Antigens, Lymphoid Cells and the Immune Response

G. J. V. Nossal, G L Ada, F. J. Dixon, Henry G. Kunkel

• Publisher: Academic Press
• Year: 2014
• ISBN:
  9781483218953
• Topic: Medicina
• Subtopic: Fisiología

Antigens, Lymphoid Cells, and the Immune Response deals with the nature and properties of antigens and with the functional anatomy and cell physiology of the mammalian lymphoid system which responds to antigens. The book discusses the central questions in cellular immunology; the antigens and the afferent limb of the immune response; and antibodies and the afferent limb of the immune response. The text also describes the organ distribution of antigens; the functional anatomy of the lymphoid system; and the behavior patterns of lymphoid cells. The microscopic and electron microscopic distribution of antigen in lymphoid organs; the interaction of antigens with cells of the reticuloendothelial system; and the interaction of antigen with lymphoid cells are also considered. The book further tackles the role of antigen in immunological tolerance; antibody production and tolerance dissociated; and antigen and lymphoid cells.

CHAPTER 1

INTRODUCTION: CENTRAL QUESTIONS IN CELLULAR IMMUNOLOGY

Publisher Summary

The decade of the 1960’s brought a remarkable change to immunology. From the discovery of the multichain nature of the immunoglobulins, progressively more detailed knowledge of their structure soon followed, and the realization that Bence-Jones proteins were homogeneous immunoglobulin light chains stimulated extensive investigations into the amino acid sequence of first light and later heavy immunoglobulin chains. In 1969, the first sequence analysis of a complete immunoglobulin molecule became available. In any broad overview of the problem of antibody formation it is usual to divide the immune response into three major compartments: (1) afferent, (2) central, and (3) efferent. The first compartment is concerned with the mechanisms by which the “antigenic message” is brought to the lymphoid system that eventually responds by antibody production. The second deals with the origin, nature, and function of lymphoid cells and with the key question of the genetic basis of the information necessary for the synthesis of antibodies. The third covers the cellular events that follow an effective encounter between antigen and reactive lymphocyte, including the intervening steps of cell multiplication, differentiation, and migration.

The decade of the 1960’s brought a remarkable change to immunology. From the discovery of the multichain nature of the immunoglobulins, progressively more detailed knowledge of their structure soon followed, and the realization that Bence-Jones proteins were homogeneous immunoglobulin light chains stimulated extensive investigations into the amino acid sequence of first light and later heavy immunoglobulin chains. In 1969, the first sequence analysis of a complete immunoglobulin molecule became available, so that it is reasonable to conclude that the problem of antibody structure is nearing a definitive solution. In fact, it is becoming evident that many investigators who have contributed to our knowledge of antibody structure are turning their attention to cellular immunological problems. The way in which antigen affects lymphocytes and activates antibody production is still far from being fully understood, but methods of increasing sophistication have recently become available to help accelerate progress. While the main chemical truths about antibody structure are generally known to and accepted by cellular immunologists, it appears that the key discoveries about lymphocytes and antibody-producing cells made during the 1960’s have been less fully digested by immunochemists. Thus we felt that, both from the point of view of advanced students in immunology, and of workers in immunochemistry wishing to delve deeper into cellular problems, the time was ripe for a book which summarized current knowledge about antigens, lymphoid cells, and the immune response. In particular, we will concentrate on the induction of antibody formation. We felt 1970 to be an appropriate publication time because studies on the fate of antigen reached a new stage of precision and value when radioautographic techniques were applied to them. This approach has now been in wide use for about 7 years, and while it is clear that it will continue to yield fruitful information, we believe that the broad principles determining the localization of injected antigen molecules have now been fairly fully uncovered and should be summarized.

The dominant research theme in the authors’ laboratories over the past several years has been to seek an answer to the question: how does antigen work? In any broad overview of the problem of antibody formation it is usual to divide the immune response into three major compartments: (1) afferent; (2) central; (3) efferent. The first compartment is concerned with the mechanisms by which the “antigenic message” is brought to the lymphoid system which eventually responds by antibody production. The second deals with the origin, nature, and function of lymphoid cells and with the key question of the genetic basis of the information necessary for the synthesis of antibodies. The third covers the cellular events which follow an effective encounter between antigen and reactive lymphocyte, including the intervening steps of cell multiplication, differentiation, and migration. In this context, the main emphasis in this book will be on the afferent component. However, as our story unfolds, it will become increasingly clear that the above separation of the problem into three compartments is highly arbitrary and that the inductive function of antigen can only be understood if due regard is given to certain aspects of the central and efferent limbs as well.

