The Adaptive Immune Response And The Lymphatic System

The human lymphatic system shown in Fig. 7.2 is part of the general circulatory system and plays a critical role in developing the immune response to the presence of foreign proteins in the body. When any protein that is not part of the vast protein repertoire making up the vertebrate host is presented to the immune system by an antigen-presenting cell (APC), both B-cell immunity (humoral immunity) and T-cell immunity (cell-mediated immunity [CMI]) are mobilized. Such a foreign protein is usually termed an antigen and can be derived from an invading pathogen (virus, bacteria, or parasite), or it can be a novel cellular protein expressed as a result of abnormal growth properties of the cells — a tumor antigen. In general, an antigen that is not part of a host's normal protein composition can be recognized by host's immune system as foreign and can become a target of the immune response.

Lymphocytes are produced, differentiate, and mature in certain specialized tissues, including bone marrow, spleen, and thymus. They circulate throughout the body in the circulatory and lymphatic system and can migrate between cellular junctions into tissue in response to infection. They are most concentrated in lymph nodes where stimulation to provide a systemic immune response often begins. B cells produce antibodies that are secreted proteins able to bind specifically to the antigenic determinants on proteins. Activated T cells have antigen-binding sites on their surfaces and upon encountering cells expressing foreign antigens (such as virus-infected cells), interact with them, resulting in lysis of the infected target cells. Certain

  • a) Direction of lymph flow Lymphatic —
  • a) Direction of lymph flow Lymphatic —
Lymphatic Organs
Fig. 7.2 The human lymphatic system. The lymphatic system is the principal organ of the immune system. (a) The relationship between the lymphatic circulation and that of the blood. (b) Some of the important components of the lymphatic system as related to the immune response.

T cells (CD4+ T helper cells) can also function in helping to promote the development of B-cell and cytolytic CD8+ T-cell immunity.

Together, these two arms of the adaptive immune system interact to allow the host to detect and destroy or render noninfectious (inactivate or neutralize) both free virus and virus-infected cells that display viral proteins at their surface. A general outline of the interaction between an antigenic pathogen and the adaptive immune system is shown in Fig. 7.3.

Two pathways of helper T response - the fork in the road

An early event in the development of a specific immune response is the presentation of virus-specific antigens to cells of the adaptive immune response. These include helper and regulatory T cells, cytotoxic T cells, and B cells. A key event in this process is defined by the presentation of antigens to CD4+ helper T cells. Following this antigen presentation, some of the cells will differentiate into T helper 1 cells (Th1), and some will differentiate into T helper 2 cells (Th2). Th1 cells primarily secrete y-interferon (see Chapter 8), which mediates the

B cells

Bone marrow

Stem cells->

B cells

Bone marrow

Stem cells->

Circulatory system

Spleen /

Peyer's patch (intestines)

Lymph node

Activated B and T lymphocytes, antibodies

High endothelial venule

Lymph node

Activated B and T lymphocytes, antibodies

High endothelial venule

Afferent lymphatics

Germinal center (site of B lymphocyte activation)

Antigens and antigen Paracortex presenting cells (site of T lymphocyte activation)

Afferent lymphatics

Fig. 7.2 Continued

Germinal center (site of B lymphocyte activation)

Antigens and antigen Paracortex presenting cells (site of T lymphocyte activation)

Antigen Capture And Presenting Images
  1. 7.3 T and B cells in immunity. T lymphocytes play the central coordinating role in evoking the immune response. Upon activation by interaction with a specific antigenic determinant with which they can interact, they proliferate and carry out the functions shown. B cells reactive with specific antigens require reactive T cells for their maturation. Upon maturation, they secrete antibody proteins that bind to antigenic determinants.
  2. 7.3 T and B cells in immunity. T lymphocytes play the central coordinating role in evoking the immune response. Upon activation by interaction with a specific antigenic determinant with which they can interact, they proliferate and carry out the functions shown. B cells reactive with specific antigens require reactive T cells for their maturation. Upon maturation, they secrete antibody proteins that bind to antigenic determinants.

differentiation of CD8+ T cells to generate a cytolytic cellular immune response. Conversely, Th2 cells produce primarily IL-4, IL-5, IL-10, and IL-13, which promote the differentiation of B cells with resulting humoral antibody response.

A number of the TLRs discussed above have been shown to have roles in promoting either a Th1 or Th2 response. In this sense the innate immune response serves not only to buy time for the development of a specific immune response against a viral pathogen, but also plays a role in guiding the development of the type and degree of response that is elicited. This is only one of a large number of examples of the interleaving of various components of the immune system into a functional whole.

The immunological structure of a protein

In any protein, certain clusters of amino acids (usually between 10 and 12) are able to interact with the appropriate antigen-recognizing T cells or antibody-producing B cells to lead to proliferation of those cells. These clusters are called antigenic determinants (epitopes). B-cell reactive epitopes are usually hydrophilic, and thus hydrated. A viral protein can have none, a few, or many antigenic determinants, depending on its protein structure, amino acid sequence, sequence relation to cellular proteins, degree of glycosylation, and other factors. Two proteins can share some of the same or closely related determinants, and the closer the relation between the proteins, the greater the shared ones. This is why closely related viral serotypes share a high degree of immunological reactivity. A schematic representation of epitope types present in proteins is shown in Fig. 7.4.

