Immune System

T he immune system is responsible for safeguarding the body from disease-causing microorganisms. It is part of a complex system of host defenses.

Host defenses may be innate or acquired. Innate defenses include physical and chemical barriers, the complement complex, and cells such as phagocytes (cells programmed to destroy foreign cells, such as bacteria) and natural killer lymphocytes.

Physical barriers, such as the skin and mucous membranes, prevent invasion by most organisms. Chemical barriers include lysozymes (found in such body secretions as tears, mucus, and saliva) and hydrochloric acid in the stomach. Lysozymes destroy bacteria by removing cell walls. Hydrochloric acid breaks down foods and destroys pathogens carried by food or swallowed mucus.

Organisms that penetrate this first line of defense simultaneously trigger the inflammatory and immune responses, some innate and others acquired.

Acquired immunity comes into play when the body encounters a cell or cell product that it recognizes as foreign, such as a bacterium or a virus. The two types of cell-mediated immunity are humoral (provided by B lymphocytes) and cell-mediated (provided by T lymphocytes). All cells involved in the inflammatory and immune responses arrive from a single type of stem cell in the bone marrow. B cells mature in the marrow, and T cells migrate to the thymus, where they mature.

The inflammatory response is the immediate local response to tissue injury, whether from trauma or infection. It involves the action of polymorphonuclear leukocytes, basophils and mast cells, platelets, and, to some extent, monocytes and macrophages. Each of these cells is described in a later section.

IMMUNE RESPONSE

The immune response primarily involves the interaction of antigens (foreign proteins), B lymphocytes, T lymphocytes, macrophages, cytokines, complement, and polymorphonuclear leukocytes. Some immunoactive cells circulate constantly; others remain in the tissues and organs of the immune system, such as the thymus, lymph nodes, bone marrow, spleen, and tonsils. In the thymus, the T lymphocytes, which are involved in cell-mediated immunity, become able to differentiate self (host) from nonself (foreign) substances (antigens). In contrast, B lymphocytes, which are involved in humoral immunity, mature in the bone marrow. The key mechanism in humoral immunity is the production of immunoglobulin by B cells and the subsequent activation of the complement cascade. The lymph nodes, spleen, liver, and intestinal lymphoid tissue help remove and destroy circulating antigens in the blood and lymph.

Antigens

An antigen is a substance that can induce an immune response. T and B lymphocytes have specific receptors that respond to specific antigen molecular shapes, called epitopes. In B cells, this receptor is an immunoglobulin, also called an antibody.

Major histocompatibility complex

The T-cell antigen receptor recognizes antigens only in association with specific cell-surface molecules known as the major histocompatibility complex (MHC).

The MHC, also known as the human leukocyte antigen (HLA) locus, is a cluster of genes on human chromosome 6 that has a pivotal role in the immune response. Every person receives one set of MHC genes from each parent, and both sets of genes are expressed on the individual's cells. These genes produce MHC molecules, which participate in:

• the recognition of self versus nonself
• the interaction of immunologically active cells by coding for cell-surface proteins.

MHC molecules differ among individuals. Slightly different antigen receptors can recognize a large number of distinct antigens, coded by distinct, variable region genes.

Groups or clones of lymphocytes exist that have identical receptors for a specific antigen. The clone of a lymphocyte rapidly proliferates when exposed to the specific antigen. Some lymphocytes further differentiate, while others become memory cells, which allow a more rapid response ― the memory or anamnestic response ― to subsequent challenge by the antigen.

Haptens

Most antigens are large molecules, such as proteins or polysaccharides. Smaller molecules, such as drugs, that aren't antigenic by themselves are known as haptens. They can bind with larger molecules, or carriers, and become antigenic or immunogenic.

Antigenicity

Many factors influence the intensity of a foreign substance's interaction with the host's immune system (antigenicity):

• physical and chemical characteristics of the antigen
• its relative foreignness; for example, little or no immune response may follow the transfusion of serum proteins between humans, but a vigorous immune response (serum sickness) commonly follows transfusion of horse serum proteins to a human
• the host's genetic makeup, especially the MHC molecules.

Humoral immunity

The humoral immune response is one of two types of immune responses that can occur when foreign substances invade the body. The other is the cell-mediated response. The humoral response is also called an antibody-mediated response.