When we commenced our series of investigations on the role of antigens in immunity in 1963, the tracing of radioactively marked antigen molecules through the body of an injected animal already had a long history. Yet, the yield of information truly relevant to inductive mechanisms had been slender. Nevertheless, it seemed to us that a detailed knowledge of where antigen was, and (perhaps more importantly) where it was not, during critical stages of immunological events, constituted information worth possessing. If nothing else, such information was a sine qua non for an eventual complete appreciation of inductive mechanisms. However, as we thought about the matter in 1963, two flaws in the majority of the then available literature on distribution of radioactive antigens became apparent to us. First, far too little attention appeared to have been given to questions of the nature, dose, and specific activity of the labeled antigens. Frequently large quantities of lightly labeled material had been injected with obvious loss of sensitivity; and the antigens chosen were materials of low inherent immunogenicity and possessing a tendency to permeate widely through extracellular fluids, resulting in high “noise levels.” Second, relatively little use had been made of the very powerful tool of radioautography, let alone quantitative or high-resolution variants of the technique. We thus decided to design an extensive set of investigations using chiefly a pure protein antigen, flagellin, and its various polymerized and fragmented versions, rendered radioactive to as high a substitution level as practicable with the external label ¹²⁵I. The advantages and disadvantages of this type of labeling will be discussed in Chapter 4.

We will make no attempt at an exhaustive review of the extensive early literature on antigen tracing, as this has already been dealt with by Campbell and Garvey (1963) and we will not cover problems of delayed hypersensitivity or allograft rejection. However, immunological memory and immunological tolerance will naturally be considered. The many uncertainties which continue to surround cellular immune phenomena complicate considerably the task of authors wishing to deal logically with the subject. It is clear that the two broad categories of cells involved in interacting with antigens are phagocytic and lymphocytic cells, but the detailed relationships between the two categories remain problematical. For this reason we have deemed it best to discuss these two cell categories separately before attempting any speculative synthesis. Thus Chapters 4, 7, and 8 will be chiefly concerned with the reticuloendothelial cells which capture antigens, and 5, 6, 9, and 10 with lymphocytes and the effects which antigens may have on them. These seven chapters are preceded by two fairly general ones which discuss the nature of antigens and antibodies from the viewpoint of their function in the afferent limb of the antibody response. There has been a great expansion of interest in antibody production in vitro over recent years; while certain in vitro studies will be considered in Chapters 2 through 10, and particularly in Chapter 8, we hope to summarize most of the new knowledge on this subject in Chapter 11.

In Chapters 2 through 11 we will concentrate mainly on experimental findings and their immediate implications. In Chapter 12, we present a speculative synthesis of currently available information on mechanisms of induction of antibody formation, and will point out what we consider to be key questions requiring experimentation. Each chapter has its own summary, and these should constitute a useful guide for the reader interested in only certain facets of the book.

We trust that for some investigators this book may also serve a practical function and act as an aid in the planning of future experiments. Therefore we have included several appendixes which describe in detail some of our chief research techniques. It is not always possible to include the various little “tricks” of a particular method in a normal research paper, and we hope that some readers will find useful practical hints in this section of the book.

As already mentioned, we are currently in the midst of a phase of research in cellular immunology where in vitro studies of antibody formation have gained preeminence. We share the general view that the precise tools of tissue culture will contribute much to our understanding of immunocyte behavior but will attempt to point out throughout this book that in vitro and in vivo observations on lymphoid cells complement each other, and that both are necessary for a satisfactory understanding. Thus, it would be unwise to neglect a detailed consideration of lymphatic tissue architecture, such as is presented in Chapter 5.

A final reason for the presentation of this book comes from the enormous practical implications of cellular immunology. The urgent demands of clinical medicine often cannot await a complete scientific knowledge of a particular phenomenon. It is true that we do not know all about how antigen affects lymphoid cells, yet in the clinic this interaction is constantly being manipulated. It is clearly an interaction subject to manifold and subtle controls. There will be no attempt in this book to discuss clinical aspects of immunosuppression. However, we believe that an eventual satisfactory manipulation of the mammalian immune response will depend on the application of fundamental principles of immunogenicity and “tolerogenicity” that are our primary concern here. Therefore we hope that those interested in clinical control of immune processes will find in this volume material of value to them. At present, most immunosuppression is aimed at either the central or the efferent components of the immune response. There is one outstanding exception, as the brilliant success of passive anti-D antibody in the prevention of Rh-sensitization (Finn et al., 1961; Freda et al., 1964) must be considered as affecting the afferent limb. We predict that manipulation of the afferent limb of immune responses will play an increasing role in clinical practice. For this reason alone, it is proper to attempt to collate what we know about antigen and its in vivo effects.

