Mary E. Saunders

4 – Innate Immunity

The innate immune response is phylogenetically older than the adaptive response. Innate immunity encompasses anatomical and physiological barriers, cellular internalization mechanisms, and inflammatory responses that are rapidly induced by the presence of antigen. Innate immune mechanisms inhibit pathogen entry, prevent the establishment of infection, and clear both host and microbial debris. Some innate mechanisms are completely antigen nonspecific, while others involve broadly specific pattern recognition molecules (PRMs) that play a role in clearing a limited range of pathogens. Some PRMs are pattern recognition receptors (PRRs) expressed on effector cell surfaces, whereas others are soluble molecules that mark pathogens for clearance. Innate immunity either succeeds in eliminating the pathogen, or helps to hold infection in check until the slower, lymphocyte-mediated adaptive immune responses can develop. In addition, cells of the innate immune response release cytokines that are critical in lymphocyte activation and differentiation, influencing both the extent and the type of adaptive immune response to a given pathogen.

14 – T Cell Activation

The activation of the mature naive peripheral Th cell is the defining moment in an adaptive immune response, for it is the activated Th cell that supplies the T cell help usually required by both antigen-specific B cells and Tc cells. T cell activation is a defining moment in the adaptive immune response. The Dendritic cells (DC) migrate to the local lymph node, maturing as they travel, so that their powers of adhesion and antigen presentation are enhanced by the time they meet with naive CD4 T cells in the node. A CD4 T cell establishes contact with an antigen-presenting cell (APC) via the interaction of multiple adhesion molecules, followed by interaction between the T cell receptor (TCR) and peptide presented on major histocompatibility complex (MHC) class II. MHC class I complexes presented by licensed DCs. Licensed DCs express upregulated levels of costimulatory molecules due to prior interaction with an activated CD4 cell and the establishment of CD40–CD40L contacts.

Beyond the Oncogene Revolution: Four New Ways to Combat Cancer

It has become clear that tumorigenesis results from much more than just the activation of an oncogene and/or the inactivation of a tumor-suppressor gene, and that the cancer cell genome contains many more alterations than can be specifically targeted at once. This observation has led our group to a search for alternative ways to kill cancer cells (while sparing normal cells) by focusing on properties unique to the former. We have identified four approaches with the potential to generate new anticancer therapies: combatting the tactics by which cancers evade antitumor immune responses, targeting metabolic adaptations that tumor cells use to survive conditions that would kill normal cells, manipulating a cancer cells response to excessive oxidative stress, and exploiting aneuploidy. This review describes our progress to date on these fronts.

2 – Introduction to the Immune Response

This chapter introduces the important concepts of the immune system, including elements that are common to the innate and adaptive immune responses and elements that distinguish them. The chapter summarizes and compares the general characteristics of innate and adaptive immune responses. Most foreign antigens are eliminated by the mechanisms of innate immunity. Only those antigens that succeed in penetrating the innate defenses evoke adaptive immune responses. Innate immunity involves both pre-existing physical barriers that show little or no pathogen specificity and induced cellular responses of broad specificity. In contrast, adaptive immune responses must be induced and require the activation of B and T lymphocytes. Each lymphocyte clone expresses cell surface antigen receptors of a single specificity, and each clone is activated only upon the interaction of these receptors with complementary antigen. Activated Tc lymphocytes differentiate into cytotoxic effectors (CTLs) capable of lysing tumor cells and cells infected with intracellular pathogens, and activated Th lymphocytes differentiate into cytokine-secreting Th effectors that support B cell and Tc cell functions.

6 – The Nature of Antigen–Antibody Interaction

This chapter, examines the nature of B cell epitopes, the mechanism by which the antibody recognizes and binds to these epitopes on antigens, and the role of T cell help in B cell activation. The chapter provides an insight into the engagement of the B cell receptor (BCR) on the B cell surface by antigen. It also explores the assays used in the laboratory that are based on these interactions. T-independent (Ti) antigens activate B cells in the absence of major histocompatibility complex (MHC) class II-restricted T cell help. By examining the mechanics of antigen–antibody, a reasonable idea of the interactions that occur on the cell surface between an antigen and an antigen receptor is obtained. In contrast, T-dependent (Td) antigens are proteins of non-repetitive amino acid sequence that bind to mIg but cannot fully activate the antigen-specific B cells on their own. The activation of these B cells cannot occur until the Td antigen is processed and presented by APCs that stimulate T helper cells specific for that antigen. A Td antigen thus contains both B cell and T cell epitopes that facilitate the necessary co-localization of the antigen-specific lymphocytes.

