Molecular Immunity

A Chronology of 60 Years of Discovery

Kendall A Smith

• Publisher: WSPC
• Year: 2018
• ISBN:
  9789813231726
• Topic: Medicine
• Subtopic: Immunology

This book covers a scientific history of the discoveries in immunology of the past 60-years, i.e. what was discovered, who made the advances and how they accomplished them, and why others did not.

All molecular advances occurred in the last 60 years, and no one has described them.

Contents:

• Twenty Years of Cellular Discovery
• From Activities to Molecules: The Interleukins
• The Beginnings of Molecular Immunology
• Molecular Mechanisms of T Cell Cytolysis
• Molecular Mechanisms of T Cell Help
• The Molecules of Macrophages
• Additional T Cell signals: Co-Stimulatory & Co-inhibitory
• Regulatory T Cells
• Immunotherapy

Readership: Undergraduates, graduate students and academics in medicine (immunology) and life sciences (molecular biology, genetics).
Key Features:

• This will be the first history of immunology since the 1960s
• The author pioneered the field of molecular immunology
• The text is meticulously documented

1	Twenty Years of Cellular Discovery

The Legacy of Burnet

The term adaptive immunity is usually reserved for the type of immunity that adjusts to respond to an invading microbe, i.e. it adapts. A synonym that has also been used is “acquired” immunity, which is to say that it is different from “innate” or inborn immunity. Adaptive immunity carries with it the connotation of a heightened response to the re-exposure to an antigen experienced previously. This we call immunological memory. It is now recognized and well accepted that lymphocytes are the cells responsible for adaptive immunity, and that the two major types of lymphocytes, B cells and T cells, are both active participants. The phenomenon of immunological memory depends upon specificity of antigen recognition, as well as specificity of the immunological response. As such, adaptive immunity explains why vaccination is effective in preventing infectious diseases, and thus is the essence of immunity, defined as the exemption from disease.

When trying to understand any biological phenomenon, it is often helpful to take a scholarly approach and delve into the history of thought and experimental data that have been brought to bear on the problem. In this instance, a logical starting point is the discussion of “The Facts of Immunity” as laid down by Sir Macfarlane Burnet in the third chapter of his seminal monograph of the Abraham Flexner Lectures that he gave at Vanderbilt University in 1958, entitled “The Clonal Selection Theory of Acquired Immunity.”¹

Burnet stated:

“The facts of immunity that I want to summarize are those which seem most relevant to any attempt to look at the immune responses as a part of a general biological picture. They can be listed as follows”:

1.The physical nature of the populations of reactive globulin molecules in a typical antiserum.

2.The differences, quantitative and qualitative, between primary and secondary responses.

3.The lack of immunological reactivity to body components and the related phenomenon of tolerance.

4.The qualitative types of immune response (i.e. cellular vs. humoral).

5.Congenital agammaglobulinemia.

6.The part played by mesenchymal cells, particularly those of the lymphoid series in immune reactions.

Of the nature of the reactive globulin molecules, considerable progress had already been made in the first half of the 20th century by the time of Burnet’s lectures.^2,3 Now, 50 years later, we know that antibody activity is ascribable to immunoglobulin (Ig) molecules, which are identifiable in the sera of all vertebrates, and in mammals are categorized into five classes or isotypes, designated IgM, IgD, IgG, IgA, and IgE. Also, as a result of the progress made in the second half of the 20th century, we know that Burnet’s theory of Clonal Selection is correct; each Ig molecule is the product of a single B cell, which differentiates into an Ig producing plasma cell.⁴

With regard to the differences between primary and secondary immune responses, as summarized by Burnet, “A particularly clear example is that obtained with staphylococcal toxoid in early work,⁵ where the primary response is slow and of low titer, the secondary one rapid and rising almost logarithmically to a higher titer.” We now know that the major difference accounting for the rapidity of the secondary response compared with the primary response, is owing to the proliferative expansion of the antigen-selected clones of cells during the primary response, as initially proposed by Burnet.^1,6 As to the qualitative differences between the primary and secondary responses, we also know that in the process of responding to the initial primary exposure to antigen, the B cells undergo a differentiative process to become “memory” B cells, which has now been explained at the molecular level by genetic changes of recombination of the Ig genes,⁷ which accounts for isotype switching, and somatic hypermutation, which accounts for the phenomenon of affinity maturation.^8,9

Thus, for the past 30 years we have known what happens because of the primary antigenic stimulation, but we have only recently begun to unravel the secrets of exactly how these differentiative cellular changes take place at the molecular level, and what the molecular signals are that dictate them. Initially, it was assumed that antigen binding to surface Ig furnished all of the molecular signals necessary, in that after antigen selection, B cell proliferation ensues and precedes B cell differentiation. However, we are now aware that there are additional molecular ligand-receptor mechanisms that orchestrate these complicated cellular changes. It follows that it is axiomatic that B cell proliferation and differentiation are not simply pre-programmed changes that are only intrinsic to B cells and not other types of cells.