B lymphocytes

B lymphocytes and their products, immunoglobulins, are the basis of humoral immunity. A soluble antigen binds with the B-cell antigen receptor, initiating the humoral immune response. The activated B cells differentiate into plasma cells, which secrete immunoglobulins, also called antibodies. This response is regulated by T lymphocytes and their products ― lymphokines, such as interleukin-2 (IL-2), IL-4, and IL-5, and interferon-8 ― which determine which class of immunoglobulins a B cell will manufacture.

Immunoglobulins

The immunoglobulins secreted by plasma cells are four-chain molecules with two heavy and two light chains. Each chain has a variable (V) region and one or more constant (C) regions, which are coded by separate genes. The V regions of both light and heavy chains participate in antigen binding. The C regions of the heavy chain provide a binding site for Fc receptors on cells and govern other mechanisms. (See Structure of the immunoglobulin molecule .)

There are five known classes of immunoglobulins: IgG, IgM, IgA, IgE, and IgD. These are distinguished by the constant portions of their heavy chains. However, each class has a kappa or lambda light chain, which gives rise to many subtypes and provides almost limitless combinations of light and heavy chains that give immunoglobulins their specificity. (See Classification of immunoglobulins .)

A clone of B cells is specific for only one antigen, and the V regions of its Ig light chains determines that specificity. However, the class of immunoglobulin can change if the association between the cell's V region genes and heavy chain C region genes changes through a process known as isotype switching. For example, a clone of B cells genetically programmed to recognize tetanus toxoid will first make an IgM antibody against tetanus toxoid and later an IgG or other antibody against it.

Cell-mediated immunity

The cell-mediated immune response protects the body against bacterial, viral, and fungal infections and defends against transplanted cells and tumor cells. T lymphocytes and macrophages are the chief participants in the cell-mediated immune response. A macrophage processes the antigen and then presents it to T lymphocytes.

Macrophages

Macrophages influence both immune and inflammatory responses. Macrophage precursors circulate in the blood. When they collect in various tissues and organs, they differentiate into different types of macrophages. Unlike B and T lymphocytes, macrophages lack surface receptors for specific antigens. Instead, they have receptors for the C region of the heavy chain (Fc region) of immunoglobulin, for fragments of the third component of complement (C3), and for nonimmunologic substances such as carbohydrate molecules.

One of the most important functions of macrophages is presentation of antigen to T lymphocytes. Macrophages ingest and process the antigen, then deposit it on their own surfaces in association with HLA antigen. T lymphocytes become activated when they recognize the antigen-HLA complex. Macrophages also function in the inflammatory response by producing IL-1, which generates fever, and by synthesizing complement proteins and other mediators that have phagocytic, microbicidal, and tumoricidal effects.

T lymphocytes

Immature T lymphocytes are derived from the bone marrow and migrate to the thymus, where they mature. In maturation, the products of the MCH genes “teach” T cells to distinguish between self and nonself.

Five types of T cells exist with specific functions:

• memory cells, sensitized cells that remain dormant until second exposure to antigen, also known as secondary immune response
• lymphokine-producing cells, delayed hypersensitivity reactions
• cytotoxic T cells, direct destruction of antigen or the cells carrying the antigen
• helper T cells, also known as T4 cells, facilitate the humoral and cell-mediated responses
• suppressor T cells, also known as T8 cells, inhibit humoral and cell-mediated responses.

T cells acquire specific surface molecules (markers) that identify their potential role when needed in the immune response. These markers and the T cell antigen receptor together promote the particular activation of each type of T cell. T-cell activation requires presentation of antigens in the context of a specific HLA antigen: class II HLA for helper T cells; class I for cytotoxic T cells. T cell activation also requires IL-1, produced by macrophages, and IL-2, produced by T cells.

Natural killer cells. This is a discrete population of large lymphocytes, some of which resemble T cells. Natural killer cells recognize surface changes on body cells infected with a virus. They bind to and, in many cases, kill the infected cells.

Cytokines

Cytokines are low-molecular-weight proteins involved in the communication among macrophages and the lymphocytes. They induce or regulate a variety of immune or inflammatory responses. Cytokines include colony-stimulating factors, interferons, interleukins, tumor necrosis factors, and transforming growth factor.

Complement system

The chief humoral effector of the inflammatory response, the complement system includes more than 20 serum proteins. When activated, these proteins interact in a cascade-like process that has profound biological effects. Complement activation takes place through one of two pathways.