Epitopes are often composed of a specific sequence of amino acids. With such an epitope, denaturation of the antigenic protein will have little or no effect on its properties or how it is presented to the immune system. Such determinants expressed in a protein in either its native or its denatured state are called sequential epitopes.

Epitopes can also be sensitive to the structure of the protein region where they occur. For example, they could be made of amino acids that have been brought near each other by protein

  1. Epitope which requires proper folding of peptide chain - a 'conformational epitope' -2. "Burled" epitope, antigenic not found in MHC I-mediated responses
  2. Epitope which requires proper folding of peptide chain - a 'conformational epitope' -2. "Burled" epitope, antigenic not found in MHC I-mediated responses
Immune System Amino Acids
Fig. 7.4 The antigenic structure of a protein. Specific groups of amino acids (usually hydrated) serve as specific antigenic determinants, or epitopes in an antigenic protein. Some of these are insensitive to the protein's physical structure; others require a specific conformation for presentation.

folding or conformation. These are conformational epitopes, which are sensitive to denatur-ation (disruption) of the protein structure.

Either sequential or conformational epitopes can be in the interior of a protein where they are not normally seen by the humoral immune system. These are buried determinants. Many of these are sequential and can be exposed by denaturation of the protein. A buried conformational determinant could be exposed by proper limited degradation of the protein, or by denaturation of the protein followed by its being refolded in a form that exposed the epitope.

Role of the antigen-presenting cell in initiation of the immune response

Any protein and many other macromolecules can be antigenic, but antigens must be "processed" and then presented at the surface of the cell bearing them (antigen-presenting cell) in the proper context to be able to evoke an immune response. This context is as a complex with one of two closely related heterodimeric cell surface glycoproteins, the major histocompatibility proteins. These MHC glycoproteins ensure that only antigen-presenting cells (e.g., macrophages and dendritic cells) from the same organism can present antigens to the immune system. There are two basic pathways through which cells present antigens (Fig. 7.5). The first,

Peptide fragments Peptide fragments

Proteasome degrades protein

Protein

Tapasin

MHC class I bound to TAP Calreticulum

Tapasin

MHC class I bound to TAP Calreticulum

Mhc Immune System

Fig. 7.5 The processing of a foreign antigen and stimulation of the immune response. As described in the text, an antigenic protein can only stimulate the immune response when it is processed by a macrophage and then presented to cells of the immune system in lymph nodes in the presence of histocompatibility antigens. The processing is relatively rapid and involves partial degradation of the antigenic protein and expression of antigenic portions on the surface of the antigen-presenting cell. (a) MHC-I antigen processing and presentation. (b) MHC-II processing and presentation.

Endogenous Antigen Presentation

Fig. 7.5 Continued which is a function of nearly all cells, is the presentation of endogenously expressed antigens on the surface via the type I major histocompatibility complex (MHC-I). As proteins are being synthesized portions are complexed with a group of cellular proteins named ubiquitins, which target the proteins to proteolytic vesicles (proteosomes) where they are partially degraded into epitope-sized peptides. These peptides are then moved via transporter proteins (TAPs) into the Golgi apparatus where the peptides associate with newly synthesized MHC-I glyco-proteins and are presented on the surface of the cell. These MHC-I complexes serve as targets for surveying CD8+ T cells, and if reactive, the cells bearing the antigen are destroyed. In this way, the immune system surveys all cells for the synthesis of foreign or abnormal proteins. This endogenous antigen presentation is important in the early immune detection of viral-infected cells, and is clearly a major factor in local immunity.

The establishment of systemic immunity and immune memory require a relatively large population of freely circulating, relatively short-lived effector T cells that can recognize the antigen in question. This primarily occurs via the activity of long-lived specialized dendritic cells that were formed in the bone marrow and migrate to the epithelium where they remain. Dendritic cells and certain other cells of the immune system are often termed professional antigen-presenting cells, because of this primary role in evoking systemic immunity. Antigenic proteins or complexes are recognized in manners that are not fully understood, and are internalized and partially digested by receptor-mediated endocytosis. Fragments of antigens containing epitopes are reexpressed on the cell surface in the presence of cellular type II major histocompatibility complex (MHC-II) proteins. The antigenic fragment and the major histocompatibility complex (MHC) molecules together form a surface structure that can be recognized by CD4+ T and certain B cells in lymph nodes to begin the amplification of cells able to recognize the antigen - this is shown schematically in Fig. 7.5(b). MHC-II-mediated antigen presentation occurs in lymph nodes. Because antigen concentration must reach a high enough level to evoke the immune response, the process takes time and occurs only following a lag after initial infection and early replication of the virus. This delay is important in virus infections — such as HSV infections — where virus can invade sensory neurons and establish latent infections before a powerful immune response is achieved. Indeed, HSV, like some other viruses, can actually interfere with the MHC-I-mediated early presentation of its antigenic proteins at the surface of the infected cell by the action of a specific viral protein expressed immediately following infection.

