Theoretical Immunology, Part One

Alan S. Perelson

• Publisher: CRC Press
• Year: 2018
• ISBN:
  9780429972331
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Assuming that the complex phenomena underlying the operation of the immune system may be better understood through the collaborative efforts of theorists and experimentalists viewing the same phenomena in different ways, the Sante Fe Institute and the Theoretical Division of Los Alamos National Laboratory cosponsored a workshop entitled "Theoretical Immunology". The workshop focused on themes spanning the field of immunology, with emphasis on areas where the theorists have made the most progress. This book covers the discussions a that workshop on the topics of immune surveillance, mathematical models of HIV infection, complexities of antigen-antibody systems, immune suppression and tolerance, and idiotypie networks. In each of these areas there is reason to believe that advances can be made either through interactions among experimentalists and theorists or through the critical look experimentalists and theorists will bring to bear upon one another's work.

PART ONE

THEORETICAL IMMUNOLOGY

Cell Stimulation and Receptor Crosslinking

BYRON GOLDSTEIN

Theoretical Division, University of California, Los Alamos National Laboratory, Los Alamos, New Mexico 87545 USA

Desensitization, Histamine Release and the Aggregation of IgE on Human Basophils

INTRODUCTION

Since antibodies and antigens have valences of two or greater, they often form aggregates when they come together. Antibody-antigen aggregates play an important role in immune responses. When antibodies act as cell surface receptors, their aggregation is a requirement for signal generation. Some of the best studied examples of cellular responses being triggered by the aggregation of cell surface antibody arise in allergic reactions of the immediate hypersensitive type. Individuals who are allergic to a particular antigen produce immunoglobulin E (IgE) that is specific for that antigen. Some of the IgE binds to monovalent, high affinity Fc_ϵ receptors on the surface of mast cells and basophils. When surface-bound IgE is aggregated by the antigen, it triggers the cells to both release prestored granules that contain histamine, serotonin and other mediators of anaphylaxis, and to synthesize products that are rapidly secreted. Recently it has been shown that aggregation of IgE initiates many physical changes on rat basophilic leukemia (RBL) cells. It triggers internalization of IgE aggregates (Isersky et al., 1983), increased fluid-phase pinocytosis, transformation of the cell surface from finely microvillous to highly folded, cell spreading, an increase in the F-actin content of detergent extracted cell matrices (Pfeiffer et al., 1985), an increase in the immobile fraction of cell surface IgE (Menon et al., 1986a; 1986b), and direct interactions between IgE-Fc_ϵ receptors and the cytoskeleton (Robertson et al., 1986). In this chapter, we shall review the relationship between IgE aggregation and some of the biological responses of basophils and mast cells. We shall focus on human basophils. In the chapters by Baird et al. and Oliver et al., and the recent reviews by Metzger et al. (1986), Pecht and Corcia (1987) and Oliver et al. (1987), the responses of RBL cells to IgE aggregation are discussed in detail.

THE BINDING OF IGE TO BASOPHIL SURFACES: SENSITIZATION

The Fc_ϵ receptor on human basophils binds IgE with high affinity. The equilibrium constant for the reaction, K_Fc, is of the order of 10¹⁰M⁻¹ (Malveaux et al., 1978). Similar values for K_Fc have been found for RBL cells (Conrad et al., 1975; Mendoza and Metzger, 1976; Sterk and Ishizaka, 1982) and mouse mast cells (Mendoza and Metzger, 1976; Sterk and Ishizaka, 1982). The large value for K_Fc reflects the slow dissociation of IgE from its Fc_ϵ receptor. For intact RBL cells, Kulczycki and Metzger (1974) found the IgE-Fc_ϵ receptor dissociation constant was ≤ 1.6 × 10⁻⁵s⁻¹ at 37°C which corresponds to a half-life ≥ 19 hrs. More recently, Wank et al. (1983) determined the dissociation constant to be 4.3 × 10⁻⁶s⁻¹ at 37°C which corresponds to a half-life of 45 hrs. By determining the forward rate constant and knowing the equilibrium constant, a similar value was estimated for the half-life of dissociation of IgE from Fc_ϵ receptors on human basophils (Goldstein et al., 1979). Isersky et al. (1979) followed the dissociation of IgE from Fc_ϵ receptors on RBL cells for over 100 hr and found that the dissociation could not be described by a single exponential. When they resolved their dissociation curves into two exponentials, they found that the fast component had a half-life of 7–12 hrs. and the slow component a half-life of 131–252 hrs. Whether the different rates of dissociation reflect Fc_ϵ receptor heterogeneity, a time-dependent modification of the IgE-Fc_ϵ receptor complex, or other events, is unknown.