7 – Exploiting Antigen–Antibody Interaction

This chapter examines the aspects of how the interaction between antigen and antibody can be exploited in research and clinical laboratories. The specificity and sensitivity of antibodies make them useful biochemical tools. Because immunology evolved from the sciences of biochemistry, genetics, histology, and pathology, many of the techniques used to characterize features of the immune system are derived from the methodologies of these fields. General methodologies appropriate for examining cellular, enzymatic, and genetic components are frequently used. However, immunologists can also take advantage of a unique feature of their science, the antigen–antibody bond, which has the specificity of an enzymatic reaction without its sometimes inconvenient permanent alteration of the bound substrate. The development of hybridoma technology and monoclonal antibodies has resulted in an explosion of technical applications. Antibodies are used in two main categories of assays—those based on immune complex formation, and those based on unitary antigen–antibody pair formation. Direct tag assays involve the antigen and the primary antibody, one of which is tagged. Indirect tag assays involve the antigen, the primary antibody, and a third component that is labeled and used to detect the antigen–antibody pair. This chapter closes with a discussion on antibodies as effectors and antibodies as laboratory tools.

22 – Immunity to Pathogens

Immune responses have evolved to combat the five major types of pathogens—extracellular bacteria, intracellular bacteria, viruses, parasites, and fungi. For all types of pathogens, the mechanisms of innate immunity offer an immediate response that either foils the establishment of infection or slows the infection down until adaptive immune mechanisms can target the pathogen more effectively. When an adaptive immune response is activated, the elements that are most effective depend on whether the pathogen is extracellular or intracellular. Extracellular entities that are relatively small, such as extracellular bacteria, virus particles, protozoan parasites, and some fungi, can be targeted by antibody and then cleared effectively by antibody and complement-mediated mechanisms that involve either direct lysis or phagocytic destruction. A successful immune response against a given pathogen thus depends on cells and cytokines of the innate response inducing Th responses of the appropriate subtype, with Th1 responses being required for cell-mediated immunity against internal threats, and Th2 responses being needed for humoral responses against external threats.

3 – Cells and Tissues of the Immune Response

Hematopoietic stem cells in the bone marrow give rise to all cells of the myeloid and lymphoid lineages involved in both innate and adaptive immune responses. Hematopoiesis occurs throughout life, and is balanced by the ongoing programmed cell death of spent cells to maintain the health of the host. The primary lymphoid organs are the anatomical sites where T and B lymphocytes develop. Like most leukocytes, B cells complete their maturation in the bone marrow. T cells originate in the bone marrow but complete their maturation in the thymus. While in the thymus, T cells are selected for their ability to recognize self-major histocompatibility complex (MHC) complexed to peptide. Once mature, leukocytes of all lineages migrate throughout the body via the blood circulation and lymphatic system. Although different leukocytes tend to concentrate in either the blood or tissues, they can move among these compartments when infection or injury occurs. At such times, inflammation activates endothelial cells to allow an influx of leukocytes, including effector and memory lymphocytes, into the damaged tissue. To facilitate lymphocyte activation, secondary lymphoid tissues are distributed throughout the body to serve as junctions where lymphocytes, antigens, and antigen-presenting cells can co-localize. The major secondary lymphoid structures are the lymph nodes, the spleen, and the mucosa- and skin-associated lymphoid tissues.

17 – Cytokines and Cytokine Receptors

Cytokines are structurally diverse, soluble proteins that are synthesized under tight regulatory controls mainly by leukocytes. They act in an autocrine or paracrine fashion as intercellular messengers, exerting their effects primarily on other leukocytes. This chapter examines a number of cytokines and their receptors in isolation, focusing on their pleiotropic effects on the many different aspects of the immune system that are subject to their influence. The chapter concentrates on those cytokines which are most directly associated with the immune response. It also investigates the nature of cytokine receptors, without which a cytokine would have no effect. The chapter concludes with a series of tables summarizing how certain constellations of cytokines cooperate in important physiological events, including innate and adaptive immune responses. Current work on cytokines has centered on the delineation of their precise physiological functions in vivoand their potential clinical applications. The roles of cytokines in vivo are addressed using both transgenic and knockout mice, and some surprising differences between in vivo and in vitro effects are observed. The importance of cytokines and cytokine receptors in immunity is underscored by the fact that various viruses have evolved homologues of these molecules to serve as means of evading the immune response.

Fighting Fire with Fire in Cancer

Cancer will not be cured until we understand and target the unique alterations that distinguish tumor cells from normal cells. This chapter briefly describes four new approaches to anticancer therapy based on boosting the immune system’s response to tumor cells, countering the metabolic adaptations that allow tumor cells to thrive under conditions that kill normal cells, manipulating the increased oxidative stress associated with the tumor environment, and exploiting the aneuploidy characteristic of many advanced tumor cells. The long-term goal is to devise biomarkers and novel therapeutic agents able to more effectively fight aggressive cancers.