Vertebrate Immune Responses

All vertebrates have what is traditionally termed an innate immune response, a rather generic, nonspecific system. Gnathostomes (jawed vertebrates) also have an adaptive response, that "learns" via antigen-antibody reactions to combat specific pathogens. Innate immunity does not improve with subsequent exposures to a pathogen. Adaptive immunity is specific and has memory in that the adaptive response to a pathogen improves with each subsequent exposure during an individual's life, but this knowledge is not transmitted to the next generation. This does not mean that jawed vertebrates have a more effective immune system in general; agnathic vertebrates are still around, and their rarity relative to gnathostomes is generally attributable to their having been outcompeted by jawed vertebrates, not pathogen attack. However, it certainly raises the question as to what forces led to the evolution of the complex adaptive system (see below).

Innate vertebrate immune Responses

The overwhelming majority of multicellular organisms face the world with innate immunity alone. These systems may work against particular types of pathogen, but do not depend on recognizing specific organisms. Innate immunity begins with physical barriers, such as the skin or bark, mucous membranes, the cough response, chem ical barriers such as pH of the stomach, or temperature, which produce conditions in which microorganisms cannot live. If a microorganism breaches these first lines of defense, the innate immune system detects this and launches an immediate response. Innate immunity in vertebrates is mediated by cells of a general class known as phagocytes, of which specific types called macrophages and neutrophils use surface receptors for common bacterial components to trap, engulf, and destroy the pathogen. Cells of the immune system are shown in Figure 11-1. The complement system, described below, is also activated, to opsonize the bacteria, that is coat

Innate Immunity

Monocyte

Monocyte

Neutrophil

Neutrophil

Mast Cell

Mast Cell

Eosinophil

Eosinophil

Basophil

Basophil

Natural killer cell

Natural killer cell

Acquired Immunity

Antigen

Presenting

Cells

Antigen

Presenting

Cells

Dendritic Cell

Dendritic Cell

Macrophage

Macrophage

Lymphocytes

T-Cell B-Cell

Figure 11-1. Basic cell types of vertebrate immune systems.

them for recognition and destruction by phagocytes, or to destroy it outright. These receptors are encoded in the germline, but unlike the components of the adaptive response (see below), they are inflexible. These cell lineages are part of a generalized hemopoietic differentiation process that generates the circulating blood cells.

To establish an infection, a pathogen must either avoid detection by the innate immune system or defeat or overwhelm it. To evade recognition by phagocytes, many extracellular bacteria (that is, those that do not enter the host's cells but circulate in the blood or live in mucosal tissues) develop a thick polysaccharide coating or capsule. Some pathogens have developed a way to grow inside the phagosome (inside a cell that has engulfed the pathogen).

If enough bacteria enter the body they can overwhelm the innate response, and the adaptive immune system (in jawed vertebrates) must then respond if the organism is to survive the attack. If a pathogen evades or overwhelms the innate response, the early induced responses, humoral and cell-mediated effector mechanisms to be described below, are activated. This second wave of responses may contain the infection until the adaptive responses are ready to mount a defense, and they also influence the kind of adaptive response that is mounted. Some of the same mechanisms of the innate immune response may later be enlisted to eliminate the pathogen.

On activation, phagocytes release cytokines into the circulation. When received by cytokine receptors, these molecules alter the behavior or induce the proliferation of the recipient cell types in the immune system. Cytokine genes include a family of genes called Interleukins, which induce the liver to produce proteins that activate complement and the opsonization of microbes. Cytokines can also trigger a fever response that can be helpful, because many bacteria do not function well at elevated body temperature.

The innate immune system fairly quickly elicits a localized inflammatory response at detected sites of infection. This involves the recruitment of more phagocytes and effector cells (lymphocytes that are immediately able to mediate the destruction of a pathogen without having to undergo the further differentiation that other classes of cells in the adaptive immune system require) to the infection and the release of cytokines that have local effects like inducing increased blood flow to the area, helping, for example, by improving access for more effector cells. There is also an increase in vascular permeability, which allows the local accumulation of fluid (with concomitant pain and swelling of infection) and an increase in the number of immunoglobulins and complement, among other effector cells, in the area (Janeway 2001).

Phagocytes release many other molecules as well, such as nitric oxide, toxic oxygen radicals, mediators of inflammation, and the like, that both fight the pathogen and facilitate further adaptive response. One class of molecules called defensins is a family of short antibacterial peptides that help to permeabilize bacterial membranes so that they can be destroyed. Similar defense mechanisms are found in plants. Viral infection induces the production and secretion of proteins known as interferons. Interferons, true to their name, interfere with the replication of viruses by binding to interferon receptors, initiating a signal cascade that ultimately activates the transcription of genes that degrade viral RNA or otherwise inhibit viral replication inside a cell, preventing the spread of infection to neighboring cells.

