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Immunology Overview

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Immunology Overview Empty Immunology Overview

Post by Dr Sarhan Mon Jan 07, 2008 10:19 am

GENERAL CONCEPTS


Evolution of the Immune System


The immune system consists of factors that provide innate and acquired immunity, and has evolved to become more specific, complex, efficient, and regulated. One of the principal functions of the human immune system is to defend against infecting and other foreign agents by distinguishing self from non-self (foreign antigens) and to marshal other protective responses from leukocytes. The immune system, if dysregulated, can react to self antigens to cause autoimmune diseases or fail to defend against infections.
Organization/Components/Functions


The immune system is organized into discrete compartments to provide the milieu for the development and maintenance of effective immunity. Those two overlapping compartments: the lymphoid and reticuloendothelial systems (RES) house the principal immunologic cells, the leukocytes. Leukocytes derived from pluripotent stem cells in the bone marrow during postnatal life include neutrophils, eosinophils, basophils, monocytes and macrophages, natural killer (NK) cells, and T and B lymphocytes. Hematopoietic and lymphoid precursor cells are derived from pluripotent stem cells. Cells that are specifically committed to each type of leukocyte (colony-forming units) are consequently produced with the assistance of special stimulating factors (e.g. cytokines).
Cells of the immune system intercommunicate by ligand-receptor interactions between cells and/or via secreted molecules called cytokines. Cytokines produced by lymphocytes are termed lymphokines (i.e., interleukins and interferon-gamma) and those produced by monocytes and macrophages are termed monokines.
Lymphoid System


Cells of the lymphoid system provide highly specific protection against foreign agents and also orchestrate the functions of other parts of the immune system by producing immunoregulatory cytokines. The lymphoid system is divided into 1) central lymphoid organs, the thymus and bone marrow, and 2) peripheral lymphoid organs, lymph nodes, the spleen, and mucosal and submucosal tissues of the alimentary and respiratory tracts. The thymus instructs certain lymphocytes to differentiate into thymus-dependent (T) lymphocytes and selects most of them to die in the thymus (negative selection) and others to exit into the circulation (positive selection). T lymphocytes circulate through the blood, regulate antibody and cellular immunity and help defend against many types of infections. The other classes of lymphocytes, B cells (antibody-forming cells) and natural killer (NK) cells, are thymic-independent and remain principally in peripheral lymphoid organs.
Reticuloendothelial System


Cells of the RES provide natural immunity against microorganisms by 1) a coupled process of phagocytosis and intracellular killing, 2) recruiting other inflammatory cells through the production of cytokines, and 3) presenting peptide antigens to lymphocytes for the production of antigen-specific immunity. The RES consists of 1) circulating monocytes; 2) resident macrophages in the liver, spleen, lymph nodes, thymus, submucosal tissues of the respiratory and alimentary tracts, bone marrow, and connective tissues; and 3) macrophage-like cells including dendritic cells in lymph nodes, Langerhans cells in skin, and glial cells in the central nervous system.
Leukocytes


Leukocytes, the main cells in the immune system, provide either innate or specific adaptive immunity. These cells are derived from myeloid or lymphoid lineage. Myeloid cells include highly phagocytic, motile neutrophils, monocytes, and macrophages that provide a first line of defense against most pathogens. The other myeloid cells, including eosinophils, basophils, and their tissue counterparts, mast cells, are involved in defense against parasites and in the genesis of allergic reactions. In contrast, lymphocytes regulate the action of other leukocytes and generate specific immune responses that prevent chronic or recurrent infections.
Myeloid Cells


Neutrophils: These are one of the major types of cells that are recruited to ingest, kill, and digest pathogens. Neutrophils are the most highly adherent, motile, phagocytic leukocytes and are the first cells recruited to acute inflammatory sites. Each of their functions is dependent upon special proteins, such as the adherence molecule CD11b/CD18, or biochemical pathways, such as the respiratory burst associated with cytochrome b558.
Eosinophils: Eosinophils defend against many types of parasites and participate in common hypersensitivity reactions via cytotoxicity. That cytotoxicity is mediated by large cytoplasmic granules, which contain the eosinophilic basic and cationic proteins.
Basophils: These cells and their tissue counterparts, mast cells, produce cytokines that help defend against parasites and engender allergic inflammation. These cells display high affinity surface membrane receptors for IgE antibodies and have many large cytoplasmic granules, which contain heparin and histamine. When cell-bound IgE antibodies are cross-linked by antigens, the cells degranulate and produce low-molecular weight vasoactive mediators (e.g. histamine) through which they exert their biological effects.
Monocytes/Macrophages: Monocytes and macrophages are involved in phagocytosis and intracellular killing of microorganisms. Macrophages process protein antigens and present peptides to T cells. These monocytes/macrophages are highly adherent, motile and phagocytic; they marshal and regulate other cells of the immune system, such as T lymphocytes; serve as antigen processing-presenting cells; and act as cytotoxic cells when armed with specific IgG antibodies.
Macrophages are differentiated monocytes, which are one of the principal cells found to reside for long periods in the RES. Macrophages may also be recruited to inflammatory sites, and be further activated by exposure to certain cytokines to become more effective in their biologic functions.
Lymphoid Cells


These cells provide efficient, specific and long-lasting immunity against microbes and are responsible for acquired immunity. Lymphocytes differentiate into three separate lines: thymic-dependent cells or T lymphocytes that operate in cellular and humoral immunity, B lymphocytes that differentiate into plasma cells to secrete antibodies, and natural killer (NK) cells. T and B lymphocytes are the only lymphoid cells that produce and express specific receptors for antigens.
T Lymphocytes: These cells are involved in the regulation of the immune response and in cell mediated immunity and help B cells to produce antibody (humoral immunity). Mature T cells express antigen-specific T cell receptors (TcR) that are clonally segregated (i.e., one cell lineage-one receptor specificity). Every mature T cell also expresses the CD3 molecule, which is associated with the TcR. In addition mature T cells display one of two accessory molecules, CD4 or CD8. The TcR/CD3 complex recognizes antigens associated with the major histocompatibility complex (MHC) molecules on target cells (e.g. virus-infected cell). The TcR is a transmembrane heterodimer composed of two polypeptide chains (usually, alpha and beta chains). Each chain consists of a constant (C) and a variable (V) region, and are formed by a gene- sorting mechanism similar to that found in antibody formation. The repertoire is generated by combinatorial joining of variable (V), joining (J), and diversity (D) genes, and by N region (nucleotides inserted by the enzyme deoxynucleotidyl-transferase) diversification. Unlike immunoglobulin genes, genes encoding TcR do not undergo somatic mutation. Thus there is no change in the affinity of the TcR during activation, differentiation, and expansion.
T Helper Cells: These cells are the primary regulators of T cell- and B cell-mediated responses. They 1) aid antigen-stimulated subsets of B lymphocytes to proliferate and differentiate toward antibody-producing cells; 2) express the CD4 molecule; 3) recognize foreign antigen complexed with MHC class II molecules on B cells, macrophages or other antigen-presenting cells; and 4) aid effector T lymphocytes in cell-mediated immunity. Currently, it is believed that there are two functional subsets of T helper (Th) cells. Th1 cells aid in the regulation of cellular immunity, and Th2 cells aid B cells to produce certain classes of antibodies (e.g., IgA and IgE). The functions of these subsets of Th cells depend upon the specific types of cytokines that are generated, for example interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) by Th1 cells and IL-4 and IL-10 by Th2 cells.
Cell-mediated immunity (delayed hypersensitivity) plays an important role in defense against many intracellular infections such as Mycobacterium tuberculosis. This inflammatory reaction is initiated by the recognition of specific antigens by Th1 cells. Consequently, lymphokines are generated which recruit activated macrophages to eliminate foreign antigens or altered host cells.
T Cytotoxic Cells: These cells are cytotoxic against tumor cells and host cells infected with intracellular pathogens. These cells 1) usually express CD8, 2) destroy infected cells in an antigen-specific manner that is dependent upon the expression of MHC class I molecules.
T Suppressor Cells: These cells suppress the T and B cell responses and express CD8 molecules.
Natural Killer Cells: NK cells are large granular lymphocytes that nonspecifically kill certain types of tumor cells and virus-infected cells. Killing by NK cells is enhanced by cytokines such as IL-2 and IFN-gamma. NK cells are also activated by microorganisms to produce a number of cytokines [(IL-2, IFN-gamma, IFN-alpha, and tumor necrosis factor-alpha (TNF-alpha)]. These circulating large granular lymphocytes do not express CD3, TcR or immunoglobulin, but display surface receptors (CD16) for the Fc fragment of IgG antibodies.
B Lymphocytes: These cells differentiate into plasma cells to secrete antibodies and are involved in processing proteins and presenting the resultant peptide antigen fragments in the context of MHC molecule to T cells. The genesis of µ and delta chain-positive, mature B cells from pre-B cells is antigen-independent. Pre-B cells in the bone marrow undergo gene rearrangement for IgM heavy (H) chains and consequently express those proteins in the cytoplasm (the µ chain), but no immunoglobulin light (L) chains. B cell development is characterized by recombinations of immunoglobulin H and L chain genes and expression of specific surface monomeric IgM molecules. At this stage of development, B cells are highly susceptible to the induction of tolerance. Once these cells acquire IgD molecules on their surface, they become mature B cells that are able to differentiate after exposure to antigen into antibody-producing plasma cells.
The activation of B cells into antibody producing/secreting cells (plasma cells) is antigen-dependent. Once specific antigen binds to surface Ig molecule, the B cells differentiate into plasma cells that produce and secrete antibodies of the same antigen-binding specificity. If B cells also interact with Th cells, they proliferate and switch the isotype (class) of immunoglobulin that is produced, while retaining the same antigen-binding specificity. This occurs as a result of recombination of the same Ig VDJ genes (the variable region of the Ig) with a different constant (C) region gene such as IgG. In the case of protein antigens, Th2 cells are thought to be required for switching from IgM to IgG, IgA, or IgE isotypes.
IgM is therefore the principal antibody produced during a primary immunization. This primary antibody response is manifested by serum IgM antibodies as early as 3-5 days after the first exposure to an immunogen (immunizing antigen), peaks in 10 days, and persists for some weeks. Secondary or anamnestic antibody responses following repeated exposures to the same antigen appear more rapidly, are of longer duration, have higher affinity, and principally are IgG molecules.
When antibodies bind to antigens, they may 1) neutralize pathogenic features of antigens such as their toxins, 2) facilitate their ingestion by phagocytic cells (opsonization), 3) fix to and activate complement molecules to produce opsonins and chemoattractants (vide infra), or 4) participate in antibody-dependent cellular cytotoxicity (ADCC).
In addition to antibody formation, B cells also process and present protein antigens. After the antigen is internalized it is digested into fragments, some of which are complexed with MHC class II molecules and then presented on the cell surface to CD4+ T cells.
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Immunology Overview Empty Re: Immunology Overview

