Sunday, 14 July 2013



A. Immunogens, antigens, and haptens
1. Immunogens are chemical compounds that cause a specific immune response.
2. Antigens are chemical compounds that interact with products of the adaptive immune response. An antigen may have several antigenic determinants (epitopes).
3. Factors influencing immunogenicity of an antigen
a. In general, molecules recognized as “self ” are not immunogenic.
b. The most potent immunogens are usually large (> 5000 Da) proteins (Dalton (Da) is an alternate name for the atomic mass unit). Carbohydrates, lipids, and even nucleic acids can elicit an antibody response, although association with a protein improves immunogenicity (e.g., glycoproteins, lipoproteins, nucleoproteins).
c. Some low-molecular-weight molecules (haptens) become immunogenic only when linked to a carrier protein. Certain drugs (e.g., penicillin) as well as some environmental substances (e.g., pentadecacatechol of poison ivy) are known to be haptens.
d. Adjuvants are substances that enhance the immunogenicity of an antigen.
4. The term antigen may be used for compounds that are both immunogens and antigens.
B. The cells of the immune system are principally the white blood cells or leukocytes. These cells are derived from hematopoietic stem cells that originate in the bone marrow.

1. Granulocytes have prominent cytoplasmic granules containing reactive substances that kill microorganisms and stimulate other divisions of the immune response by activating inflammation.
a. Neutrophils (also known as polymorphonuclear leukocytes or PMNs because of their multilobed nucleus) are the most numerous white blood cells in the blood. They are particularly good at phagocytosis (the process of capturing, engulfing, and killing microorganisms). Neutrophils are rapidly recruited to sites of inflammation.
b. Eosinophils are granulocytes that are important for defenses against helminth worms and other intestinal parasites. They also play a role in allergies (hypersensitivity reactions) and asthma.
c. Basophils also participate in the defense against parasites, although that process is less well understood.
2. Monocytes are leukocytes that circulate in the blood; as they migrate into the tissue, they become resident tissue macrophages. Macrophages are phagocytic cells that rid the body of dead cells, cellular debris, and serve as sentinel cells for the early detection of infection and tissue damage. They also produce cytokines that activate inflammation, recruit leukocytes such as neutrophils and additional macrophages to the site of the infection, and assist in activating the adaptive immune response by serving as antigen-presenting cells for T cells.
3. Dendritic cells are branched or dendritic-shaped cells that are very effective for initiating T-cell responses. Dendritic cells are resident within the tissues of the body, where they are phagocytic. They then enter the lymphatics to travel to the local secondary lymph tissue, where they express additional adhesins for interaction with T cells and present the antigens from the peripheral tissues.

4. Mast cells are resident in all connective tissues. They possess granules that contain a number of preformed inflammatory mediators, including histamine and tumor necrosis factor (TNF)-a. Together with IgE, they are involved in type I hypersensitivity reactions.

5. Natural killer (NK) cells are large, granular, lymphocyte-like cells that function in the targeted killing of cells such as virus-infected cells and tumor cells.
6. Lymphocytes are the primary cells of the adaptive immune response. All B and T lymphocytes are antigen specific via antigen receptors on the cell surface. Lymphocyte antigen receptors structurally consist of globular protein motifs know as immunoglobulin (Ig) domains. Ig domains are characteristic of many cell surface and secreted proteins of the immune system. The terms B cell and T cell are used instead of B lymphocyte and T lymphocyte.
a. B lymphocytes (B cells) are primarily responsible for humoral immunity (antibody re– sponse). The antigen-specific receptor on the surface of the B cell is essentially a membranebound antibody molecule in association with accessory proteins (Iga and Igb), which together make up the B-cell receptor (BCR). The antibody is roughly “Y” shaped with the transmembrane region positioned in the stem of the “Y” and the antigen-binding region at the ends of the arms. (Antibodies will be further described later) Different B cells have different antigen specificity, but each B cell has only one specificity. Binding of the specific antigen stimulates the B cell for proliferation to form new B cells (clonal expansion) and differentiation into plasma cells, which secrete free-soluble antibody.
(1) Naive B cells have antigen-specific immunoglobulin on the surface but have not yet interacted with a specific antigen.
(2) Memory B cells are long-lived B cells that were selected as part of a previous immune response and are more rapidly activated if the antigen enters the body again.
b. T lymphocytes (T cells) are responsible for cell-mediated acquired immunity. The T-cell receptor (TCR) consists of two membrane proteins (typically alpha-beta or less often, gamma-delta), which are responsible for the antigen specificity, and several other membrane and cytosolic proteins known as the CD3 complex, which is responsible for intracellular signaling. Different T cells have different antigen specificity, but each T cell has only one specificity. Two major subsets of T cells exist: helper T cells (TH cells), which also express the coreceptor glycoprotein CD4, and cytotoxic T cells (TC cells), which express the coreceptor glycoprotein CD8.
(1) The TCR binds to a peptide fragment of an antigen that has been processed and presented with major histocompatibility complex (MHC, also known as human leukocyte antigens or HLAs) on the surface of another cell. The coreceptors, CD4 and CD8, assist with the recognition of the MHC presenting the antigen. MHC proteins involved in antigen presentation are divided into two classes.
(a) Class I MHC. Peptides that originate from inside the host cell (e.g., viral antigens) are processed via a cytosolic pathway and presented on the surface with class I MHC. Class I MHC is present on all nucleated cells and presents peptides to TC cells. The class I MHC genes are known as HLA-A, -B, and -C.
(b) Class II MHC. Peptides that originate from outside of the host cells are engulfed via phagocytic, endocytic, or pinocytic processes, degraded and then complexed with class II MHC in specific membranous vesicles prior to presentation on the cell surface. Class II MHC is typically only expressed on “professional” antigen-presenting cells (B cells, macrophages, and dendritic cells), which then present peptides to TH cells. The class II MHC genes are known as HLA-DP, -DQ, and -DR.
(c) Each person inherits one set of MHC genes (haplotype) from each parent, and all inherited genes are expressed simultaneously on the appropriate cell types. HLA type is important for transplantation.
(2) Naive T cells are those that are mature but have not yet encounter the specific antigen for activation.