These diverse measures, each involving families of gene products that activate other cell types and thus trigger the production of many attack molecules, besiege an infected site with generic defenses. The same process induces changes in the endothelial cells (the lining of blood vessels) during inflammation to induce these cells to trigger blood clotting in small vessels near the site of infection. This reduces the ability of surviving pathogens to enter the bloodstream and travel to other sites in the body. Meanwhile, phagocytes that have engulfed pathogen are carried by the fluid that leaked into the area at the early stages of infection to nearby lymph nodes, where they trigger an adaptive immune response in which T cell receptors (TCRs) or antibodies (see below) recognize the foreign peptide on the surface of the cells and are prompted to proliferate. This leads to the destruction of the infected phagocytes (Janeway 2001).

The Complement System

This system enhances the ability of the adaptive immune system to destroy bacteria, thus the term complement. It is particularly important in the destruction of bacteria. It seems to be a part of the innate immune system that was partly coopted in the evolution of adaptive response. Comprised of some 20 serum proteins, the system works as a cascade of cleavage reactions, one reaction activating the next component of the system. The effector mechanisms of complement include opsonization of the surface of pathogens so that phagocytes can recognize and engulf them, direct killing of microorganisms by creating holes in their surface membrane, chemotactic attraction of leukocytes to sites of infection, and activation of leukocytes.

The system is activated via three pathways. The first is called the classical pathway, activated by antigen-antibody complexes and active in both innate and adaptive immunity. The second is the mannan-binding lectin pathway (MBLectin pathway), which responds to the binding of a serum protein called mannan-binding lectin to carbohydrates on bacteria or viruses that contain mannose, a type of sugar molecule. Finally, the alternative pathway is activated when the surface of a pathogen is bound by a previously activated complement component (Janeway 2001).

These "innate" systems are invoked generically, without regard to the specific pathogen involved. In that sense they are preprogrammed for a kind of blind defense. A diversity of rather crude mechanisms is used, like destroying cell walls, that are possible because innate defenses recognize generic components of broad classes of pathogen, or exploit common constituents of these organisms (such as mannose) which the pathogens cannot shed because they are so intrinsic to their survival. In that sense the innate system evolved as a response by complex organisms to constituents of bacteria in place possibly since their origin. An assault on cells that is too generic can also damage the host as well, but if the response occurs early enough and is kept localized, the damaged area can be regenerated or sloughed harmlessly, and the infection is overcome.

The Adaptive Immune Response System

Bacteria and viruses can mutate and evolve much more rapidly than animals that reproduce slowly like vertebrates, and we might expect the microbe always to be able to outevolve any specific adaptation by the host—a race that must always go to the swift. Although many slowly reproducing species nonetheless manage, immune systems in higher vertebrates include a component that is adaptive on a scale to match that of microbial parasites.

In vertebrates both the innate and adaptive immune responses are mediated cel-lularly by leukocytes. Two phagocytic classes, macrophages and neutrophils, were mentioned earlier; along with monocytes they are primarily involved in the innate immune response system. Phagocytes mount a first-line defense in the immune response, which is immediate but generic.

The adaptive immune response is specific but can take up to seven days (in humans) to prepare to defend against a pathogen while the innate response attempts to rid the body of it. A class of leukocytes known as lymphocytes are the workhorses of the adaptive response. These cells recognize specific intra- or extracellular pathogens. The two predominant types of lymphocytes are known as B and T cells, named for the location in which they have been thought mainly to develop. In mammals, B cells differentiate in the liver in the fetus, and in bone marrow post-natally whereas T cells develop in the thymus. B and T cells acquire specificity to pathogens via receptors they produce, known as antibodies, that recognize antigens, molecules on the surface of the target pathogen or a toxin that it produces.

As currently understood, the major differences between the receptors on B and T cells are that the B cell receptor has two identical antigen recognition sites and can be secreted into the circulation whereas the T cell receptor always remains anchored to the cell surface and has only one recognition site. Antibodies circulating freely in the blood or lymph are called immunoglobulins (Ig). Other antibodies are anchored on the surface of B or T lymphocytes.