Post by Dr Sarhan Mon Jan 07, 2008 10:20 am

Immunoglobulin Supergene Family


Immunoglobulins (Ig)/Antibodies



Immunoglobulins (antibodies) are globular glycoproteins found in body fluids or on B cells where they act as antigen receptors. These molecules are either expressed on the surface of B cells or are secreted by terminally differentiated cells from this lineage (plasma cells) into the circulation or external secretions. An immunoglobulin molecule is a symmetrical multi-chain peptide consisting of two identical H chains and two identical L chains. Each chain is divided into a V region that is responsible for specific antigen binding and a C region that carries out other functions such as the binding of IgG to complement or leukocytes. These antibody molecules are formed as a result of the assembly of separate germ-line genes for the V, J, and C regions of the H and L chains of the final immunoglobulin molecule. This combinatorial mechanism is responsible for the great diversity of antibody molecules.
There are five major isotypes (classes) of immunoglobulins (IgG, IgA, IgM, IgD, and IgE). These isotypes are distinguished by differences in the C regions of H chains of each immunoglobulin isotype (gamma, alpha, µ, delta, and epsilon, respectively). These differences are responsible for the particular functions of immunoglobulin classes.
T Cell Receptor


The specific receptor for antigen on T lymphocytes, the TcR, is a heterodimeric protein with motifs that are similar to immunoglobulin molecules, but whose structure is encoded by a different set of V, J, D, and C genes. Moreover, T cells consist of two subsets carrying different receptors, that have been designated alpha/beta and gamma/delta. The T cell receptors act as specific antigen recognition molecules. Unlike antibody molecules, the TcR molecules cannot recognize soluble antigens. In contrast, they recognize protein antigens that have been processed and presented as peptides on the surface of antigen-presenting cells in the context of MHC class I or MHC class II molecules (vide infra).
Major Histocompatibility Complex (MHC)


These genes encode for cell surface molecules that are involved in the genesis and regulation of specific immune responses to T-cell dependent antigens and in tissue transplantation. They principally encode cell surface protein molecules that bind antigenic peptides, which are recognized by T cells.
The MHC is a cluster of ~ 40-50 genes located on chromosome 6. These genes belong to the super-immunoglobulin gene family. There are three classes of these molecules. MHC class I molecules are found on all nucleated somatic cells and aid in presenting endogenously synthesized antigens, whereas MHC class II molecules are found principally on antigen processing/presenting cells (i.e., macrophages, B cells) and are involved in presenting processed exogenous protein antigens. The MHC class III region contains a heterogeneous group of genes that encode for some components of the complement system, heat shock proteins, tumor necrosis factor-alpha, and tumor necrosis factor-beta.
T Cell Activation


The presentation of antigen in the context of MHC molecules is essential for T cell recognition of peptide antigens. However, interactions between the MHC-bound peptide and TcR and the MHC class I or class II molecules with CD8 or CD4, respectively, is not sufficient to activate T cells. Other ligands on antigen presenting cells and their receptors (co-receptors/co-stimulators) on T cells are required to complete the process of T cell activation.
Tolerance-Autoimmunity


Immunologic tolerance (unresponsiveness) normally prevents reactions against self-antigens; if immunologic tolerance is broken, autoimmune reactions may occur. Much of the development of tolerance occurs in the thymus by the elimination (clonal deletion) or inactivation (clonal anergy) of self-reactive clones of T cells. Other mechanisms of tolerance occur extrathymically and include activation of antigen-specific T suppressor cells and clonal deletion, which results in the elimination of self-reactive B cells or T cells, and clonal anergy.
Tolerance may be broken because of a genetic predisposition to immune dysregulation, altered self-antigens, exposure to microbial antigens that cross-react with self-antigens, or exposure to a self-antigen that is normally not revealed to the immune system (e.g., an antigen in the eye). When tolerance against self-antigens is broken, autoimmunity is produced, which could result in an autoimmune disease.
The Complement System


The complement system consists of inactive circulating glycoproteins that can be sequentially activated by antigen-antibody (IgG or IgM) complexes or bacterial products to enhance inflammation or to attack cellular membranes. The system consists of the classical and alternative pathways that converge to activate the membrane attack complex. After activation, opsonic, chemoattractant, or cytotoxic fragments are produced.
Defenses Against Infections


Natural (innate) and acquired defenses are marshalled to combat infecting agents. The first line of defense includes the skin, mucous membranes, protective inhibitors, and IgA antibodies produced at mucosal sites. The second line of defense consists of local factors and cells that are activated or recruited to the site of microbial invasion. These include: 1) the coagulation system, 2) the fibrinolytic system, 3) vasoactive peptides, 4) the complement system, 5) resident macrophages, 6) recruited inflammatory leukocytes, and 7) cytokines. The third line of defense includes the expansion of populations of antigen-specific B cells and T cells, the production of systemic antibodies, and the activation of T cells. Successful defense is followed by a clearance of opsonized pathogens by the RES and tissue repair.
Immune Responses to Microorganisms Lead to Disease


Excessive or otherwise inappropriate immune responses to infecting agents may lead to disease. Examples of such excessive immunologic responses that can be protective or cause disease include: 1) circulating antigen-antibody (immune) complexes of microbial antigens bound to IgM or IgG antibodies, 2) antibodies to microorganisms that cross-react with self-antigens, 3) vasoactive compounds from the complement system and from the metabolism of arachidonic acid, 4) excessive production of proinflammatory cytokines, 5) delayed hypersensitivity reactions, and 6) cytotoxic T cells directed against the infected host cells.
Ontogeny of the Immune Response


The immune system undergoes an orderly development during the prenatal and postnatal periods. Mature T and B cells appear in the fetus, but are not activated until the infant is exposed to immunogens. Memory T cells are not present during early infancy and the antibody repertoire is not fully established for many months. IgM is the first type of antibody produced postnatally. IgG antibodies to protein antigens are formed in early infancy, but IgG antibodies to polysaccharides do not appear until 2 - 2.5 years of age. There are also developmental delays in the production of several cytokines such as the interferons.
Maternal Immunologic Contributions to the Infant


Maternal immune factors are transmitted to the fetus via the placenta and to the young infant by mammary gland secretions. These transferred maternal factors compensate for developmental delays in the production of those immune factors by the recipient fetus/infant. Developmental delay in the production of IgG is overcome by transfer of maternal antibodies of that same isotype via the placenta. Other immune factors (whose production is developmentally delayed), such as secretory IgA, lactoferrin, and lysozyme; leukocytes; anti-inflammatory agents; and immunomodulating agents are provided by mammary gland secretions via human milk. These factors are not as well represented in non-human milk. Therefore, the breast-fed infant is less at risk for gastrointestinal and respiratory infections and for inflammatory disorders including common allergic diseases.
Immunologic Deficiency


Immune deficiencies are genetic or acquired and result in an increased susceptibility to certain infections, the types of which depend upon the exact nature of the defect.
Genetic Defects: X-linked agammaglobulinemia is a genetic defect in a B cell progenitor kinase that is essential for B cell development. Consequently, few B cells and only low levels of antibodies are produced. This leads mainly to an increased susceptibility to highly virulent, encapsulated respiratory bacterial infections.
T cell deficiency is the primary problem in severe combined immunodeficiency (deficiencies of B and T cells). Most cases are due to an X-linked recessive defect in the formation of the gamma-chain common to a number of cytokine receptors. Some autosomal recessive types are due to deficiencies in enzymes such as adenosine deaminases in the purine salvage pathway. Patients with these diseases display few T cells, decreased T cell functions, poor antibody formation, and an increased susceptibility to opportunistic infections such as Pneumocystis carinii.
Hereditary defects also occur in neutrophils. For example, a decrease in leukocyte adherence is due to an autosomal recessive defect in the formation of the common CD18-subunit of leukocyte adherence glycoproteins, whereas deficiency in intracellular killing (chronic granulomatous disease) is due to a deficiency in the production of subunits of cytochrome b558 or ancillary proteins necessary for their stabilization. Consequently, reactive oxygen compounds required for intracellular killing are not produced.
Acquired Defects: Protein-energy malnutrition is the leading cause of immunologic deficiency. A second, but important cause of acquired immunodeficiency is the human immunodeficiency virus (HIV) that attacks CD4+ T cells and macrophages. Also, certain other infections depress or destroy parts of the immune system by different mechanisms.
Immunology Overview Divider6
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Immunology Overview Empty Re: Immunology Overview

Post by Dr Sarhan Mon Jan 07, 2008 10:20 am

EVOLUTION OF THE IMMUNE SYSTEM

The human defense system consists of factors that provide innate and acquired immunity against microorganisms. The system evolved from primitive but effective defenses found in more ancient animal species. The innate defenses include 1) structural barriers, 2) acids, bases, and other chemical agents produced at various sites, such as mucosal surfaces, and 3) highly phagocytic, motile scavenger cells that have well-developed killing and digestive powers. As a result of the evolutionary process, the mammalian immune system has become more specific, efficient, regulated, and complex. The development of specialized innate and acquired recognition/regulatory proteins (antibodies, cell receptors, and cytokines) expanded the repertoire, and control the magnitude of the protective responses. One of the most important consequences of this evolution is the ability of the immune system to discriminate between self and non-self antigens and maintain a memory of previous encounters with antigens, including those from microorganisms.
The evolutionary changes allowed development of B and T cells which express antigen-specific receptors on their cell surface. These changes permit humans to survive in an environment laden with microbial pathogens and environmental toxins. The pathogenic features of those microorganisms include the ability to 1) enter the body through portals such as the skin, respiratory system, and the alimentary tract; 2) utilize nutrients from those sites; 3) adhere to epithelium; 4) produce virulence factors and toxins; 5) commandeer the replicative machinery of the host's cells; 6) evade the immunologic system; 7) cripple the defenses of the host; and Cool cause autoimmune responses by acting as cross-reactive antigens.
The salient features of the human defense system that evolved to counteract the pathogenic microorganisms and prevent autoimmune problems will be presented in the rest of this chapter.
Organization/Components/Functions


The production, maturation, and function of cells of the immune system occur to a great extent in two overlapping organ systems, 1) the lymphoid system consisting of lymphocytes and their supporting structures and 2) the RES consisting of macrophages and related mononuclear phagocytes (Fig. 1-1). In postnatal life, bone marrow is the principal source of pluripotent stem cells that produce precursors of cells that operate in host defense (Fig.1-2). The development of each type of leukocyte is precisely controlled and the controls account for the great specificity of the defense system and the fact that untoward immunologic reactions are relatively uncommon.
Immunology Overview Fig1_1

Figure 1-1. Major organs in the lymphoid and reticuloendothelial systems
Immunology Overview Fig1_2

Figure 1-2. Production of blood cells from pluripotent stem cells in the bone marrow.