(3) Binding of the specific antigen in the right context activates the T cell for proliferation to form new T cells (clonal expansion) and differentiation into effector T cells. The effector activity of the T cell depends on the type of T cell and the environment of the activation. The activity of the T cell is accomplished through the cytokines (see next table) that the T cell produces and via contact with nearby cells. TH effector cells can be divided into two functional groups: type 1 TH cells (TH1) and type 2 TH cells (TH2).
(4) TH1 cells are primarily involved in cell-mediated immunity. The main cytokines of TH1 cells (interleukin [IL] 2, interferon-g [IFN-g], and others) lead to inflammation, macrophage activation, and the production of opsonizing antibodies (those that assist with phagocytosis).
(5) TH2 cells are primarily involved in humoral immunity and anti-inflammatory immune defenses. The main cytokines produced by TH2 cells include IL-4 and IL-5.
(6) TC cells become cytotoxic effector cells (cytotoxic T lymphocytes or CTLs) either directly via antigen presented by the dendritic cell or with the help of activated TH cells. The naive TC cell requires strong signals to become a CTL. The effector function of the CTL is to kill target cells that express the peptide: MHC, usually virus-infected cells or tumor cells . The target cell dies by apoptosis (programmed cell death).
(7) T regulatory (TREG) CD41 T cells are autoreactive T cells whose function is to suppress activity of effector T cells and prevent the activation of naive autoreactive CD41 and CD81 T cells. This is accomplished through direct contact and through the expression of immunosuppressive and anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor [TGF]-b).
C. Organs of the immune system
1. Primary immune organs (thymus and bone marrow) are the sites of lymphocyte development and maturation. The creation of the antigen-specific receptors of the lymphocytes occurs during development in the primary organs before the lymphocyte encounters antigen. B-cell development occurs in the bone marrow; T-cell development begins in the bone marrow and finishes in the thymus.
2. Secondary immune tissues are the sites throughout the body where antigen-specific lymphocytes contact antigens. Antigens enter the different types of secondary lymph tissues via different mechanisms. Both B and T cells circulate throughout the body, passing through the secondary lymphoid tissue. Lymphocyte circulation is influenced by chemokines and cell surface receptors. Each secondary lymph tissue has T- and B-cell zones for activation and differentiation of lymphocytes. Upon immune stimulation, activation of appropriate B and T cells will lead to the formation of germinal centers, which are areas of intense B-cell proliferation and differentiation.
a. Lymph nodes throughout the body are connected via lymphatic vessels. Fluid (lymph) from extravascular spaces is collected in the lymphatic vessels and returned to the circulation via the left subclavian vein. The naive lymphocytes enter the lymph node via the blood vessels and migrate to their respective B- and T-cell zones. Free antigens from the tissue, dendritic cells (with processed antigen), and immune complexes enter the lymph node in the lymph. Lymphocytes that recognize specific antigens (either free antigens in the case of B cells or presented with appropriate MHC in the case of T cells) will proliferate and differentiate into effector lymphocytes.
b. The spleen is primarily responsible for surveillance of the blood. Antigens that arrive in the blood activate B cells and T cells for proliferation and differentiation in the same manner as for the lymph node.
c. The mucosal epithelium of the respiratory and the gastrointestinal tracts are particularly vulnerable to infection and contain specialized secondary lymph tissue broadly referred to as mucosa-associated lymphoid tissue (MALT). Gut-associated lymphoid tissues (GALTs) include the tonsils, adenoids, and Peyer patches. Antigens are delivered across the mucosa and into the MALT by specialized epithelial cells, such as M cells (microfold cells).

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