One crucial aspect of Burnet’s view of immunity that still had to be developed concerned the cellular immune response as compared with humoral immunity. By the time that Burnet formulated his theory, Medawar had already shown in 1944 that skin allografts prompt a remarkable rejection reaction with graft-infiltrative round inflammatory cells,¹⁰ and in 1945, Chase had shown that it is possible to transfer cutaneous delayed-type hypersensitivity (DTH) to tuberculin with cells but not sera.¹¹ Moreover, in 1952 Bruton reported a child with agammaglobulinemia who was unable to produce antibodies, and thus had great difficulty with bacterial infections, but had no difficulty recovering from viral infections.¹²

Burnet first proposed that lymphocytes are the cells responsible for immunity in 1957,⁶ and in his more extensive 1959 treatise¹ he summarized the available data indicating that there are at least three types of immune reactions:

1.Classical antibody responses

2.Hay-fever type responses

3.Tuberculin type responses

The first two types he convincingly attributed to Ig molecules. However, the third type was problematic, in that “Type (3) differs sharply in that there is no evidence that any circulating antibody is produced”.¹ Burnet went on to discuss that perhaps lymphocytes might be responsible for these cellular reactions, but he was still unsure of the origin of lymphoid cells, and he speculated that perhaps all mesenchymal cells were interchangeable, including lymphocytes, monocytes/macrophages, plasma cells, and even fibroblasts. There seemed to be no controversy that plasma cells were the source of antibody molecules as a result of Fagraeus’ 1948 seminal report,⁴ but there was a lack of convincing evidence of the interchangeability of each of these cells, especially as to whether lymphocytes could become plasma cells.

Because of the uncertainty of the cellular origins of immune responses, both humoral as well as cellular, Burnet could not furnish experimental support for his Clonal Selection Theory. In his monograph, Burnet comes to the following conclusion:

“Only by the use of a pure clone technique of tissue culture, which allows mesenchymal cells to retain full functional activity, would we be likely to find an answer. The clonal selection hypothesis would be completely validated if it could be shown that single cells from a nonimmune animal gave rise to clones, each cell of which under proper physiological conditions contained, or could liberate, antibody-type globulin of a single pattern.”¹

Of course, now with the advantage of hindsight, we know the answers to the questions posed by Burnet. However, it took another two decades to acquire the experimental data to prove the Clonal Selection Theory, to make it the Clonal Selection Law of immunology. Moreover, Burnet was prescient in his prediction that only the capacity to develop pure clones of functional cells would make it possible.

Lymphocytes: The Cellular Basis for Immunity

The initial breakthrough was supplied only one year later in 1960 by Peter Nowell,¹³ who made the serendipitous discovery that a plant lectin extracted from the kidney bean, phytohemagglutinin (PHA), had the remarkable capacity to promote a morphological change in small round resting human lymphocytes to one in which the cells resembled immature leukemic blast cells, a process that came to be termed “lymphocyte blastic transformation.” Moreover, following this blastic transformation, the cells underwent mitosis and cytokinesis. These findings were truly seminal, because prior to Nowell’s discovery, lymphocytes were described in textbooks as terminally differentiated, end-stage cells, incapable of self-renewal. Soon thereafter, in 1962 Gowans demonstrated that small lymphocytes would undergo proliferation in vivo after antigenic stimulation and give rise to circulating antibodies.¹⁴ Other reports followed soon thereafter in 1963 and 1964 by Kurt Hirschhorn and Fritz Bach and their co-workers that extended the phenomenon to specific antigen in vitro.^15–17 Accordingly, Burnet’s prophecy that antigen selected lymphocytes could undergo proliferative clonal expansion became a reality.

Also in 1963, the capacity to visualize and enumerate antibodyforming cells in vitro was first reported by future Nobel Laureate (1984) Neils Jerne together with Al Nordin and Claudia Henry.¹⁸ This technique, which came to be called the Jerne Plaque Assay, employed a source of lymphocytes from an animal immunized with Sheep Red Blood Cells (SRBCs), and a source of complement, which was supplied by using guinea pig sera. Thus, splenocytes or lymph node cells from SRBC-immunized rabbits or mice could be mixed with SRBCs and soft agar, and placed in Petri dishes, followed by the addition of complement, which would facilitate antibody-mediated lysis of the SRBCs, thereby forming a clear “plaque” against the homogeneous red background formed by the SRBCs. Each clear plaque could be observed under the microscope to contain a single central lymphoid cell, thus providing the first evidence that individual lymphocytes could give rise to cells that secrete antibody molecules. However, these data did not actually prove Burnet’s theory, in that the antibody molecules secreted by single cells still had to be shown to be “monoclonal” or identical individual Ig molecules.

In addition, the thymus had intrigued immunologists for some time, but experiments removing the thymus from animals failed to yield any immunological consequences, so that it was not clear whether this curious lymphoid organ played a role or not in the immune system. Since newborns were immunologically naive, Jacques Miller reasoned in 1962 that the thymus might play a role in lymphocyte development, and thus he conjectured that “neonatal thymectomy might be associated with some detectable effect on the maturation of immunological faculty.”¹⁹

Accordingly, Miller devised a method to thymectomize mice within the first three days of life (day 3 thymectomy; d3Tx). He found that such d3Tx mice grew normally during the first month, but thereafter suffered from “runting disease” very similar to Graft vs. Host Disease (GvHD), “characterized by progressive weight loss, lethargy, ruffled fur, humped posture and diarrhea.”¹⁹ Most mice succumbed before three months of age with lymphocytes invading multiple organs. Within th...

Table of contents

• Cover Page
• Title
• Copyright
• Dedication
• Contents
• Prologue
• Chapter 1 Twenty Years of Cellular Discovery
• Chapter 2 From Activities to Molecules: The Interleukins
• Chapter 3 The Beginnings of Molecular Immunology
• Chapter 4 Molecular Mechanisms of T Cell Cytolysis
• Chapter 5 Molecular Mechanisms of T Cell “Help”
• Chapter 6 The Molecules of Macrophages
• Chapter 7 Additional T Cell Signals: Co-stimulatory and Co-inhibitory
• Chapter 8 Regulatory T Cells
• Chapter 9 Immunotherapy
• Epilogue
• Name Index
• Subject Index