Lymphoid System


The lymphoid system consists of organs that house 1) T and B cells that are responsible for antigen-specific immunity and 2) NK cells that are innately cytotoxic to tumor cells and cells expressing foreign antigens. The system is divided into a) central lymphoid organs, the thymus and bone marrow, and b) peripheral lymphoid organs including lymph nodes, spleen, and the mucosa/submucosa of the respiratory and alimentary tracts (Fig. 1-1). Lymphocytes are one of the principal leukocytes found in these organs. There are three major types of lymphocytes (T, B, and NK) that have distinctive surface markers and functions (see sections on T cells, B cells, and NK cells (Fig.1-3 and Table 1-1). Furthermore, the T and B cells in the lymph nodes are confined to discrete zones (Fig. 1-4).
Immunology Overview Fig1_3

Figure 1-3. Principal surface markers of lymphocyte populations. Molecules that serve as receptors are shown in bold type.
Immunology Overview Tbl1_1Immunology Overview Fig1_4

Figure 1-4. Lymph node. Discrete B and T cell zones are found.

Reticuloendothelial System (RES)


The second major cellular system, the RES, (Fig. 1-1) harbors macrophages, which are cells that play major roles in 1) defending against many microbial pathogens and 2) generating specific immune responses by processing protein antigens and presenting the resultant peptide antigen fragments in the context of MHC molecules to T cells. The system consists of 1) monocytes in the blood, 2) macrophages in the liver, spleen, lymph nodes, thymus, bone marrow, connective tissues, and submucosal tissues of the respiratory and alimentary tracts, 3) dendritic cells in lymph nodes, 4) Langerhans cells in skin, and 4) glial cells in the central nervous system. Macrophages not only operate in direct defense (phagocytosis and intracellular killing) but also marshal other parts of the immune system, such as T lymphocytes (see section on T lymphocytes) (Table 1-1).
Molecular Communications in the Immune System


Cells of the immune system have profound immunoregulatory influences on each other. This regulation is mediated in large part by potent bioactive molecules, called cytokines, which may have autocrine, paracrine, or systemic effects. These polypeptides and glycoproteins are produced by diverse types of cells and act on many different types of cells by binding to high affinity receptors on their surfaces. Their functions include 1) activating or attracting specific types of leukocytes, 2) regulating cell division, 3) modulating the production or actions of other cytokines, 4) promoting or abrogating inflammation, 5) directing certain cells to switch the types of proteins that they produce, and 6) influencing the production of cellular or humoral immunity. Those produced principally by lymphocytes have been termed lymphokines and those principally produced by monocytes and macrophages, monokines. Interleukin is also used to designate many of these agents.
A detailed description of the sources, target cells, and principal functions of these agents is beyond the scope of this presentation, but a synopsis of that information is found in Table 1-2 and the specific roles of certain cytokines are discussed in sections of this chapter that will follow.
Immunology Overview Tbl1_2


Ligands, such as surface molecules, on certain cells of the immune system that bind to receptors on other types of cells may activate the cells bearing the receptors and thus modulate immune responses. Interactions between T cell receptors and the processed peptide in the context of the MHC molecule are examples of the importance of such ligand (peptide)-receptor (T cell receptor) interactions in the immune system.
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Immunology Overview Empty Re: Immunology Overview

Post by Dr Sarhan Mon Jan 07, 2008 10:21 am

Cells of the Immune System


Myeloid Cells


Neutrophils


Neutrophils are the first circulating phagocytic cells recruited to the site of infection and inflammation to ingest, kill, and digest pathogens. These cells are produced from myeloid stem cells in the bone marrow (Fig. 1-2). Neutrophils constitute the large number of leukocytes in the blood. After stimulation, mature neutrophils display more motility, adherence, phagocytic activity, and intracellular killing than any other type of cell (Fig. 1-5). Neutrophils persist in the circulation for only several hours. Then, they are either removed by the RES or migrate into inflammatory sites.
Immunology Overview Fig1_5

Figure 1-5. Development and function of neutrophils.
Adherence: The transmigration of leukocytes through the intercellular junctions of endothelium and their adherence to endothelium are dependent in part upon membrane glycoproteins such as LFA-1 and Mac-1. These belong to the integrin family of proteins and consist of alpha/beta heterodimers, which are restricted to leukocytes. Their beta-chains are identical, whereas the alpha-chain of each class of protein is distinct. Other adherence molecules distinct from integrins are L-selectin and ELAM-1.
Chemoattraction: Chemoattractants play a very important role in the recruitment and activation of leukocytes. The movement of leukocytes within the interstitium is largely adherence- independent and due mainly to hydraulic forces. Once neutrophils enter the interstitium, they may be further activated by chemoattractant agents released by invading microorganisms or produced by the host in response to injury. These chemoattractants include N-formylmethionyl peptides from bacteria, a proteolytic fragment of the fifth component of complement (C5a) (see section on complement system), an inflammatory mediator leukotriene B4 produced from the metabolism of arachidonic acid, and interleukin-8.
Opsonization: Molecules that coat the surface of foreign particles and are ligands for receptors on the surface of phagocytes (opsonins) aid in the ingestion of those particles (opsonization). Four major types of opsonins are fibronectin (a cold-insoluble globulin), specific IgG antibodies, and active fragments of the third component of complement, C3b and C3bi. The antibodies and complement fragments facilitate the adherence of microorganisms to neutrophils by binding to specific receptors in the external membranes of the leukocytes. Mac-1 not only aids in adherence but also in phagocytosis by its role as the C3bi receptor.
As a result of the membrane perturbation caused by foreign particles adhering to the external membrane of the phagocyte, a chain of events is initiated that culminates in the engulfment of the particle (i.e., phagocytosis or the formation of a phagosome), the fusion of the phagosome with primary (lysosomal or azurophilic) and secondary (specific) cytoplasmic granules, and the assembly of the major intracellular microbicidal system. The sequence of events is as follows. As the plasma membrane of the phagocyte invaginates, microfilaments accumulate in the nearby cytoplasm. Consequently, the invagination closes to form a phagosome. Simultaneously, a signal is transduced from the receptor-ligand complex through a guanine nucleotide binding protein to activate phospholipase-C in the plasma membrane. As a result, two secondary messengers are produced. The first, inositol triphosphate, stimulates the flux of intracellular calcium. The second, diacylglycerol, participates in the activation of protein kinase C and phospholipase A2. Primary granules contain a high content of acid hydrolases and proteolytic enzymes that inactivate or digest microorganisms; secondary granules contain lactoferrin, gelatinase, complement receptors CR1 and CR3, and an essential part of the intracellular killing machinery, cytochrome b558.
Microbicidal Mechanisms: Neutrophils produce chemicals that are capable of inactivating ingested microorganisms. Once neutrophils are activated, intracellular mechanisms are turned on that lead to the conversion of oxygen to superoxide and then to hydrogen peroxide in the presence of superoxide dismutase. The process includes the assembly of NADPH oxidase, and up-regulation of cytochrome b558 from membranes of specific granules. Hydrogen peroxide then reacts with chloride ions in the presence of myeloperoxidase to form chlorinated derivatives. In addition to the formation of microbicidal agents, simultaneously, primary and secondary granules extrude from the cell where they attack extracellular pathogens, or if the process is excessive, host tissues.
Eosinophils


Eosinophils play a major role in the killing of parasites, particularly hemoflagellates, echinococcus, and enteric nematodes. This killing is due to a basic protein and a cationic protein contained in large cytoplasmic granules that are unique to eosinophils. These cells also play a prominent role in the pathogenesis of the allergic inflammation. These cells are induced to grow and differentiate by interleukin-5 and are recruited to inflammatory sites by agents such as platelet-activating factor from the lipoxygenase segment of the arachidonic acid pathway.
Basophils


Basophils and their tissue counterparts, the mast cells, play a major role in defense against parasites and in allergic inflammation. These cells are distinguished by many large cytoplasmic granules that contain heparin and histamine and by high affinity receptors for IgE antibodies. If these cell bound IgE antibodies are cross-linked by antigens, the cells degranulate and are activated to produce and secrete a group of low-molecular weight vasoactive mediators and certain proinflammatory cytokines, e.g. tumor necrosis factor alpha (TNF-alpha) and interleukin-5 (IL-5).
Monocytes and Macrophages


Some functions of macrophages such as phagocytosis and intracellular killing are similar to those of neutrophils, whereas others are distinct. The distinctive features are as follows: a) They are able to reside in the RES for long periods. b) They process protein antigens and present the resultant peptide fragments to T cells in the context of MHC class II molecules. They produce cytokines (Table 1-2). These cells are also highly adherent, motile and phagocytic. These properties are greatest in activated macrophages, somewhat less in unstimulated macrophages, and least in monocytes. The role of these cells in processing and presenting antigens is dealt with in the next section.
Monocytes and macrophages are activated by bacterial products such as endotoxin (lipopolysaccharides); autocrine agents, such as TNF-alpha, IL-1, and IL-8; cytokines such as interferon-gamma (IFN-gamma) and a special group of mediators called chemokines. Activated macrophages play a prominent effector role in cellular immunity by 1) ingesting and killing pathogens, 2) clearing immune complexes, and 3) aiding in the genesis of specific immune responses by antigen presentation.
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Post by Dr Sarhan Mon Jan 07, 2008 10:23 am

Lymphoid Cells


These cells are responsible for the development and maintenance of specific immunity. Lymphocytes are comprised of three separate populations, T cells, B cells, and NK cells, each of which express different phenotypic and functional properties (Fig. 1-3). Two major types, T and B cells, produce and express specific receptors for antigens.
T Lymphocytes


T lymphocytes are thymus-derived lymphocytes and play a central role in the generation and regulation of the immune response to protein antigens. T cells originate from bone marrow stem cells (Fig. 1-2) that develop into T precursor cells that migrate to the thymus where they multiply and differentiate (Fig. 1-6). The rate at which the thymus produces T cells is very high in childhood and declines thereafter. Because mature T cells are long lived and recirculate (Fig. 1-7), they comprise about 70-80% of lymphocytes in blood and lymph, and they are responsible for much of the immunologic memory.
Immunology Overview Fig1_6

Figure 1-6. Ontogeny of B and T lymphocytes.
Immunology Overview Fig1_7

Figure 1-7. Lymphocyte circulation pathways. T cells are principally recirculating; B cells are principally sequestered in peripheral lymphoid organs.
Maturation: The maturation of T cells takes place in the thymus and is characterized by a sequential appearance of certain cell surface molecules. Among the first surface molecules to appear are CD3, T cell receptors (TcR), which are alpha/beta positive (Fig. 1-Cool ; CD4; and CD8. Thus immature thymocytes are CD3+CD4+CD8+. Cortical T cells lose either CD4 or CD8 molecules to become CD3+TcR+CD4+ or CD3+TcR+CD8+. Mature T cells migrate to the medulla of the thymus from where they exit into the systemic circulation.
Immunology Overview Fig1_8
Figure 1-8. The TcR-CD3 complex on helper (CD4+) or cytotoxic/suppressor (CD8+) T cells. The TcR receives peptide fragments from antigen presenting cells. CD3 is a signaling molecule.