The number of Fc_ϵ receptors per basophil varies widely in the human population, from ∼ 10³ to 10⁶, with basophils from allergic individuals tending to have more Fc_ϵ receptors on their surfaces than basophils from nonallergic individuals (Conroy et al., 1977; Malveaux et al., 1978; Garcia et al., 1978). Allergic individuals also tend to have elevated levels of serum IgE (Conroy et al., 1977). Because of this, basophils from most allergic donors have their Fc_ϵ receptors saturated with IgE. The correlation between Fc_ϵ receptor number and serum IgE levels, raises the possibility that the solution IgE concentration can regulate the concentration of Fc_ϵ receptors on basophil surfaces. This has been directly demonstrated with RBL cells, where the incubation of these cells in high concentrations of IgE leads to an increase (up regulation) in the number of cell surface Fc_ϵ receptors (Furuichi et al., 1985; Quarto et al., 1985).

Basophils that have IgE on their surface that is specific for a known antigen are said to be sensitized to the antigen. A standard way to obtain sensitized basophils for in vitro studies is to incubate basophils that initially have unoccupied Fc_ϵ receptors in a solution containing specific IgE. This procedure is know as passive sensitization (Levy and Osler, 1966). A small number of allergic individuals and approximately 20% of nonallergic individuals have basophils with sufficient numbers of free Fc_ϵ receptors that they can be passively sensitized without having to first elute off the bound IgE. Dissociation of IgE from its Fc_ϵ receptors can be achieved through acid treatment that maintains the functional integrity of the basophils (Pruzansky et al., 1983).

IgE AGGREGATION AND MEDIATOR RELEASE

Monovalent ligands that bind to, but cannot bridge, IgE molecules do not trigger basophil degranulation (Becker et al., 1973; Siraganian et al., 1975). Ligands with valence of two or greater that can crosslink IgE, whether by binding to Fab or Fc portions of the IgE, can induce basophils to degranulate (Osler et al., 1968; Ishizaka et al., 1969; Siraganian et al., 1975; Dembo et al., 1978). Although aggregation is required, the formation of large aggregates of IgE is not necessary for triggering basophil degranulation. Segal et al. (1977) showed that preformed IgE-dimers (two IgE molecules covalently linked) triggered the degranulation of mast cells that had free Fc_ϵ receptors on their surfaces. Trimers and higher oligomers of IgEs also triggered degranulation. Similarly, when human basophils where passively sensitized with either IgE-dimers or -trimers they released histamine (Kagey-Sobotka et al., 1981).

Even though the smallest aggregate, the IgE-dimer, is capable of triggering histamine release, there is now considerable evidence that larger aggregates of IgE generate intrinsically different signals than the dimer. This was first proposed by Fewtrell and Metzger (1980), based on their observation that IgE-trimers and higher oligomers of IgE were effective stimulators of degranulation, while IgE-dimers were ineffective in stimulating RBL cells, even in the presence of D₂O, a potent enhancer of histamine release. Another striking difference in the response of RBL cells to dimers and higher oligomers is that clusters of two IgE molecules are predominantly mobile on the RBL cell surface, while clusters of more than two IgE molecules rapidly become immobile after formation (Menon et al., 1986a). These experiments, as well as experiments using a monoclonal anti-IgE to crosslink surface IgE (Menon et al., 1986b), indicate that on RBL cells, larger aggregates of IgE interact with the cytoskeleton while aggregates of two IgEs do not (see the chapter by Baird et al.).

Intrinsic differences in the signals generated by different size oligomers of IgE were first reported for human basophils by MacGlashan et al. (1983a) who observed that the pharmacologic agent indomethacin enhanced histamine release that was triggered by IgE-trimers, but not release that was triggered by IgE-dimers. Recently, in a study of basophils from 14 nonallergic donors, MacGlashan et al. (1986) found marked differences in the responses of these cells to IgE-dimer...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• PART ONE
• Foreword
• Cell Stimulation and Receptor Crosslinking
• Antigen Presentation and the Structure of Antigenic Determinants
• Dynamics of the Immune Response
• Maturation of the Immune Response
• Index