Chapter 1: The Need for Self-Recognition

Intro

Unit I: Introduction

This dictum—short in length but deep in meaning—encapsulates a basic need for all forms of life.

In a way, most organisms in our world live alone. They are composed of single cells or particles, and as such, their need to distinguish themselves is seemingly simple. Their single cell or particle is “I,” and all else is “them.” They need to sense which of “them” is appropriate to mate with or perhaps to congregate with, but otherwise their version of self is limited by their own membrane.

Multicellular organisms faced a new problem as they evolved. They gave up some of their independence to reap the advantages of being part of a greater whole—an organism composed of multiple semi-independent units. Initially, any such unit was pretty much like every other one within the greater structure, so extending the concept of self to include others that were essentially identical was perhaps a relatively small leap.

“I” became “us” but only as multiples of “I.” As organisms became more complex and the different cells within a single organism began to engage in a division of labor, they generated an array of cells with different forms and functions. Distinguishing “I” or “us” from “them” became increasingly complex: Is that adjoining cell, which seems so different from “I,” really a part of “us,” or is it an intruder from “them”?

The development of commensal arrangements between organisms (e.g., moss and fungi combining to form lichens, humans and normal bacterial flora in the gut and on the skin) required yet more questions: If there is an intruder, does it represent a threat or can it safely be ignored? If it represents a threat, what should be done to eliminate it?

These questions are the starting points from which the immune system operates. The human immune system uses various methods to ask and answer these questions. Some of these methods have been widely used for eons; others have been developed more recently by more restricted groups of organisms. This unit introduces how the human immune system deals with these questions.

Overview

A wide variety of organisms and their associated molecules pose a constant threat to the human body. The human immune system—the defensive mechanisms that identify and neutralize these threats—is able to distinguish “nonself” organisms and molecules from “self,” that which is part of the body (Fig. 1.1). Threats may enter the body from the outside (e.g., infectious organisms or toxic agents) or may arise from potentially harmful changes occurring within the body (e.g., the malignant transformation of a previously normal cell into a cancer cell).

Fortunately, the immune system consists of three layers of defense (Fig. 1.2). The first line of defense is provided by a set of mechanical (e.g., skin), chemical (e.g., acidic environment of stomach), and biologic (e.g., commensal microbes) barriers that protect the body. If these barriers are breached, the second and third lines of protective systems are activated: first the innate immune system and then the adaptive immune system.

Figure 1.1.Threats to the individual.

Threats to the individual.

The body is continuously exposed to many infectious agents, cancerous cells, toxic molecules, and even therapeutic drugs.

Figure 1.2.Protection from and response to microbial invasion.

Protection from and response to microbial invasion.

Initial protection is provided by a set of barriers. When breached, invading microbes trigger the innate immune system and, if necessary, the adaptive immune system.

The innate and adaptive immune systems use cell-surface and soluble receptors to sense potential threats. These receptors of the innate and adaptive systems are generated in different ways, however, providing a major distinction between the two systems (Fig. 1.3).

Figure 1.3.Innate pattern recognition receptors and adaptive somatically generated receptors.

Innate pattern recognition receptors and adaptive somatically generated receptors.

Each individual expresses pattern recognition receptors (innate immune system) and somatically generated receptors (adaptive immune system).

Some receptors recognize and bind to self molecules. Other receptors recognize and bind to nonself molecules. Some receptors for nonself are limited in number and are “hard-wired” in the genome, common to all normal individuals. They specifically detect molecules produced by a wide variety of other organisms (e.g., molecules commonly found on bacterial cells but not on human cells).

These “common” receptors, called pattern recognition receptors (PRRs), number perhaps a hundred or so and are part of the innate immune system, the second line of defense (Fig. 1.4A). Cells and molecules of the innate immune system respond rapidly to a microbial invasion and are often sufficient to eliminate many infections.

Figure 1.4.Diversity of receptors of the innate and adaptive immune systems.

Diversity of receptors of the innate and adaptive immune systems.

A. Receptors of the innate immune system (pattern recognition receptors) are limited in number and diversity and are consistent from one normal individual to another. B. The somatically generated receptors of lymphocytes in the adaptive immune system use random combinations of genes to assemble a very large number of different receptors.

The adaptive immune system (Fig. 1.4B), with its unique cells and molecules, is the third level of defense against these potential threats to the body, following the barriers and the innate immune system. Bone marrow–derived and thymus-derived lymphocytes (B cells and T cells, respectively) generate distinct receptors during development. Each lymphocyte randomly generates a unique receptor through the rearrangement and rejoining of a relatively small number of genes into a merged gene encoding the receptor.

These receptors, called somatically generated receptors, are generated randomly prior to any contact with self or nonself; the process is described in detail in Chapter 8. By combining multiple genes, therefore, each individual can generate enormous numbers of B and T cells, each with a unique receptor. A subsequent process, in which the receptors are uniquely vetted by each individual, results in the retention of a set of receptors that is individualized to that particular self and his or her nonself environment.

In addition, the initial responses of the cells of the adaptive immune system to a given threat or stimulus can lead to enhanced or depressed responses during subsequent encounters with the same threat or stimulus. This ability to modify the immune response to substances encountered on multiple occasions is the basis for immunologic memory, one of the hallmarks distinguishing the adaptive from the innate immune system.

Both the innate and adaptive immune systems involve various molecules and cells. Some of these are unique to one or the other system, whereas some contribute to both innate and adaptive responses. For example, cells of the innate system can act by themselves to resist infectious organisms. But some of them are also critical for activation of cells in the adaptive system and can in turn have their activity elevated and directed by activated cells from the adaptive system.

The immune system employs several defense mechanisms against foreign agents: killing them, consuming them, and isolating them. Many of these mechanisms also involve the proliferation of relevant host cells, following recognition of the intruders, to provide sufficient numbers for defense. Like many biologic systems, the immune system employs redundancy—multiple mechanisms with overlapping functions—to ensure that if one mechanism is not effective, another may be.

Through time, hosts and microbes have repeatedly changed their tactics. Some microbes have developed means of evading some immune responses. Hosts, in return, have developed additional defensive strategies. These strategies could eventually be evaded by some microbes. These new microbial innovations again drive development of yet additional defensive mechanisms, and so on. Thus, the relationship between host and microbe is essentially an ever-spiraling arms race.