The TcR recognizes protein antigen determinants that are presented by MHC molecules (see below). In addition, TcR are physically associated with CD3. This association with CD3 is required for transmembrane signaling that culminates in T cell activation.
Role of MHC in T Cell Development: One major function of MHC molecules is to present antigens to T cells. Lymphocytes in the thymus are exposed to various endogenous (self) proteins, particularly the products of MHC (see below). Some nascent T cells that have specificity towards self MHC molecules are eliminated (negative selection), while remaining T cells become "educated" to recognize foreign antigenic peptides that are associated with self MHC (positive selection). Thus, antigen recognition by T cells becomes "MHC restricted," that is, the mature T cell recognizes its specific antigen only if that antigen is presented by the correct MHC molecule.
Two kinds of MHC genes, class I and class II (see Fig. 1-9 for their protein products) (see section on MHC), are involved in the development of T cells. In the course of selective adaptation, T cells learn to recognize foreign antigens in association with protein products of either MHC class I or II genes. MHC class I-restricted T cells express CD8 molecules that bind to the invariant portion of MHC class I, whereas MHC class II-restricted T cells express the CD4 molecule that binds to MHC class II molecule. Thus, mature T lymphocytes leaving the thymus are either CD4+ or CD8+ (single positive) and express CD3 and TcR molecules.
Immunology Overview Fig1_9
Figure 1-9. Structures of MHC class I and II molecules. Binding sites in the molecules are shown for processed protein antigens for presentation to T cells. Leters N and C represent N and C termini of the polypeptide, respectively.

T-Cell Subpopulations: Both CD4 and CD8 molecules participate in T cell activation. CD4+ T cells are principally regulatory cells, which control the functions of other lymphocytes. Based on the lymphokines they produce, CD4+ Th cells are divided into two subsets, namely Th1 cells that promote cellular immunity (Fig. 1-10), and Th2 cells that help antibody production (Fig. 1-11). CD8+ T cells are cytotoxic/suppressor cells which participate in cell-mediated immunity against viruses, fungi, bacteria, and against certain tumors and play a role in immune regulation.
Immunology Overview Fig1_10

Figure 1-10. Genesis of cellular immunity and T-cytotoxic cells by activation of Th1 cells.
T Helper (Th) Cells: These cells are involved in the regulation of both T cell and B cell- mediated immune responses. IgG, IgA, and IgE antibody responses against T-dependent antigens require Th2 cells. Th2 cells aid antigen-activated B cells to proliferate and differentiate into antibody-producing plasma cells and to undergo class switching (Fig. 1-11). They recognize foreign antigens complexed with MHC class II molecules on antigen-presenting cells (B cells, macrophages, dendritic cells and Langerhans cells).
Immunology Overview Fig1_11

Figure 1-11. Immunoglobulin isotype switching. Reconfiguration of genes for IgM to IgA while retaining the same antigen binding specificity. According to which switch sites combine, the intervening DNA is looped out and eventually deleted. In this illustration, an IgA antibody gene containing VDJ genes and C-alpha gene is formed.
Antigens are presented to Th2 cells in two ways. In the first (Fig. 1-12), the antigen is taken up and processed by accessory cells, such as macrophages or B cells, that present the Ag/MHC complex to Th2 cells. Activated T cells then produce lymphokines that recruit and activate B cells to produce antibodies. Unlike phagocytic cells, B cells bind the antigen by specific antibodies, then they internalize and process the antigen (Ag), and express a fragment of it bound to MHC class II molecules on the cell surface in the context of MHC class II molecules. Antigen-specific Th2 cells that bind the Ag/MHC complex on the antigen-presenting cells become activated and produce helper factors for adjacent B cells. Furthermore, macrophages may process and present antigens without MHC products to B cells or, in the case of complex polysaccharides, the antigen may be presented directly to B cells (Fig. 1-12) without the aid of other cells. Which pathway is used depends on the nature of the antigen.
Immunology Overview Fig1_12

Figure 1-12. Antigen presentation mechanisms.
Helper T cells (Th1) also aid effector T lymphocytes (vide infra) in cell-mediated immunity. This process occurs according to the pathway depicted in Figure 1-12, except that the recipients of the helper factor are effector T cells.
B and T cells require different cytokines for growth and differentiation. The pattern of the production of those particular factors define whether the cells are Th1 or Th2. For example, Th1 cells produce IFN-gamma, a cytokine that activates macrophages. Those activated macrophages in turn participate in delayed hypersensitivity, a major aspect of cell-mediated immunity (Fig. 1-10). In contrast, Th2 cells produce cytokines such as IL-4 and IL-10, which activate certain phases of antibody production and inhibit the genesis of delayed hypersensitivity.
Delayed Hypersensitivity: Cell-mediated antibacterial resistance (delayed hypersensitivity) is mediated by CD4+ Th1 cells in concert with macrophages. T cells activate macrophages via the production of IFN-gamma and other lymphokines. Initially, antigen-specific Th cells migrate to the site of infection. After activation by antigen, the cells produce a myriad of cytokines that attract and activate monocytes, macrophages, and other lymphocytes. If the infection is not resolved promptly (as in Mycobacterium tuberculosis infection), it could lead to chronic inflammation or even to granuloma formation.
Suppressor T Cells: These cells are involved in antigen-specific suppression and thus play an important role in maintenance of self-tolerance. T suppressor cells are less well understood than Th cells. T-suppressor lymphocytes are usually CD8+.
Cytotoxic T Cells: These cells destroy virus-infected cells and certain types of tumor cells in an antigen-specific manner. Cytotoxic T cells (CTL) (Table 1-1) are usually CD8+ and MHC class I-restricted. Recognition of endogenous foreign peptide (i.e., viral antigenic peptide) in the context of MHC Class I molecule by TcR of CD8+ cells, stimulates the CD8+ cells to become CTLs. The CTL killing is antigen-specific and MHC class I restricted (i.e., target cells infected by a different virus or infected cells that do not express the correct MHC class I molecule are spared). Th cells could also influence the CTL function.
In special cases, alloreactive (reactivity against foreign histocompatibility antigen) CTL recognize and kill target cells expressing a foreign MHC molecule, as found in MHC-incompatible tissue transplants.
Natural Killer Lymphocytes


These cells provide innate protection by killing tumor cells and cells infected with intracellular pathogens. Natural killer cells are large granular lymphocytes that do not express CD3, TcR, or immunoglobulins (Table 1-1), but display a low-affinity surface receptor for the Fc fragment of IgG (CD16; e.g. CR3) and CD56 (Fig. 1-3). Natural killer cells account for 10-15% of blood lymphocytes and are found in low numbers in the peripheral lymphoid system.
Natural killer cells regulate certain aspects of T and B cell activation and hematopoiesis, and they defend against certain tumors and intracellular infections by killing the involved cells. In contrast to cytotoxic T cells, the NK cell-mediated cytotoxicity neither requires previous sensitization nor is MHC-restricted. The cytotoxicity of NK cells is increased after exposure to cytokines such as IL-2 or IFN-gamma. NK cells also mediate antibody-dependent, cell-mediated cytotoxicity via the CD16 Fc receptor. NK cells can be activated to produce cytokines (IL-2, IFN-gamma, IFN-alpha, TNF-alpha) that aid in immunomodulation.
B Lymphocytes


These cells are primarily involved in antibody production and antigen presentation to T cells. B cells originate from lymphoid stem cells in the fetal liver and the bone marrow (Fig. 1-2). B lymphocytes are thymus-independent cells that express intrinsically produced immunoglobulins (vide infra) on their external membranes and upon stimulation by antigen differentiate into plasma cells that produce and secrete large numbers of antibody molecules (Fig. 1-6). Pre-B cells, the immediate precursors of B cells, are restricted to the bone marrow and are characterized by the presence of cytoplasmic µ chains (H chains for IgM) but no L chains. Mature but unstimulated B cells express monomeric IgM antibodies, MHC class II molecules, CD19, CD20, the Epstein-Barr virus/C3d (CR2) (CD21) receptor, and T cell interaction molecules, B7-1, B7-2, and the CD40 ligand, CD39 (Fig. 1-13). B cells account for 10-15% of blood lymphocytes. They, and their progeny, antibody-producing cells, primarily reside in peripheral lymphoid organs.
Immunology Overview Fig1_13

Figure 1-13. Surface markers on B cells.
Each B cell expresses and produces immunoglobulin molecules of one antigen-binding specificity. Clones expressing different specificities are involved in the production of antibodies to a complex immunogen because of the multiplicity of antigenic determinants (epitopes) on the molecules. Hence, many separate clones of B cells are required to produce the overall antibody response (a polyclonal response). If the immunogen has a very limited set of epitopes, the antibody response will be oligoclonal or monoclonal.
Development: The development of B cells from stem cells through mature B cells is antigen-independent. Antigen is, however, the initial trigger for B cells to transform into antibody-producing, secretory plasma cells. After antigens bind to immunoglobulins on the cell surface, the antigens are internalized and processed. This antigen/receptor interaction sends the first biochemical signal for the B cell activation. In the case of proteins, a fragment of the antigen is transported to the surface where it is expressed in a complex with MHC class II molecules. This allows B cells to interact with antigen-specific helper T cells. Consequently, cytokine receptors are expressed on the B cell surface and T cells are activated to produce cytokines, such as IL-2, IL-4, IL-6, and IL-10 (Table 1-2), that further stimulate proliferation and differentiation of B cells. In addition, certain bacterial products (generically called mitogens) such as lipopolysaccharides, activate B cells to proliferate regardless of their antigen specificity. That results in a non-specific polyclonal antibody response.
Isotype Switching: B lymphocytes switch their immunoglobulin production from IgM to IgG, IgA, or IgE, during the course of immune response against T cell-dependent antigens. Lymphokines from T helper cells are necessary for the class (isotype) switch that occurs in antigen-stimulated B cells. These events in B-cell differentiation are accompanied by immunoglobulin gene rearrangements, which will be described later in this chapter (Fig. 1-14). As a result of the recombination of the same VDJ genes with a different C region gene, a different isotype of immunoglobulin with the same antibody specificity is produced (Fig.1-11). Once the mature B cell encounters the appropriate antigen, the cell differentiates to form a plasma cell. Plasma cells are characterized by a lack of surface membrane immunoglobulin, but have an extensive production and secretion of antibodies of one isotype and specificity for a single epitope (idiotype).
Immunology Overview Fig1_14

