on 21-Dec-2019 (Sat)

HIGHLIGHTS AND PEARLS

Immunity is defined as resistance to disease, specifically infectious disease.

It prevents the growth of some tumors, and some cancers can be treated by stimulating immune responses against tumor cells. Immune responses also participate in the clearance of dead cells and in initiating tissue repair

In innate immunity, the first line of defense is provided by epithelial barriers of the skin and mucosal tissues and by cells and natural antibiot- ics present in epithelia, all of which function to block the entry of microbes. If microbes do breach epithelia and enter the tissues or circulation, they are attacked by phagocytes, specialized lympho- cytes called innate lymphoid cells, which include natural killer cells, and several plasma proteins, including the proteins of the complement system. All these mechanisms of innate immunity spe- cifically recognize and react against microbes. In addition to providing early defense against infec- tions, innate immune responses enhance adaptive immune responses against the infectious agents

One of the most important functions of antibodies is to stop microbes that are present at mucosal surfaces and in the blood from gaining access to and colonizing host cells and connective tissues. In this way, antibodies prevent infections from ever being established. Antibodies cannot gain access to microbes that live and divide inside infected cells

Defense against such intracellular microbes is called cell-mediated immunity because it is mediated by cells, which are called T lympho- cytes.

The specificities of B and T lymphocytes differ in important respects. Most T cells recognize only protein antigens, whereas B cells and antibod- ies are able to recognize many different types of molecules, including proteins, carbohydrates, nucleic acids, and lipids

The diversity of the lymphocyte repertoire, which enables the immune system to respond to a vast number and variety of antigens, also means that very few cells, perhaps as few as 1 in 100,000 or 1 in 1,000,000 lymphocytes, are specific for any one antigen. Thus, the total number of naive (unactivated) lymphocytes that can recognize and react against any one antigen ranges from about 1000 to 10,000 cells

Only B cells are shown, but the same features are seen with T cell responses to antigens. The time after immunization may be 1 to 3 weeks for a primary response and 2 to 7 days for a secondary response, but the kinetics vary, depending on the antigen and the nature of im- munization.

These cells often are distinguishable by surface proteins that may be identified using panels of monoclonal antibodies. The standard nomen- clature for these proteins is the CD (cluster of differentiation) numerical designation, which is used to delineate surface proteins that define a particular cell type or stage of cell differentiation and that are recognized by a cluster or group of antibodies.

B cells express membrane forms of antibodies that serve as the receptors that recog- nize antigens and initiate the process of activa- tion of the cells. Soluble antigens and antigens on the surface of microbes and other cells may bind to these B lymphocyte antigen receptors, initiating the process of B cell activation. This leads to the secretion of soluble forms of anti- bodies with the same antigen specificity as the membrane receptors

T lymphocytes are responsible for cell-medi- ated immunity. The antigen receptors of most T lymphocytes recognize only peptide fragments of protein antigens that are bound to special- ized peptide display molecules, called major histocompatibility complex (MHC) molecules, on the surface of specialized cells, called anti- gen-presenting cells

All lymphocytes arise from stem cells in the bone marrow (Fig. 1-10). B lymphocytes mature in the bone marrow, and T lymphocytes mature in an organ called the thymus.

FIGURE 1-10 Maturation of lymphocytes. Lymphocytes develop from precursors in the generative lymphoid organs (bone marrow and thymus). Mature lymphocytes enter the peripheral lymphoid organs, where they re- spond to foreign antigens and recirculate in the blood and lymph. Some immature B cells leave the bone marrow and complete their maturation in the spleen (not shown)

Naive lymphocytes express receptors for antigens but do not perform the functions that are required to eliminate antigens. These cells reside in and circulate between peripheral lymphoid organs and survive for several weeks or months, waiting to find and respond to antigen. If they are not activated by anti- gen, naive lymphocytes die by the process of apoptosis and are replaced by new cells that have arisen in the generative lymphoid or- gans

The effector cells in the B lymphocyte lineage are antibody-secreting cells, called plasma cells.
Plasma cells develop in response to antigenic stimulation in the peripheral lymphoid organs, where they may stay and produce antibodies.