Some viruses (notably HIV) can survive internalization by dendritic cells, and their presentation to T cells leads to infection of lymphocytes. HIV can replicate in CD4+ lymphocytes, and eventually replication of the virus in infected lymphatic cells leads to destruction of the immune system.

As the T and B cells able to interact with the presented epitope continue to proliferate, immature B cells with surface receptors that can bind to antigen also internalize and process the antigen. These B cells provide an alternative mechanism for presenting antigen in the lymph nodes.

The internalization and processing of antigens is clearly of paramount importance to the ability to generate effective immunity. Nevertheless, in addition to the generation of sequential determinants, the host can generate immune responses to complex conformational epitopes, such as portions of dimeric and multimeric proteins found at the surface of the virus. Indeed, the host preferentially mounts strong antibody responses to the surface proteins of viruses. Part of the reason for these responses is that such proteins are present in large amounts and are at the "interface" between the infection and the host antigenic response. Other factors are also involved, including structural features of the proteins, inherent resistance to extensive degradation, and the ability of surface antibody (IgG) on immature B cells to recognize native (unprocessed) antigens.

Clonal selection of immune reactive lymphocytes

When antigens are presented to immune cells that can recognize them, those T and B cells are stimulated to proliferate. As shown in Fig. 7.6, the process of clonal selection takes place because each specific antibody-producing B cell and each specific epitope-recognizing T cell are derived from a single reactive cell (i.e., clones of that cell). This process takes place mainly in the lymph nodes because of the high concentration of cell populations that must interact. The ability to generate clones of antibody-producing B cells in the laboratory has provided an extremely important tool for studying the functional structure and relationships between various cellular and viral proteins. Some basic techniques using such material are outlined in Chapter 12, Part III.

As they are stimulated by the presence of a specific epitope that they recognize, B cells divide and differentiate (mature). Fully differentiated B cells secrete soluble antibodies. One class of effector T cells (CD4+ helper cells) mediates the maturation of B cells. Another class, CD8+ cytotoxic T cells, attacks and destroys cells with foreign antigens on them, such as virus-infected cells. A third class of T cells (regulatory or Treg) suppress the immune response toward the end of the "crisis" when immunity is at a high level and antigen levels begin to decline.

Fig. 7.6 The clonal selection of B lymphocytes. Only the B lymphocytes reactive with a specific epitope can be stimulated to mature by the action of a helper T lymphocyte. Specific mature B cells secrete specific types of antibody molecules, but the same epitope will result in only the stimulation and maturation of B-cell clones reactive with it.

Viral antigen Lymphokines

Mature B cell

Activated B lymphocyte can recognize antigen free of MHC protein

Mature B cell

Helper T cell

Activated helper T cell secretes lymphokines which stimulate B cell

Antibody-secreting cell

Fc region of bound antibody activates various host responses

Antigen-antibody complex

Helper T cell

Activated helper T cell secretes lymphokines which stimulate B cell

Antibody-secreting cell

Fc region of bound antibody activates various host responses

Antigen-antibody complex

Immune memory

The immune system "remembers" the antigenic response and can rapidly respond to reexposure to the antigen. Long-lived memory T and B cells mediate immune memory. Such memory cells reside mainly in lymph nodes and circulate in the blood and lymph. As antigen persists, the cells that respond to it continue to proliferate. While most have a finite lifetime and then undergo apoptosis, memory cells do not function in dealing with the antigen, but rather are long-lived and remain ready to respond to a second infection with the same or closely related pathogen. A second stimulation results in rapid interaction of the antigen with such memory cells and a secondary (remembered) immune response that is more rapid and more extensive than the first or primary response. The effect of immune memory on the strength and speed of the immune response is shown in Fig. 7.7.

Complement-mediated cell lysis

Although T cells have a primary role in the destruction of cells bearing foreign antigens, B cells can also destroy antigen-bearing cells by use of the complement system, which leads to complement-mediated cell lysis. This system works because cells with antibodies bound to them trigger a cascade of interactions with serum complement proteins that leads to destruction of the cell; this process is outlined in Fig. 7.8.

The T and B cells with antigenic recognition sites having the highest affinity for a given epitope are stimulated most efficiently. As general levels of antigens fall late in infection and during recovery, lower levels of high-affinity interactions can continue to stimulate immunity. Thus, the nature of the immune response changes with time after infection. A recovering patient will generally have higher-affinity and more specific antibodies than will an individual early in the course of a disease.

A population of CD4+, CD25+ regulatory T cells mature very late in the immune response and shut down immunity. These cells are important to the regulation of immunity. If they do not function properly, hyperimmune responses such as allergic reactions may occur. If they

Secondary response (second inoculation of antigen)

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Responses

  • diane
    How the innate immunity and adaptive immunity are interleaved?
    2 years ago

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