Figure 1-14. Antibody diversity is principally generated by immunoglobulin gene rearrangement. H-chain gene rearrangement is depicted.
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Immunology Overview Empty Re: Immunology Overview

Post by Dr Sarhan Mon Jan 07, 2008 10:24 am

Immunoglobulin Supergene Family


The immunoglobulin supergene family is a group of structurally similar glycoproteins, which mediate antigen recognition and cellular interactions. They are derived from a family of genes which evolved from a common primordial gene. The products of these genes are transmembrane glycoproteins characterized by a common structural motif of functional domains. Some important members of this immunoglobulin supergene family are the immunoglobulins, MHC, TcR, secretory component, and adherence proteins such as ICAM-1.
Immunoglobulins


Structures


The basic structure of all immunoglobulin molecules consists of two identical L chains and two identical H chains (Fig. 1-15). The antibody molecule consists of three major domains connected by a hinge region. As shown in Fig. 1-15, digestion of antibody molecule with a proteolytic enzyme-papain results in the separation of these three domains. Two domains are identical and are called fragment antigen binding (Fab), and the third domain is called fraction crystallizable (Fc). However, treatment with proteolytic enzyme pepsin results in a fragment that contains both antigen binding arms (Fab')2 and several pieces of the Fc fragment. Fab interact with the antigen, and Fc bind to Fc-receptors on different cells.
Immunology Overview Fig1_15

Figure 1-15. Prototypic structure of immunoglobulins. The complementarity regions (e.g., antigen receptor sites that make specific contact with ligands) sites of the V region are shown in the insert.
Various forms of immunoglobulins such as IgG and IgE are found as monomers, secreted IgA as dimers and IgM as pentamers (Fig. 1-16). Consequently, two distinct regions of the assembled immunoglobulin occur: the first, which binds to an antigenic determinant and the second, which has other functions, such as binding to special cells and the first component of complement. The two H chains and each H chain and L chain are linked by disulfide bonds. Each chain is divided into two regions: the C region at the carboxyl-terminus and the variable region at the amino-terminus. The C region of each L chain consists of about 107 amino acids and has an invariant structure except for isotypic features (kappa or lambda) and allotypic variants (e.g., molecular structures that are individually inherited). V and C regions of H chains are further divided into domains characterized by folding of the polypeptide chain into 110 amino acid loops. V regions of H and L chains display great variability in the sequence of amino acids. Localized areas of these hypervariable regions of H and L chains interact to form antigen binding sites (i.e., CD1, CD2 and CD3; Fig. 1-15). In contrast, C regions of H chains dictate other functions of immunoglobulins, including binding to cell surface receptors. Eight immunoglobulin isotypes, IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgD, and IgE, are produced by B cells as a result of rearrangements of V genes for H chains (VH), D genes for H chains (DH), J genes for H chains (JH), V genes for L chains (VL), J genes for L chains (JL), and C region genes (vide infra) The special properties of each immunoglobulin class are as follows (Table 1-3).
Immunology Overview Fig1_16
Figure 1-16. Diagram of various forms of immunoglobins; IgG and IgE are found as monomers, secreted IgA as dimers and IgM as pentamers. Dimers and pentamers are held together by the J chain.
Immunology Overview Tbl1_3

IgG: IgG is a monomeric, four-chain structure consisting of two gamma heavy chains and two kappa or lambda light chains. The C region of the H chain of the molecule consists of three domains. Inter-chain disulfide linkages between the Cgamma1 and Cgamma2 domains stabilize the structure and define the hinge region of the molecule. IgG is the dominant immunoglobulin in extracellular fluids and is the only immunoglobulin transported across the placenta, and directly acts as an opsonin.
There are four subclasses of IgG, each of which displays unique antigenic determinants on the C region of the H chains. The approximate proportion of each subclass in blood is IgG1, 70%; IgG2, 20%; IgG3, 8%; and IgG4, 2%. The antibody specificities are distributed in somewhat specific patterns in each subclass. Neutralizing antibodies to protein toxins are mostly found in IgG1, antibodies to polysaccharides in IgG2, and antibodies to viruses in IgG3.
IgM: IgM is a pentamer of 4-chain units that are bound to a separate peptide called the J chain. IgM molecules consist of µ H chains and kappa or lambda L chains. Monomeric IgM is the principal antigen receptor on B cells. IgM is found principally in blood, but also occurs in external secretions. It binds most efficiently the C1q subunit of the first component of complement (vide infra), and is the first immunoglobulin expressed in B cell development.
IgA: IgA consists of a heavy chains and kappa or lambda light chains. There are two principal molecular forms of IgA, monomers whose basic structure and numbers of domains are similar to IgG and dimers that bind to J chains. Monomeric IgA, the second most common immunoglobulin in adult serum, is primarily produced by plasma cells in the bone marrow, whereas dimeric IgA, the dominant immunoglobulin in external secretions, is produced by plasma cells at mucosal sites.
Dimeric IgA is complexed and transported with a secretory component to form secretory IgA (Fig. 1-17). Dimeric IgA binds to polymeric immunoglobulin receptors (secretory component) on the basolateral membranes of epithelial cells; the complex is internalized and transported across the cells in an endocytic vesicle to the apical pole of the cell where it is secreted as secretory IgA. The addition of a secretory component not only facilitates the transport of dimeric IgA, but protects the molecule from proteolysis.
Immunology Overview Fig1_17
Figure 1-17. Assembly and secretion of secretory IgA.

There are two subclasses of IgA, IgA1 and IgA2. IgA1 predominates in the blood; there is an equal distribution of the two subclasses in external secretions. IgA2 is more resistant than IgA1 to bacterial IgA proteases that attack the hinge region of the molecule.
IgD: IgD is a monomeric four-chain polypeptide structure that is similar to IgG but its heavy chain (delta) is unique. Although this protein is expressed along with monomeric IgM on mature B cells, only small amounts of it are found in extracellular fluids.
IgE: IgE is also a four-chain polypeptide structure that is similar to IgG, but its heavy chain (epsilon) is distinct. Only trace amounts of this immunoglobulin are found in serum. IgE binds avidly to circulating blood basophils and mast cells in the submucosal sites and the skin. Cell-bound IgE antibodies defend against tissue parasites and initiate the pathogenesis of immediate hypersensitivity by triggering the release of low-molecular weight vasoactive compounds, including histamine, leukotrienes, and platelet-activating factor and certain proinflammatory cytokines such as TNF-alpha and IL-5, once they are cross-linked by antigens.
Sequence of Antibody Formation

Initial exposure to an antigen results in the production of low affinity antibodies, but continued exposure to antigen leads to the production of high affinity antibodies. In the primary antibody response (the first immunization), B cells are activated to produce IgM antibody. By 3-5 days, specific antibodies, mainly of the IgM isotype, appear in the serum and the concentration (titer) increases until a peak is reached in 10-14 days (Fig. 1-18). Antibody titers then fall to preimmunization levels after some weeks. Upon reimmunization, there is a more rapid and extensive development of antibody-producing cells in regional lymph nodes, and many of them undergo an isotype switch to produce IgG or other immunoglobulin classes of specific antibodies. As a result, in most cases following re-immunization, serum antibodies are primarily IgG and have a greater affinity for antigens; also, the antibody titers are higher and persist for much longer periods.
Immunology Overview Fig1_18

Figure 1-18. Isotypes of serum antibodies in primary and secondary immunization.
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Immunology Overview Empty Re: Immunology Overview

Post by Dr Sarhan Mon Jan 07, 2008 10:25 am

Antibody Binding to Antigen


There are a number of important consequences of antibody binding to antigens, depending upon the nature of the antigen. These include the neutralization of adherence sites or toxins from bacteria, the formation of opsonins, and the activation of the classical pathway of the complement system for that purpose or to create other bioactive factors that enhance inflammatory reactions. 1) In the case of IgM, antigen-antibody complexes are created that most efficiently activate the classical pathway of the complement system and thereby lead to the formation of functional complement fragments including opsonins that facilitate the removal of the complexes by the RES. 2) IgG antibodies, which are the dominant immunoglobulins in extracellular fluids, neutralize toxins and viruses, opsonize particles for ingestion by phagocytes, or when complexed to antigens, activate the classical pathway of complement. 3) Secretory IgA antibodies defend mucosal sites by binding toxins and preventing adhesion of microbial pathogens. 4) IgE antibodies on the surface of mast cells and basophils play an important role in defense against parasites and development of immediate hypersensitivity as previously noted.
Genetic Basis of Antibody Diversity


Specific antibodies are generated as a consequence of immunoglobulin gene rearrangement, i.e., recombination of V, D, J, and C genes (Fig. 1-14). The immune system generates millions of different antibody molecules from the pool of V genes. Separate sets of V genes encode the variable domains of immunoglobulin H and L chains. The two chains are produced separately, but the mechanisms by which their diversity is achieved are similar in principle.
Light Chain Formation: Most antibody molecules use the kappa light chain. The kappa gene cluster consists of several hundred (~300) VL genes; a few J genes (~4) and one C gene. These germline genes are tandemly arranged on the chromosome and are transcriptionally inactive. As the B cell matures, genes are arranged (recombined) so that one V gene is joined to a J gene, and the rearranged VJ segment together with the C gene is transcribed. The portion of DNA between the joined segments is deleted, and the transcripts are processed by splicing to produce the messenger RNA for the L chain. kappa chains are encoded by a separate cluster of V, J and C genes, but the rearrangement and transcription are similar to that of the lambda chain. Any given B cell uses only one type of L chain to produce the immunoglobulin molecule. The L chain combines with the H chain during their transport from polyribosomes to the membrane.
Heavy Chain Formation: The H chain gene system has a design that is similar to that of light chain, but is slightly more complex (Fig. 1-14). In addition to ~ 1,000 VH genes, there are > 10 D genes and ~ 4 J genes. Furthermore, this genetic cluster has nine C genes that encode different immunoglobulin isotypes. The mature B cell (Fig. 1-14) rearranges its immunoglobulin genes, joins them together, and deletes the DNA between the joined segments. The rearranged VDJ gene segment is transcribed together with a Cµ or Cdelta gene, and this long transcript is spliced into VDJCµ or VDJCdelta messages resulting in the expression of IgM and IgD, respectively, on the B cell surface. Both immunoglobulin molecules use the same VDJ segment and, therefore, possess the same immunological specificity. The B cell is now ready to bind to a specific antigen and become further differentiated.
Generation of Antibody Diversity