Small numbers of antibody-secreting cells are also found in the blood; these are called plasmablasts.
Some of these migrate to the bone marrow, where they mature into long-lived plasma cells and continue to produce small amounts of antibody long after the infection is eradicated, providing immediate protection in case the infection recurs

Effector T lymphocytes are short-lived and die as the antigen is eliminated

In fact, memory cells make up less than 5% of pe- ripheral blood T cells in a newborn, but 50% or more in an adult (Fig. 1-12). As individu- als age, the gradual accumulation of memory cells compensates for the reduced output of new, naive T cells from the thymus, which in- volutes after puberty

Dendritic cells are the most effective APCs for initiating T cell responses

This function of antigen capture and presentation is best understood for a cell type that is called dendritic cells because of their long surface membrane processes.

Dendritic cells capture protein antigens of microbes entering through the epithelia and transport the antigens to regional lymph nodes, where the antigen-bearing dendritic cells display portions of the antigens for recognition by T lymphocytes.

If a microbe has invaded through the epithelium, it may be phagocytosed and presented by tissue macrophages.

Microbes or their antigens that enter lymphoid organs may be captured by dendritic cells or macrophages that reside in these organs and presented to lymphocytes.

These specialized cells respond to microbes by producing surface and secreted proteins that are required, together with antigen, to activate naive T lymphocytes to proliferate and differentiate into effector cells.

Specialized cells that display antigens to T cells and provide additional activating signals sometimes are called professional APCs.
The prototypic professional APCs are dendritic cells, but macrophages, B cells, and a few other cell types may serve the same function in various immune responses

Less is known about cells that may capture antigens for display to B lymphocytes.

B lymphocytes may directly recognize the antigens of microbes (either released or on the surface of the microbes), or macrophages lining lymphatic channels may capture antigens and display them to B cells.

A type of cell called the follicular dendritic cell (FDC) resides in the germinal centers of lymphoid follicles in the peripheral lymphoid organs and displays antigens that stimulate the differentiation of B cells in the follicles (see Chapter 7).
FDCs do not present antigens to T cells and differ from the dendritic cells described earlier that function as APCs for T lymphocytes

It is not possible for the few lympho- cytes specific for any antigen to patrol all possible sites of antigen entry. The anatomic organization of peripheral lymphoid organs enables APCs to concentrate antigens in these organs and lympho- cytes to locate and respond to the antigens

Furthermore, different types of lympho- cytes often need to communicate to generate effective immune responses. For example, helper T cells specific for an antigen interact with and help B lymphocytes specific for the same antigen, resulting in antibody production. An important function of lymphoid organs is to bring these rare cells together after stimulation by antigen so they interact.

As the lymph passes through lymph nodes, APCs in the nodes are able to sample the an- tigens of microbes that may enter through epithelia into tissues. In addition, dendritic cells pick up antigens of microbes from epi- thelia and other tissues and transport these antigens to the lymph nodes

Blood-borne antigens are captured and con- centrated by dendritic cells and macrophages in the spleen. The spleen contains abundant phagocytes, which ingest and destroy microbes in the blood.

At any time, at least a quarter of the body’s lymphocytes are in the mucosal tissues and skin (reflecting the large size of these tissues) (see Fig. 1-13), and many of these are memory cells

In lymph nodes, the B cells are concen- trated in discrete structures, called follicles, located around the periphery, or cortex, of each node. If the B cells in a follicle have recently responded to an antigen, this follicle may contain a central lightly staining region called a germinal center.

The follicles contain the FDCs described earlier that are involved in the activation of B cells, and the paracortex contains the dendritic cells that present antigens to T lymphocytes.

In the spleen, T lymphocytes are concentrated in periar- teriolar lymphoid sheaths surrounding small arte- rioles, and B cells reside in the follicles

FDCs in the follicles secrete a particular chemokine for which naive B cells express a receptor, called CXCR5. The chemokine that binds to CXCR5 attracts B cells from the blood into the follicles of lymphoid organs. Similarly, T cells are segregated in the paracortex of lymph nodes and the periar- teriolar lymphoid sheaths of the spleen, because naive T lymphocytes express a receptor, called CCR7, that recognizes chemokines that are pro- duced in these regions of the lymph nodes and spleen

The B cells and T cells then migrate toward each other and meet at the edge of follicles, where helper T cells interact with and help B cells to differentiate into antibody-pro- ducing cells (see Chapter 7). Thus, these lympho- cyte populations are kept apart from each other until it is useful for them to interact, after expo- sure to an antigen. This is an excellent example of how the structure of lymphoid organs ensures that the cells that have recognized and responded to an antigen interact and communicate with one another only when necessary

Migration of effector lymphocytes to sites of infection is most relevant for T cells, because effector T cells have to locate and eliminate microbes at these sites.

