to make ‘hybridomas’ demonstrates that the tradition lives on.
It is interesting to speculate that the immunologist’s early use of aggregation as a favored analytical tool stemmed from a subconscious prescience that aggregation was of fundamental importance to what the immunologist was interested in studying; namely, the mechanisms of immune responsiveness. Whether one accepts this psycho-immunologic thesis or not, the significance of aggregation in immunologic mechanisms cannot be disputed. At the cellular level, direct cell to cell interactions have been implicated in a variety of phenomena; e.g., T cell interaction with macrophages and B cells, and T cell killing. Similarly, the significance of aggregation in antibody-mediated mechanisms is well recognized. After some brief comments on the latter subject, we shall describe how still another technique of clumping – the use of chemical cross-linking reagents – has permitted us to explore some basic questions in the system with which we are working.
Antibodies have no ability to alter the antigen with which they combine directly; they change the ultimate fate of the antigen only by interacting with effector systems. In some instances, this leads to a direct and prompt change in the antigen’s prospects, as in phagocytosis. Alternatively, a much more indirect pathway is chosen, such as stimulation of antibody-forming precursor cells. The mechanisms by which antibodies mediate these effects have received considerable attention, especially in recent years, as our detailed knowledge of antibody structure has increased. Several plausible models have been proposed and discussed in reviews [1–3]. A recent workshop, the first to discuss this topic comprehensively [4], did not come up with a consensus report. Nevertheless, with only one significant exception – the observations of Koshland and her colleagues [5,6] – all of the data on activation of effector systems by antibodies point to the critical requirement for aggregation of antibody; specifically, of the Fc regions of the antibodies. Whether the findings of Koshland’s group (that apparently univalent antigens induce complement fixation by IgM) are a valid exception is uncertain. Univalent ligands assuredly don’t cause intermolecular aggregation, but it is less clear whether the special antigens required to mediate the effects studied by these investigators cause intramolecular aggregation of the Fc pentamers in IgM.
In no system is the need for aggregation of antibody more persuasively supported than in the IgE-mast cell system [7–9]. In this instance, antigen reacts with cell-bound IgE (alternatively, preformed IgE-antigen complexes become cell-bound), resulting in the triggering of noncytotoxic degranulation. Any procedure which serves to aggregate the surface IgE will cause stimulation, although hyper-aggregation is inhibitory. The reason why aggregation of the IgE is critical has recently been elucidated by the use of antibodies directed to the cellular membrane component (receptor for IgE) to which the IgE is bound [10,11]. These studies showed that what is important is that the receptor becomes aggregated. Even cells grown in vitro in the total absence of IgE can be stimulated to secrete with bivalent antireceptor antibodies [11].
II NEW STUDIES
We shall now describe two studies recently completed in our laboratory which have used chemical cross-linking procedures as a probe for studying how receptor aggregation may mediate mast cell (or basophil) secretion [12,13]. The reagents used in these studies (Fig. 1) are somewhat more useful than the one traditionally used by immunologists – bisdiazobenzidine. The latter compound is sufficiently carcinogenic to make its use banned in the United States; in addition, the newer reagents are more stable, specific, and versatile [14]. The versatility arises because one can vary the length between the reactive groups as well as prepare analogs which can be cleaved under mild conditions. The latter property has been particularly useful for some of our work.
FIG. 1 Chemical cross-linking reagents used in the experiments discussed in this paper. The chemistry of these reagents is reviewed in Ref. 14.
A Effect of IgE Oligomer Size in the Triggering of Mast Cells
The first study made use of cross-linking reagents to analyze the extent of receptor aggregation that is required for optimal stimulation of mast cell degranulation. Our original work in this area involved the use of dimethylsuberimidate (DMS) to prepare well-defined stable oligomers of rat IgE [15]. These were then used to elicit passive cutaneous anaphylactic reactions in the rat. These experiments led us to conclude that dimers of IgE could generate so-called ‘unit signals’. It might take many such signals to trigger a cell completely, but the individual signal could be generated by as small a unit as a receptor dimer.
What was not entirely clear from these studies was whether higher oligomers might yield stronger signals. While the in vivo data suggested that they did not, the in vitro data were less definitive. Furthermore, a recent investigation using oligomers of human IgE on human peripheral blood basophils studied in vitro has suggested that all oligomers may not be equal [A. Sobotka and L. Lichtenstein, submitted for publication].
In an attempt to resolve this question in our system, rat IgE was reacted with DMS and separated into monomers, dimers, trimers, and higher oligomers by gel filtration (Fig. 2A). We principally studied rat basophilic leukemia (RBL) cells [16], which can be grown as solid tumors in animals or in cell culture and are a unique resource for detailed structural analyses such as those described below. The cells were allowed to incorporate radioactive serotonin and the stimulated release of the latter by the oligomers was then assayed (Fig. 2B). Our experiments will be published in complete form elsewhere [12], and only the most significant findings will be summarized here:
FIG. 2 Separation of IgE oligomers and assay of their relative activities. A A trace amount of iodinated IgE was added to nonradioactive IgE (21 mg, 60 mg/ml) and the solution reacted with a 16-fold molar excess of DMS for 1 h at 30°C in 0.2 M Tris buffer, pH 8.6. The preparation was applied to sequential Sephadex G-200 and Ultrogel Ac A 22 columns, and the radioactivity in the effluent was measured. The peaks are labeled to indicate the relative effluent volumes for monomer (M), dimer (D), trimer (T), and higher oligomers (H). B Analysis of column fractions (numbers on the right) for their capacity to stimulate the release of incorporated tritiated serotonin (3H.5HT) from RBL cells. The test material was incubated with 2 × 106 cells/ml for 1 h at 37°C. The medium contained 1.8 mM Ca++ but not D2O.
(1) Dimers by themselves were adequate to stimulate secretion of at least a portion of the releasable serotonin, although this was often barely observable in the absence of D2O (Fig. 2B).
(2) Trimers were more active than dimers, while the higher oligomers were even more effective (Fig. 2B, Table I).
TABLE I
Serotonin Release by Oligomers of...
Erscheint lt. Verlag | 28.6.2014 |
---|---|
Sprache | englisch |
Themenwelt | Sachbuch/Ratgeber ► Natur / Technik ► Naturführer |
Studium ► Querschnittsbereiche ► Infektiologie / Immunologie | |
Naturwissenschaften ► Biologie ► Zoologie | |
ISBN-10 | 1-4832-7026-2 / 1483270262 |
ISBN-13 | 978-1-4832-7026-5 / 9781483270265 |
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