Antibody diversity is generated by the following mechanisms.
Immunoglobulin Gene Rearrangements: 1) The joining of various V, D and J genes is entirely random that results in ~ 50,000 different possible combinations for VDJ(H) and ~ 1,000 for VJ(L). Subsequent random pairing of H and L chains brings the total number of antibody specificities to ~107 possibilities. 2) Diversity is further increased by the imprecise joining of different genetic segments. 3) Rearrangements occur on both DNA strands, but only one strand is transcribed (allelic exclusion). 4) Only one rearrangement occurs in the life of a B cell because of irreversible deletions in DNA. Consequently, each mature B cell maintains one immunologic specificity and is maintained in the progeny or clone. This constitutes the molecular basis of the clonal selection; i.e., each antigenic determinant triggers the response of the pre-existing clone of B lymphocytes bearing the specific receptor molecule. It also follows that deletion of the B cell clone results in immunologic unresponsiveness to the antigen.
Somatic Mutations: This mechanism leads to a fine-tuning of the antibody specificity after immunization. Rearranged VDJH, and VJL genes in the B cells are uniquely susceptible to point mutagenesis by enzymes that become activated following stimulation of the cell by antigen. The clonal progeny of an antigen-driven B cell thus produce antibodies that may differ in one or more amino acid positions in the regions of the protein that are responsible for antigen binding. Cells producing the mutant antibody with highest affinity for the antigen are preferentially stimulated and thus eventually dominate the response. Therefore, antibodies produced after repeated immunization commonly display numerous point mutations (derived by somatic mutations in B cells found in peripheral lymphoid organs) and have higher affinities for antigens (affinity maturation), as compared to antibodies produced in the primary immune response.
Antibody Function: Antibody molecules perform a number of important functions that are necessary for mounting an effective immune response against microbial pathogens. CH region genes encode the biological functions of immunoglobulins (Table 1-3). For example, IgM and IgG bind to the C1q subunit of C1, IgG crosses the placental barrier to the fetal circulation, and polymeric immunoglobulins, particularly dimeric IgA, are transported across epithelial cells into mucosal secretions.
To accomplish these functions, B cells switch their immunoglobulin isotype. The VDJ genes which are associated with Cµ or Cdelta, which are the original constant genes expressed in mature B cells, become associated with another C gene (Fig. 1-11). This has been termed the isotype switch, because the C gene determines the antibody isotype. The switch is accomplished by genetic recombination, whereby the VDJ gene segment is transferred from the Cµ/Cdelta junction onto another C region gene downstream (Fig. 1-11). Because the Cµ/Cdelta and other interposed genes are deleted, the switch is irreversible. The new antibody maintains the same L chain and the same VH region (encoded by VDJ), but has new properties determined by the acquired C gene. The isotype switch mechanism is promoted by physical interactions between T and B cells (for example, the binding of CD40 on B cells to its ligand on T cells) and by specific cytokines from T cells (for example, IL-5 and IL-10 promote IgA production; IL-4 promotes IgE production).
Furthermore, each antibody molecule may exist in either a membrane-bound or secreted form. Every C gene contains a 3' sequence encoding the hydrophobic cytoplasmic tail of the H chain, so that the immunoglobulin molecule produced by the B cell is inserted in the surface membrane to function as the receptor for antigen. When the B cell differentiates into a plasma cell, an enzyme is activated that modifies the RNA transcript. Consequently, the translated protein ends with a hydrophilic peptide and is secreted from the cell.
TcR


The specific receptor for antigen on T lymphocytes, the TcR (Fig. 1-Cool, is a heterodimeric protein with motifs that are similar to immunoglobulin molecules, but whose structure is encoded by a different set of V, J, D, and C genes. Moreover, T cells consist of two subsets carrying different receptors, that have been designated alpha/beta and gamma/delta.
A minority of T cells express a TcR consisting of gamma and delta chains and those cells are primarily CD4+. These chains are encoded by very few genes; the gamma/delta repertoire is accordingly very limited. The gamma gene cluster consists of seven V genes, two J genes, and four C genes. The delta genes are interspersed within a gene locus that appears to include 10 V genes, two D genes, two J genes, and one C gene. Mature gamma/delta T cells seem to migrate primarily to mucosal and cutaneous tissues. The functions of gamma/delta T cells are not yet understood. Moreover, the recognition of antigen by gamma/delta T cells are not MHC-restricted.
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Immunology Overview Empty Re: Immunology Overview

Post by Dr Sarhan Mon Jan 07, 2008 10:25 am

TcR alpha/beta


Most T cells express the alpha/beta type of TcR. The genomic organization of the alpha and beta genes is more complicated than that of the immunoglobulin genes. Indeed, although a locus genes are interspersed with genes for the delta TcR (vide infra), alpha and beta genes are rearranged and expressed at different times and on different T lymphocytes.
The smaller alpha chain is encoded in a gene cluster consisting of ~100 V genes, ~50 J genes (a high number compared to immunoglobulin J genes) and one C gene. The alpha chains of various binding specificities are generated by a random genetic recombination of one V and one J gene, which are then joined with Calpha, by a mechanism analogous to that of the immunoglobulin L chain. The heavier beta chain is encoded by ~ 30 V genes, two D genes, >10 J genes and two C genes. The random joining of one of each V, D and J genes and their rearrangement to one C gene is similar to the process described for immunoglobulin genes. Rearranged VJCalpha and VDJCbeta DNA encodes the alpha and beta chain transcripts, respectively.
TcR genes are rearranged as lymphocytes mature in the thymus. Mature T cells, which are released from the thymus, are irreversibly committed to recognize one specific antigenic epitope in complex with self-MHC molecule.
Generation of TcR Diversity: The combinatorial diversity of TcR is greatly increased by junctional diversity, i.e., the variability of the junctions between different VDJ genes. New nucleotide base pairs are often added at the junction. Indeed, the junctional diversity of TcR is several orders of magnitude greater than that of an immunoglobulin gene. On the other hand, rearranged TcR genes are not subject to somatic mutations that contribute significantly to the generation of antibody diversity. The lack of somatic mutations appears to be related to the fact that the alpha/beta T cells always recognize a complex of antigenic fragment with the self MHC molecule. The receptor mutation could divert the specificity towards self molecules.
CD3 COMPLEX


The TcR cannot bind to soluble antigens but they recognize antigenic peptides bound to MHC molecules (i.e. class I or class II). Even after TcR binds MCH-peptide complex, it cannot transmit optimal signal necessary for T cell activation. Intracellular signalling of T cells requires non-covalent association of TcR with cell surface CD3 complex (Fig. 1-Cool. The CD3 complex consists of four transmembrane peptides designated gamma, delta, epsilon, and zeta. The CD3 complex itself does not recognize the antigen and does not have variable domains. However, the CD3 complex transmits the biochemical signals generated by the TcR/antigen/MHC interaction on the surface that lead to lymphocyte activation.
Major Histocompatibility Complex (MHC)


General Features: These molecules play a very important role in the recognition of self and non-self antigens by T cells. The MHC consists of a cluster of >100 genes on chromosome 6 that encode a number of biologically important molecules (Fig. 1-9). These molecules are responsible for the rejection of tissue grafts by genetically disparate individuals, as the name histocompatibility indicates. These molecules present antigens to T lymphocytes; govern interactions between T cells, B cells and accessory cells; and control the intrathymic development of the TcR repertoire against foreign antigens (positive selection) and against self (negative selection) Human MHC protein products are called human leukocyte antigens (HLA).
Genes and Structures: The two most important HLA glycoproteins are designated as class I and class II molecules (Fig. 1-9).
MHC Class I/II Molecules: MHC class I molecules are ubiquitous on somatic cells whereas MHC class II molecules are restricted to monocytes, macrophages, dendritic cells, B cells, Langerhans cells, keratinocytes, activated T cells and certain types of epithelial cells. MHC class I molecules have three extracellular domains (alpha1, alpha2 and beta1), and a cytoplasmic tail. In contrast, MHC class II molecules have four extracellular domains (alpha1, alpha2, beta1 and beta2).
Three genes encode three independently expressed MHC class I molecules: HLA-A, -B and -C. Each gene contains three exons for the domains 1, 2 and 3. The MHC class II cluster, HLA-D, also contains three distinct genes, DP, DQ and DR, each of which has a separate set of exons for the alpha and beta chain.
MHC Alleles: An important aspect of the HLA gene system is its polymorphism. Each gene, MHC class I (A, B and C) and MHC class II (DP, DQ and DR) exists in different forms, or alleles. HLA alleles are designated by numbers and subscripts. For example, two unrelated individuals may carry class I HLA-B, genes B5, and Bw41, respectively. Allelic gene products differ in one or more amino acids in the alpha and/or beta domain(s). Large panels of specific antibodies are used to type HLA haplotypes of individuals using leukocytes that express class I and class II molecules. HLA typing is used for matching donors and recipients for organ/tissue transplantation and to predict the risk of certain diseases . In addition, the polymorphism of HLA genes has major implications for the function of class I and class II molecules (vide infra).
Role in Antigen Presentation: MHC molecules are required for antigen presentation to T cells (Fig. 1-12). Peptides associated with MHC class I and class II molecules are recognized by CD8+ and CD4+ T cells, respectively. Foreign protein antigens are taken up by various types of cells in the body, internalized and subjected to enzymatic degradation called antigen processing. Antigenic peptide fragments bind to MHC class II molecules and are then transported to the cell surface. This MHC/antigen complex is recognized by the TcR on CD4+ T cells. A CD4+ T cell activated by an appropriate class II/peptide antigen complex on an antigen-presenting cell, such as a B cell or macrophage, may become a helper cell for antibody or cell-mediated immune responses.
A different scenario is found for viral antigens in infected cells or tumor antigens. These antigens are processed to fragments, which are expressed in association with the class I molecule. The MHC class I/antigen complex is recognized via the TcR by CD8+ T lymphocytes, which become activated and differentiate into CTLs that destroy infected cells.
Variable domains of MHC class II molecules encoded by some allelic genes may be unable to bind a given antigenic peptide and thus fail to present the peptide to antigen-specific T cells. As a result, an immune response to this antigen cannot be mounted. Because of the association of high and low responses to a specific antigen with particular MHC class II alleles, MHC genes have been termed immune response genes. HLA typing reveals that individuals carrying certain alleles are at a higher risk of developing diseases such as ankylosing spondylitis, myasthenia gravis or type I diabetes mellitus. It is likely that this association reflects an underlying immunopathologic reaction involving MHC class I/II molecules or an association with other genes in the MHC.
MHC products control the selection of the immune repertoire of T lymphocytes. T cells interact with MHC class I/II molecules during their maturation in the thymus. This interaction kills immature cells whose TcR have a high affinity for self-MHC or for an MHC/self-protein complex by a mechanism called apoptosis or programmed cell death. Potentially autoreactive T cells would be eliminated in this fashion (negative selection). Furthermore, the selection process by MHC molecules determines the T cell repertoire of the individual against various foreign antigens (positive selection). This negative and positive sorting of T cells is called thymic selection.
T Cell Activation: Although, the presentation of antigen in the context of MHC molecules is essential for T cell recognition of peptide antigens, interactions between the MHC-bound peptide and TcR and the MHC class I or class II molecules, respectively, with CD8 or CD4 is not sufficient to activate T cells. Other ligands on antigen-presenting cells and their receptors on T cells are required to complete the process. These ligand-receptor interactions include the ligands ICAM-1, LFA-3, and B7-1/2 on antigen-presenting cells binding to their receptors LFA-1, CD2, and CD28/CTLA-4, respectively, on T cells (Fig. 1-19). These and other counterstructures for B7-1 and B7-2 appear to precisely control the extent of T cell activation.
Immunology Overview Fig1_19
Figure 1-19. Ligand-receptor interaction necessary for optimal T-cell activation. The requirements for CD8+ T cells are the same except for interactions between MHC class I molecules and CD8 molecules.