By contrast, plasma cells do not need to migrate to sites of infection; instead, they secrete antibodies, and the antibodies enter the blood, where they may bind blood-borne pathogens or toxins

These naive T cells enter lymph nodes through specialized postcapillary venules, called high endothelial venules (HEVs). The adhesion molecules used by the T cells to bind to the endothelium are described in Chapter 6. Chemokines produced in the T cell zones of the lymph nodes and displayed on HEV surfaces bind to the chemokine recep- tor CCR7 expressed on naive T cells, which causes the T cells to bind tightly to HEVs

Such an encounter between an antigen and a specific lymphocyte is likely to be a random event, but most T cells in the body circulate through some lymph nodes at least once a day

• B lymphocytes that recognize and respond to antigen in lymph node follicles differenti- ate into antibody-secreting cells, which either remain in the lymph nodes or migrate to the bone marrow (see Chapter 7). • Memory T cells consist of different popula- tions; some cells recirculate through lymph nodes, where they can mount secondary re- sponses to captured antigens, and other cells migrate to sites of infection, where they can respond rapidly to eliminate the infection. We know less about lymphocyte circula- tion through the spleen or other lymphoid tis- sues. The spleen does not contain HEVs, but the general pattern of naive lymphocyte migration through this organ probably is similar to migra- tion through lymph nodes

The two principal ways the innate immune system deals with microbes is by inducing inflammation and by antiviral mechanisms

In addition to recognizing microbial struc- tures, the innate immune system also recognizes and responds to dead or injured cells, which may be because of microbial infection or, in the case of sterile injury, may be a site where microbes can readily enter and grow. The innate immune response also initiates the process of tissue repair that is critical for healing damaged tissues and restoring structure and function

Microbial protein antigens are processed in the dendritic cells to generate peptides that are displayed on the cell surface bound to MHC molecules. Naive T cells recognize these peptide-MHC complexes, and this is the first step in the initiation of T cell responses. Protein antigens also are recognized by B lymphocytes in the lymphoid follicles of the peripheral lymphoid organs. Polysaccharides and other nonprotein antigens are captured in the lymphoid organs and are recognized by B lym- phocytes but not by T cells

The innate immune response to some microbes also generates peptide frag- ments of complement proteins that enhance the response of naive B lymphocytes to antigen. Thus, antigen (often referred to as signal 1) and mole- cules produced during innate immune responses (signal 2) function cooperatively to activate anti- gen-specific lymphocytes. The requirement for microbe-triggered signal 2 ensures that the adap- tive immune response is induced by microbes and not by harmless substances.

On activation, B lymphocytes proliferate and then differentiate into plasma cells that secrete differ- ent classes of antibodies with distinct functions. Many nonprotein antigens, such as polysaccha- rides and lipids, have multiple identical antigenic determinants (epitopes) that are able to engage many antigen receptor molecules on each B cell and initiate the process of B cell activation.

Protein antigens are typically folded and do not contain multiple identical epitopes, so they are not able to simultaneously bind to many antigen receptors, and the full response of B cells to protein antigens requires help from CD4 + T cells. B cells ingest protein antigens, degrade them, and display peptides bound to MHC molecules for recognition by and activation of helper T cells. The helper T cells then express cytokines and cell surface proteins, which work together to activate the B cells.

Nonprotein antigens stimulate secretion of antibodies with a limited range of functions and low affinity for the anti- gen. Protein antigens, by engaging the help of T cells, stimulate the production of several differ- ent kinds of antibodies with different functions and high affinity for antigen. In addition, protein antigens induce very long-lived antibody secret- ing cells and memory B cells.