However, although the antibody-antigen ligation is specific at the molecular level, antibodies are not programmed in advance by specific antibody genes or alleles. Instead, lymphocytes with an essentially random assortment of antibodies, called naïve lymphocytes because they have not yet come into contact with antigen, circulate from the blood into the lymphoid tissues. There, an adaptive selection process unfolds in which the specific microbial antigens themselves are used to select antibodies to which they can be bound.

B Lymphocytes

A given B cell produces only a single antibody type (see below). B cells present this antibody on their surface (surface immunoglobulin), but once the antibody recognizes (binds) an antigen, two signals induce the lymphocyte to multiply and differentiate into immunoglobulin-secreting plasma cells. The first signal is induced by the ligated receptor and the second by a costimulatory signal in the form of a B7.1 or B7.2 molecule, coded by a member of the B7 gene family. The first signal initiates the synthesis of one subunit of the API, or antigen-presenting, TF and the second signal directs the synthesis of the other subunit. The AP1 TF recognizes enhancers such as those for interleukin gene expression. Once the B cell differentiates it can proliferate and/or produce large quantities of immunoglobulin—its particular antibody—that bind to other circulating copies of the antigen that originally activated the cell (Medzhitov and Janeway 1998). B cells can also be induced to differentiate in the spleen into memory cells that will quickly produce antibody if the organism is subsequently rechallenged by the same pathogen.

In Chapter 7 we described a variety of reactions that involve ligand binding by cell surface receptors that triggers response via the receptors' intracellular domains. Immunoglobulins work in a logically similar way. They have two major functions, each carried out by different parts of the molecule. One region binds to antigen, and the other mediates effector functions, that is, the destruction of pathogens specifically based on type of infection and the pathogen's life cycle stage. There are a number of effector systems, and the same systems are used by the innate and adaptive immune systems. The simplest is neutralization, when the antibody simply binds to the pathogen and neutralizes its activity. Another is phagocytosis, where antibody activates phagocytic cells to engulf the pathogenic cell and degrade it in one of several ways. Some antibodies, as well as TCRs on T cells (see next section), when they recognize antigen, induce cytotoxic reactions that kill the pathogen outright, either by perforating the membrane of the target cell or by inducing apoptosis.

The two functions of immunoglobulins are structurally separate on the molecule. Antibodies are formed by the pairing of heavy and light polypeptide chains (see Figure 11-2). The antigen binding region, the arms of the Y, that include the light chains, varies enormously in several open-ended ways and thus is called the variable (V) region. The rest of the molecule, the leg of the Y composed of the heavy chains that are responsible for the effector functions, is not nearly so variable and so is called the constant (C) region.

There are five Ig isoforms (alternative polypeptides), each coded by a different C-region gene, and these isoforms define the functional classes of immunoglobulins in higher mammals: IgG, IgM, IgA, IgD, and IgE. IgG is the predominant immunoglobulin in humans, comprising 70-80% of the total. It is found circulating in the blood as well as interstitially (in between cells). The structure of IgGs is remarkably variable among mammals, and they cross the placenta in some but not others. Maternal IgG confers immunity to newborns for several months, until the infant is able to make its own.

IgM comprises about 10% of the body's immunoglobulins. It is generally found circulating in the blood and is the first antigen-induced response to infection. IgA accounts for 10-15% of human immunoglobulins. Secretory IgA is the primary immunoglobulin in saliva, colostrum, milk, and other secretions. IgD accounts for <1% of total immunoglobulin but exists at high levels on the surface of B cells. Its function is not known, but it may have to do with the development of the fetal immune system or with lymphocyte differentiation. IgE is usually scarce in human serum, but probably is involved with immune response to parasites as well as in allergic responses (Roitt et al. 1998).

T Lymphocytes

T cells play a variety of roles in the adaptive immune system. As currently understood, some are involved in controlling the development of B cells and their antibody production, helper T cells help phagocytes destroy the pathogens they have internalized, and cytotoxic T cells recognize and kill virally infected cells.

T cells recognize antigens that are presented on the surface of a cell by molecules of the Major Histocompatibility Complex (MHC) (see Figure 11-3). The TCR is specific for antigen-MHC complexes. T cells function either by releasing cytokines, which signal between cells during an immune response, indirectly by activating macrophages to destroy organisms they have engulfed, or directly by interacting with infected cells. Like B cells, once a T cell has recognized a pathogen, it multiplies to vastly increase the amount of TCR available, and because the TCR is specific this generates clones of the T cells appropriate to the pathogen.

A. Antibody Molecule

B. T-Cell Receptor

light chain antigen binding site light chain cell membrane antigen binding site a chain variable region constant region k b chain

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