Recognition of Self and Immune Tolerance


Self Tolerance


The immune system has evolved to distinguish between self and non-self antigens and to largely eliminate self-reactive lymphocytes. Because the repertoire of immune specificities is vast and largely random, it is not surprising that many nascent lymphocytes possess receptors for self-antigens. The mechanism of intrauterine tolerance is not well understood, but much has been learned about the mechanisms for excluding or inactivating self-reactive lymphocytes, particularly by using the model of experimentally induced immune tolerance to foreign antigens. When an antigen is introduced into immunologically immature newborn animals, they may, upon reaching maturity, become unresponsive to immunization with that antigen (neonatal tolerance). This immunological tolerance is characterized by the absence of both antibody and cell-mediated responses, and it is specific for the original antigen.
Subsequent experiments revealed that the induction of antigen-specific tolerance is not always restricted to immature organisms. Unresponsiveness can also be induced in adults by using relatively higher doses of soluble antigen (high dose tolerance). The induced state of unresponsiveness to the antigen is sometimes accompanied by the appearance of suppressor T cells that actively and specifically inhibit the responses of B and T cells. Recent studies also reveal that IgM+IgD- B cells and mature T lymphocytes may be directly inactivated by small doses of antigen in vitro (low dose tolerance). In that model, short exposure of lymphocytes to the antigen, either at a critical concentration or in a certain modality, leads to an inactivation rather than a stimulation of the cells.
Collectively, the experiments on tolerance induction demonstrate that the unresponsiveness to self is likely to be achieved at several levels. During normal development, the self-reactive lymphocyte clones may be inactivated or deleted by exposure to self macromolecules during the early stages of maturation in the thymus (Fig. 1-6). The autoselection is dependent upon MHC class I molecules for CD8+ T cells and class II molecules for CD4+ T cells. Those cells that are not eliminated and reach their full immunological potential may be inactivated, when self molecules are presented to these cells at high concentrations or in a form that is tolerogenic rather than immunogenic. Also, it is possible that some self-reactive lymphocytes are suppressed by other regulatory cells, such as CD8+ suppressor T cells.
Autoimmunity


The failure of any of the mechanisms involved in self recognition and elimination or down regulation of self-reactive clones may result in autoimmunity. Autoimmune disorders in genetically prone individuals may be generated by a) changes in the expression of self macromolecules or alterations in their presentation to lymphocytes, b) release of sequestered self-antigens into the circulation, or access of immunogens to normally immunologically privileged sites, and c) alterations in lymphocyte maturation and immune regulation. In addition, foreign antigens such as bacteria and viruses that cross-react with self antigens may augment or initiate any of the above mechanisms.
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Immunology Overview Empty Re: Immunology Overview

Post by Dr Sarhan Mon Jan 07, 2008 10:26 am

The Complement System


The complement system consists of a group of glycoproteins in the extracellular space that can be stimulated in a cascading fashion to produce biologically active fragments that either directly attack foreign substances or enhance the functions of certain types of inflammatory leukocytes. The complement system consists of two recognition-stimulation pathways that are designated as the classical and alternative pathways, either of which may lead to the formation of a cell membrane attack complex (Fig. 1-20).
Immunology Overview Fig1_20
Figure 1-20. The complement system. Activation of either wing of the system leads to the formation of peptide fragments that function on leukocytes and forms the membrane attack complex.

The Classical Pathway


The classical pathway of the complement system may be activated by antigen-antibody complexes of the IgG, IgG3, or IgM isotypes by their binding to the C1q subunit of the first component of complement (Fig. 1-20). Consequently, the C1qrs subunits of C1 form an esterase that cleaves the next component, C4, to two fragments, the larger of which, C4b, binds covalently to hydroxyl or amino groups on cellular membranes. The next component, C2, after binding to C4b is partially digested by C1s esterase to form C2b. The resultant membrane-bound complex, C4b2a, is an enzyme (C3 convertase) that cleaves C3 into two biologically active fragments, C3a and C3b.
The Alternative Pathway


The alternative pathway of the complement system is activated independently of antigen-antibody complexes (Fig. 1-20). The major exogenous activators of the pathway are microbial agents and their products. The major components of the pathway are the serum protein factors B, D, and P (properdin). A small amount of C3 in the fluid phase, which normally is spontaneously activated, interacts with factor B to form C3Bb, which cleaves other C3 molecules to form C3b. C3b in turn attaches to surfaces and binds factor B. The resultant C3bB is then cleaved by factor D to form C3bBb, the C3 convertase of the alternative pathway. That enzyme is distinct from the one generated from the classical pathway but serves the same purpose. This complex then is stabilized by factor P.
The binding of C3 to factor B is prevented, particularly in the fluid phase, by a regulatory molecule, factor H. The more vigorous activation of this pathway occurs when the host is exposed to microorganisms that are poor in sialic acid. In those circumstances, the binding of factor B to C3 is favored, and the activation of the alternative pathway is not readily inhibited by factor H. Therefore, more C3b is generated and a positive amplification loop that generates more C3bBb (C3 convertase) is created. In contrast, sialic acid-rich encapsulated microorganisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Niesseria meningitides are incapable of activating the alternative pathway and require binding to specific IgG or IgM antibodies to activate the classical pathway and generate the C3b for phagocytosis and the formation of the membrane attack complex. The receptors for activated complement fragments are 1) CR1, principally on phagocytic cells for C3b; 2) CR2, principally on B cells for a fragment called C3d (receptor for EBV); and CR3 (Mac-1), on phagocytic and NK cells for inactivated C3b (C3bi) and C3d-g fragments.
The Membrane Attack Complex


The activation of the complement system eventually leads to the formation of the membrane attack complex that consequently lyses cells. The membrane attack complex is formed in the following manner. As a result of the formation of C3b, C5 is cleaved into two fragment, C5b and C5a. The larger fragment, C5b, combines with C6 and the complex attaches to the cell surface, where it forms the foundation for the sequential binding of C7, 8 and 9, e.g., the membrane attack complex (Fig. 1-20). C3b and its degradation product, C3bi, are opsonins. C3a and C5a are chemotaxins and anaphylotoxins; C5a is the more potent of the two factors.
Once the membrane attack complex is formed, discrete holes are created in the surface membranes of the target cells. Consequently, extracellular fluid accumulates in the target cell, eventually leading to its lysis.
Defense Against Infections


Cutaneous and Mucosal Defense


The first line of defense against most potential pathogens is the skin and mucous membranes. In addition to anatomic barriers, certain protective biochemical agents are produced at mucosal sites. These include simple chemicals such as acids and bases, and macromolecular proteins, including lysozyme, lactoferrin, secretory IgA antibodies, and interferons.
The genesis of secretory IgA antibodies is as follows. Under the influence of IL-5, IL-6, and IL-10, B cells bearing surface IgM in Peyer's patches and in the submucosa of the tracheo-bronchial tree switch to IgA-bearing cells. When the surface antibodies of these altered cells combine with a specific antigen, the cells are stimulated to migrate through afferent lymphatics to the regional lymph nodes and then through efferent lymphatic channels into the vascular circulation. They then home to submucosal sites in the upper small intestine, or to the respiratory system, where they differentiate into plasma cells that secrete large amounts of specific dimeric IgA antibodies and are transported across epithelial cells to the lumen by secretory component, as previously described. The resultant secretory IgA is particularly well suited to mucosal sites since it is more resistant than other types of immunoglobulins to the digestive processes of the alimentary tract. These antibodies protect by complexing adherence structures and toxins from microbial pathogens.
Activation of Local Immunity


The second line of defense consists of local factors and leukocytes that are activated or recruited to the site of microbial invasion. These local elements of defense include the coagulation system, the fibrinolytic system, kallikrein, the complement system, resident macrophages, and elicited inflammatory cells.
Activation of Systemic Immunity


If the pathogen is able to overcome the first two lines of defense, systemic acquired responses are marshalled to prevent further invasion and damage. This third line of defense includes intracellular killing by circulating phagocytes, stimulation of monokine production, interleukin production by T cells, production of circulating antibodies by plasma cells in regional lymph nodes and the spleen, intravascular activation of the complement system, and phagocytosis of opsonized pathogens by cells of the RES. Cytotoxic mechanisms directed against ingested microbes or infected cells play a major role in defense.
Unless the microbial inoculum is overwhelming, unusually virulent, or the host defenses are compromised, the infection should be contained and finally obliterated via a combination of local and systemic responses. At the same time local fibroblasts and epithelial cells proliferate, the tissue becomes more vascularized, and debris is removed by local tissue phagocytes. The inflammatory reaction abates and the tissue heals.
Diseases Due to Immune Responses to Infectious Agents