CHAPTER 2

ANTIGENS AND THE AFFERENT LIMB OF THE IMMUNE RESPONSE

Publisher Summary

This chapter reviews some synthetic polypeptides and proteins used as natural antigens with particular reference to properties that influence their antigenic and immunogenic properties. Though the evidence from various studies suggests that an antigenic determinant might be as small a sequence as 3-5 amino acid residues, other portions of the molecule contributed to their activity. The use of synthetic polypeptides has enabled an analysis to be made of many factors that contribute to the immunogenicity of a molecule. In many of their properties, fibrous proteins appear to occupy an intermediate position between synthetic polypeptides and naturally occurring globular proteins. They occur naturally but have repeated amino acid sequences that result in repeating antigenic areas. Proteins that have been used extensively in in vivo studies may be divided into two groups: (1) those that in nature probably occur mainly as the monomer, such as serum proteins and many enzymes; and (2) those that in nature occur as a polymer consisting of an array of several or many protein units, arranged in such a fashion that a portion of the molecule is always adjacent to neighboring molecules, and portion is “exposed” to the external medium.

Antigens or immunogens are commonly defined as substances which, upon introduction into a suitable host, give rise to the formation of antibodies. This is a limited definition as it neglects those aspects of immunology in which an immune response appears to be mediated directly by cells. For the purposes of this monograph, however, we are interested primarily in the role antigen plays in antibody formation. We are especially interested in the fate of antigen both in vivo and in vitro so that those antigens which have been most used and adequately studied in this respect will be the main subject of the presentation. As emphasized in Chapter 1, this was until recently a neglected aspect of immunology.

Though most workers use the terms antigen and immunogen synonomously, it is becoming increasingly common to equate the term antigenic properties with the serological properties, i.e., the in vitro reaction between an antigen and antibody. In contrast, the term immunogenicity is now used more frequently to describe the ability of a substance to cause specific antibody formation in a suitable host or in tissue culture. Many biological macromolecules can act as immunogens but the two major classes are proteins and polysaccharides. It is not the purpose of this monograph to review knowledge about the many different types of proteins or polysaccharides used in such studies. Rather we wish to draw attention to those properties of a substance which are of importance in the expression of its antigenicity and immunogenicity. It is necessary to stress this dual interest. There are many reports about the properties of proteins, polysaccharides, and fragments thereof with respect to their in vitro reaction with antisera prepared against the original antigen or against the fragments. It is only recently that interest has been shown in the in vivo behavior of the ...

Table of contents

• Cover image
• Title page
• Table of Contents
• IMMUNOLOGY
• Copyright
• Dedication
• FOREWORD
• PREFACE
• ACKNOWLEDGMENTS
• Chapter 1: INTRODUCTION: CENTRAL QUESTIONS IN CELLULAR IMMUNOLOGY
• Chapter 2: ANTIGENS AND THE AFFERENT LIMB OF THE IMMUNE RESPONSE
• Chapter 3: ANTIBODIES AND THE AFFERENT LIMB OF THE IMMUNE RESPONSE
• Chapter 4: ORGAN DISTRIBUTION OF ANTIGENS
• Chapter 5: THE FUNCTIONAL ANATOMY OF THE LYMPHOID SYSTEM
• Chapter 6: BEHAVIOR PATTERNS OF LYMPHOID CELLS
• Chapter 7: MICROSCOPIC AND ELECTRON MICROSCOPIC DISTRIBUTION OF ANTIGEN IN LYMPHOID ORGANS
• Chapter 8: INTERACTION OF ANTIGENS WITH CELLS OF THE RETICULOENDOTHELIAL SYSTEM
• Chapter 9: THE INTERACTION OF ANTIGEN WITH LYMPHOID CELLS
• Chapter 10: THE ROLE OF ANTIGEN IN IMMUNOLOGICAL TOLERANCE
• Chapter 11: ANTIBODY PRODUCTION AND TOLERANCE IN DISSOCIATED CELL SYSTEMS
• Chapter 12: ANTIGEN AND LYMPHOID CELLS—A SYNTHESIS AND PROSPECTS
• PREPARATION OF FLAGELLAR PROTEINS FROM Salmonella ORGANISMS
• THE TECHNIQUE OF ELECTRON MICROSCOPIC RADIOAUTOGRAPHY
• SOME PROPERTIES OF RADIOISOTOPES USED COMMONLY FOR RADIOAUTOGRAPHY, WITH SPECIAL REFERENCE TO TRITIUM AND 125IODINE
• REFERENCES
• POSTSCRIPT
• AUTHOR INDEX
• SUBJECT INDEX