Classic pathway

In the classic pathway, IgM or IgG binds with the antigen to form antigen-antibody complexes that activate the first complement component, C1. This in turn activates C4, C2, and C3.

Alternate pathway

In the alternate pathway, activating surfaces such as bacterial cell membranes directly amplify spontaneous cleavage of C3. Once C3 is activated in either pathway, activation of the terminal components, C5 to C9, follows.

The major biological effects of complement activation include chemotaxis (phagocyte attraction), phagocyte activation, histamine release, viral neutralization, promotion of phagocytosis by opsonization (making the bacteria susceptible to phagocytosis), and lysis of cells and bacteria. Kinins (peptides that cause vasodilation and enhance vascular permeability and smooth muscle contraction) and other mediators of inflammation derived from the kinin and coagulation pathways interact with the complement system.

Polymorphonuclear leukocytes

Other key factors in the inflammatory response are the polymorphonuclear leukocytes: neutrophils, eosinophils, basophils, and mast cells.

Neutrophils

Neutrophils, the most numerous of these leukocytes, derive from bone marrow and increase dramatically in number in response to infection and inflammation. They're the first to respond in acute infection. Neutrophils are highly mobile cells attracted to areas of inflammation and are the main constituent of pus.

Neutrophils have surface receptors for immunoglobulins and complement fragments, and they avidly ingest bacteria or other particles that are coated with target-identifying antibodies (opsons). Toxic oxygen metabolites and enzymes such as lyzozyme promptly kill the ingested organisms. Unfortunately, in addition to killing invading organisms, neutrophils also damage host tissues.

Eosinophils

Eosinophils, also derived from bone marrow, multiply in allergic and parasitic disorders. Although their phagocytic function isn't clearly understood, evidence suggests that they participate in host defense against parasites. Their products may also diminish inflammatory response in allergic disorders.

Basophils and mast cells

Basophils and mast cells also function in immune disorders. Mast cells, unlike basophils, aren't blood cells. Basophils circulate in peripheral blood, whereas mast cells accumulate in connective tissue, particularly in the lungs, intestines, and skin. Both types of cells have surface receptors for IgE. When their receptors are cross-linked by an IgE antigen complex, they release mediators characteristic of the allergic response.

PATHOPHYSIOLOGIC MANIFESTATIONS

The host defense system and the immune response are highly complex processes, subject to malfunction at any point along the sequence of events. This malfunction may involve exaggeration, misdirection, or an absence or depression of activity leading to an immune disorder.

Immune response malfunction

When the immune system responds inappropriately, three basic categories of reactions may occur: hypersensitivity, autoimmune response, and alloimmune response. The type of reaction is determined by the source of the antigen, such as environmental, self, or other person, to which the immune system is responding.

Hypersensitivity

Hypersensitivity is an exaggerated or inappropriate response that occurs on second exposure to an antigen. The result is inflammation and the destruction of healthy tissue. Allergy refers to the harmful effects resulting from a hypersensitivity to antigens, also called allergens .

Hypersensitivity reactions may be immediate , occurring within minutes to hours of re-exposure, or delayed , occurring several hours after re-exposure. A delayed hypersensitivity reaction typically is most severe days after the re-exposure.

Generally, hypersensitivity reactions are classified as one of four types: type I (mediated by IgE), type II (tissue-specific), type III (immune-complex-mediated), type IV (cell-mediated). (See Classification of hypersensitivity reactions .)

Type I hypersensitivity. Allergens activate T cells, which induce B-cell production of IgE, which binds to the Fc receptors on the surface of mast cells. Repeated exposure to relatively large doses of the allergen is usually necessary to cause this response. When enough IgE has been produced, the person is sensitized to the allergen. At the next exposure to the same antigen, the antigen binds with the surface IgE, cross-links the Fc receptors, and causes mast cells to degranulate and release various mediators. Degranulation also may be triggered by complement-driven anaphylatoxins ― C3a and C5a ― or by certain drugs such as morphine.

Some of the mediators released are preformed, whereas others are newly synthesized on activation of the mast cells. Preformed mediators include heparin, histamine, proteolytic (protein-splitting) and other enzymes, and chemotactic factors for eosinophils and neutrophils. Newly synthesized mediators include prostaglandins and leukotrienes. Mast cells also produce a variety of cytokines, which initiate smooth muscle contraction, vasodilation,