Five major types of immune responses to infecting agents may lead to disease. 1) Circulating immune complexes formed from microbial antigens such as hepatitis B virus bound to IgM or IgG antibodies, may deposit in skin, synovia, or glomeruli and elicit inflammation by activating the classical pathway of complement. 2) Invading microorganisms may give rise to antibodies that cross-react with autoantigens. For example, antibodies produced against Group A, beta-hemolytic streptococci in patients with rheumatic fever often react against sarcolemmal antigens in cardiac muscle. 3) Vasoactive compounds may be released into local tissues or the systemic circulation because of activation of the alternative pathway of complement by certain bacteria deficient in sialic acid such as Salmonella. 4) Cytokines such as TNF-alpha, IL-1, and IFN-gamma released during infection from stimulated macrophages and T lymphocytes, may lead to fever, dysregulate nutritional pathways, and contribute to the vascular instability seen in sepsis. 5) Finally, delayed hypersensitivity reactions that damage surrounding tissues occur in indolent infections such as tuberculosis by the formation of granulomas consisting of activated macrophages and cytotoxic T cells.
Ontogeny of Immunity


There is an orderly development of the immune system during the intrauterine period. Pluripotent stem cells appear first in the yolk sac, then in the fetal liver, and finally the bone marrow (Fig. 1-2). Neutrophils, monocytes, and macrophages are produced during fetal life, but the mononuclear phagocytes do not mature until after birth. An epithelial thymus appears during the first few fetal weeks and then becomes populated with lymphocytes. Mature T and B cells appear in the blood soon thereafter, but they are largely not activated. Furthermore, IgG antibodies are usually not produced until after birth, and IgG antibodies to polysaccharide antigens do not appear until ~ 2 years of age. In addition, there are developmental delays in the production of certain cytokines, including GM-CSF, IL-10, TNF-alpha and IFN-gamma.
Neonates have as many B and T cells in the peripheral blood as do adults, these cells in the peripheral lymphoid organs are not as well developed because of the paucity of prenatal antigenic stimuli. As antigen stimulation occurs, the T and B cell zones of the peripheral lymphoid organs are progressively populated and the products of these stimulated cells, such as antibodies, begin to appear. The sequence of immunoglobulin production is as follows: IgM production occurs first and is then followed by IgG and IgA. Systemic IgG antibodies to polysaccharides are not produced, however, until the child is 2 to 2.5 years old. The secretory component is produced at birth, but the main immunoglobulin in external secretions in the first few weeks of postnatal life is IgM. Subsequently, secretory IgA becomes the dominant immunoglobulin at mucosal sites.
Maternal Immunologic Agents Transferred to the Recipient Infant


The mother transmits immune factors to the offspring both through the placenta and milk. Large quantities of IgG are transmitted via the placenta, whereas other immunoglobulin isotypes are not. Consequently, virtually all IgG in neonatal blood is of maternal origin, the concentration of IgG in umbilical cord blood is somewhat higher than in adults, and the levels of other immunoglobulin isotypes are exceptionally low. Low concentrations of some factors such as IgG and secretory IgA antibodies are also transmitted via amniotic fluid, but little is known about their in vivo effects upon the fetal mucosal immune system.
An array of host resistance factors are transmitted to the infant in human milk, including leukocytes, secretory IgA, lactoferrin, lysozyme, and oligosaccharides and glycoconjugates that are receptor analogs for microbial adhesins and toxins. In addition to those antimicrobial factors, anti-inflammatory agents, and immunomodulating agents including TNF-alpha, TGF-beta, IL-1beta, IL-6, IL-8, IL-10, G-CSF, and M-CSF. These factors are designed to act at mucosal sites and to protect by noninflammatory mechanisms. Since the endogenous production of these agents is incompletely developed in early infancy and they are scarce in cow's milk or other substitute feedings, it is not surprising that breastfeeding increases resistance to gastrointestinal and respiratory infections, allergic diseases, and certain inflammatory diseases that occur much later in childhood.
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Immunology Overview Empty Re: Immunology Overview

Post by Dr Sarhan Mon Jan 07, 2008 10:27 am

Immune Deficiencies


Immune deficiencies may be due to genetic or acquired defects, and these defects lead to increased risks to certain infectious diseases depending upon the specific immune defects. Much of the basic information concerning the development and function of the immune system has been learned from investigations of inherited, congenital, and acquired defects of the system. Examples of the principal defects that have lead to an elucidation of the immune system are as follows.
Genetic Defects


The principal genetic defects in the immune system are summarized in Table 1-4. They are as follows.
Immunology Overview Tbl1_4

X-Linked Agammaglobulinemia: In this immunoglobulin deficiency disease, there is a genetic defect in the development of B cells from pre-B cells in the bone marrow. The defect is due to mutations in the gene that encodes for B cell tyrosine kinase. Consequently, the B cells are not produced. Because of the block in the development of B cells, germinal centers, plasma cells, and specific antibodies are profoundly reduced. The rest of the immune system is normal. Affected individuals are unusually susceptible to infection by virulent encapsulated respiratory bacteria and enteroviruses. These patients benefit greatly from intravenous infusions of human IgG.
Hyper-IGM Antibody Deficiency: A second X-linked defect in antibody formation, the hyper-IgM antibody deficiency, is characterized by a block in immunoglobulin class switching. Consequently, IgM (and IgD) antibodies are produced, but IgA and IgG antibodies are not. These patients are also unusually susceptible to infection by virulent encapsulated respiratory bacteria. The disease is due to mutation in the gene that encodes for CD40 ligand (CD39) on T cells. Because of the defect, T and B cell interactions are insufficient for immunoglobulin class switching. These patients also benefit greatly from intravenous infusions of human IgG.
Severe Combined Immunodeficiency (SCID): The most common type of SCID is due to stop codon defects in the X-chromosome gene that encodes for the gamma-chain that is common to IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. A more moderate combined immunodeficiency disease has been reported and is due to a missense point mutation in a part of the gene that encodes for the cytoplasmic region of that gene. In addition, other defects reported to cause SCID involve an autosomal recessive defect in the formation of adenosine deaminase, a defect in the formation of CD3, a defect in the post TcR-CD3 receptors' signalling, and deficiency in the formation of IL-2.
Patients with these diseases display few T lymphocytes, decreased T cell functions, poor antibody formation, and variable numbers of B cells and serum concentrations of immunoglobulins. As a consequence of the deficiencies in T cells, these patients are very susceptible to opportunistic pathogens, including Candida albicans, Salmonellae, Pneumocystis carinii, Cytomegalovirus, and Varicella zoster virus. Patients with SCID usually die before the age of two years, unless definitive immunologic interventions are instituted.
Specific treatments have been devised for patients with SCID. Many patients have been treated successfully with bone marrow transplants to supply normal stem cells. Patients with adenosine deaminase deficiency may also be managed by infusing the enzyme packaged with polyethylene glycol. Recently, some patients with adenosine deaminase deficiency have been successfully treated with gene therapy. Although the beneficial effects have not been permanent, nevertheless, they are encouraging.
Two major intrinsic defects in the function of phagocytic cells have been recognized. The first one is an autosomal recessive defect in the formation of the common beta-subunit of the family of adherence glycoproteins (integrins). The deficiency interferes with the ability of these leukocytes to adhere to the surface of endothelial cells. Consequently, the motility of these cells on two-dimensional surfaces is impaired. Thus, this defect results in bacterial infections in interstitial sites, such as in the skin and periodontium.
The second disorder, chronic granulomatous disease, was the first recognized genetic defect of the function of phagocytic cells. The disease is X-linked in ~ 70% of affected patients. In those cases, the gene for the gp90 protein subunit of cytochrome b558 is abnormal. Consequently, the protein is not produced, the cytochrome does not persist, and intracellular killing is impaired. Less frequently (~ 3% of cases), the disease is due to a defect in the autosomal gene for the lower molecular weight subunit of the heterodimer, p22phox. Autosomal defects in genes for cytoplasmic proteins that stabilize the cytochrome have also been recognized.
In these disorders, phagocytes are unable to mount a respiratory burst and therefore are unable to produce toxic oxygen compounds, such as hydrogen peroxide, which are required for intracellular killing of catalase-positive microorganisms such as Candida albicans, Escherichia coli, and Serratia species. The failure to kill catalase-positive microorganisms occurs because the microbial agents do not supply the oxygen substrates required for intracellular killing. In contrast, these dysfunctional neutrophils kill catalase-negative microorganisms such as the streptococci since those microorganisms bring hydrogen peroxide into the phagolysosome.
Acquired Defects


Protein-Calorie Malnutrition: Protein-calorie malnutrition is the leading cause of immune deficiency in the world. Protein-calorie malnutrition leads principally to a profound deficiency in the production and function of T cells, rendering the victim susceptible to many of the opportunistic infections that occur in genetic T cell deficiencies. With increasing protein-energy deficiency other parts of the immune system are also affected. Specific nutrient deficits such as iron or vitamin A deficiency also depress certain parts of the immune system.
Certain types of infections temporarily depress parts of the immune system. For example, many acute viral infections suppress cellular immunity for several days to a few weeks, and serious bacterial infections inhibit the ability of neutrophils to respond to chemotactic agents. Furthermore in schistosomiasis, Th1 responses are accentuated and Th2 responses are suppressed. This leads to a decreased ability to form antibodies after antigenic challenges.
Malnutrition and infection interact to inhibit the immune system. As a result of malnutrition, the immune system becomes compromised. That leads to respiratory and gastrointestinal infections. Those infections may in turn further interfere with the immune system. Moreover, some infections further compromise nutritional status by increasing nutrient losses (intestinal malabsorption) and utilization (fever, caloric expenditure during sweating) or by interfering with normal nutrient metabolic pathways (cachectic effect of TNF-alpha). Consequently, immune function is further impaired.
Human Immunodeficiency Virus Infections: A second acquired immunodeficiency is due to human immunodeficiency virus (HIV) infection. This retrovirus infection was first encountered in homosexual males and individuals who were injecting illicit drugs or who received blood products contaminated with the virus. The infection has since spread to heterosexual populations by sexual transmission. The infection has reached epidemic proportions in developed as well as developing countries and continues to increase. The resultant acquired immune deficiency syndrome (AIDS) occurs because the virus infects and destroys CD4+ T cells. The virus binds to the CD4 surface antigen on T cells and to the same or similar moiety on macrophages. Since CD4+ T cells are essential for the genesis of cellular immunity and for orchestrating the function of many other parts of the immune system, a deficiency in these T cells increases the patient's susceptibility to opportunistic infections. The vast majority of such infected patients die after several years. No preventative immunizations or curative treatments are available for the infection at this time.
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REFERENCES


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